TY - JOUR AB - Nicotinamide adenine dinucleotide (NAD) is a ubiquitous electron carrier essential for energy metabolism and post-translational modification of numerous regulatory proteins. Dysregulations of NAD metabolism are widely regarded as detrimental to health, with NAD depletion commonly implicated in aging. However, the extent to which cellular NAD concentration can decline without adverse consequences remains unclear. To investigate this, we generated a mouse model in which nicotinamide phosphoribosyltransferase (NAMPT)-mediated NAD+ biosynthesis was disrupted in adult skeletal muscle. The intervention resulted in an 85% reduction in muscle NAD+ abundance while maintaining tissue integrity and functionality, as demonstrated by preserved muscle morphology, contractility, and exercise tolerance. This absence of functional impairments was further supported by intact mitochondrial respiratory capacity and unaltered muscle transcriptomic and proteomic profiles. Furthermore, lifelong NAD depletion did not accelerate muscle aging or impair whole-body metabolism. Collectively, these findings suggest that NAD depletion does not contribute to age-related decline in skeletal muscle function. AU - Chubanava, S.* AU - Karavaeva, I.* AU - Ehrlich, A.M.* AU - Justicia, R.M.* AU - Basse, A.L.* AU - Kulik, I. AU - Dalbram, E.* AU - Ahwazi, D.* AU - Heaselgrave, S.R.* AU - Trošt, K.* AU - Stocks, B.* AU - Hodek, O.* AU - Rodrigues, R.N.* AU - Havelund, J.F.* AU - Schlabs, F.L.* AU - Larsen, S.* AU - Yonamine, C.Y.* AU - Henriquez-Olguin, C.* AU - Giustarini, D.* AU - Rossi, R.* AU - Gerhart-Hines, Z.* AU - Moritz, T.* AU - Zierath, J.R.* AU - Sakamoto, K.* AU - Jensen, T.E.* AU - Færgeman, N.J.* AU - Lavery, G.G.* AU - Deshmukh, A.S.* AU - Treebak, J.T.* C1 - 74301 C2 - 57426 TI - NAD depletion in skeletal muscle does not compromise muscle function or accelerate aging. JO - Cell Metab. PY - 2025 SN - 1550-4131 ER - TY - JOUR AB - We developed the Adipose Tissue Knowledge Portal by centralizing previously dispersed datasets, integrating clinical and experimental results with transcriptomic and proteomic data from >6,000 women and men. The platform includes multiple adipose depots, resident cell types, and adipocyte perturbation studies. By providing streamlined data access, the portal enables integrative analyses and serves as a powerful tool to interrogate various dimensions of adipose biology down to the single-cell level. AU - Zhong, J.* AU - Zareifi, D.* AU - Weinbrenner, S. AU - Hansen, M.* AU - Klingelhuber, F. AU - Nono Nankam, P.A. AU - Frendo-Cumbo, S.* AU - Bhalla, N.* AU - Cordeddu, L.* AU - De Castro Barbosa, T.* AU - Arner, P.* AU - Dahlman, I.* AU - Muniandy, M.* AU - Heinonen, S.* AU - Pietiläinen, K.H.* AU - Hoffmann, A. AU - Ghosh, A.* AU - John, D. * AU - Tönjes, A.* AU - Ståhl, P.L.* AU - Böttcher, Y.* AU - Keller, M. AU - Kovacs, P. AU - Kerr, A.G.* AU - Langin, D.* AU - Wolfrum, C.* AU - Blüher, M. AU - Krahmer, N. AU - Massier, L. AU - Mejhert, N.* AU - Rydén, M.* C1 - 73442 C2 - 57075 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa SP - 566-569 TI - adiposetissue.org: A knowledge portal integrating clinical and experimental data from human adipose tissue. JO - Cell Metab. VL - 37 IS - 3 PB - Cell Press PY - 2025 SN - 1550-4131 ER - TY - JOUR AB - Tissue regulatory T cells (Tregs) exert pivotal functions in both immune and metabolic regulation, maintaining local tissue homeostasis, integrity, and function. Accordingly, Tregs play a crucial role in controlling obesity-induced inflammation and supporting efficient muscle function and repair. Depending on the tissue context, Tregs are characterized by unique transcriptomes, growth, and survival factors and T cell receptor (TCR) repertoires. This functional specialization offers the potential to selectively target context-specific Treg populations, tailoring therapeutic strategies to specific niches, thereby minimizing potential side effects. Here, we discuss challenges and perspectives for niche-specific Treg targeting, which holds promise for highly efficient and precise medical interventions to combat metabolic disease. AU - Becker, M. AU - Dirschl, S.M. AU - Scherm, M.G. AU - Serr, I. AU - Daniel, C. C1 - 69750 C2 - 55250 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa SP - 229-239 TI - Niche-specific control of tissue function by regulatory T cells-Current challenges and perspectives for targeting metabolic disease. JO - Cell Metab. VL - 36 IS - 2 PB - Cell Press PY - 2024 SN - 1550-4131 ER - TY - JOUR AB - Readily available nutrient-rich foods exploit our inherent drive to overconsume, creating an environment of overnutrition. This transformative setting has led to persistent health issues, such as obesity and metabolic syndrome. The development of glucagon-like peptide-1 receptor (GLP-1R) agonists reveals our ability to pharmacologically manage weight and address metabolic conditions. Obesity is directly linked to chronic low-grade inflammation, connecting our metabolic environment to neurodegenerative diseases. GLP-1R agonism in curbing obesity, achieved by impacting appetite and addressing associated metabolic defects, is revealing additional benefits extending beyond weight loss. Whether GLP-1R agonism directly impacts brain health or does so indirectly through improved metabolic health remains to be elucidated. In exploring the intricate connection between obesity and neurological conditions, recent literature suggests that GLP-1R agonism may have the capacity to shape the neurovascular landscape. Thus, GLP-1R agonism emerges as a promising strategy for addressing the complex interplay between metabolic health and cognitive well-being. AU - Chen, B.* AU - Yu, X.* AU - Horvath-Diano, C.* AU - Ortuño, M.J.* AU - Tschöp, M.H. AU - Jastreboff, A.M.* AU - Schneeberger, M.* C1 - 71895 C2 - 56405 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa SP - 2173-2189 TI - GLP-1 programs the neurovascular landscape. JO - Cell Metab. VL - 36 IS - 10 PB - Cell Press PY - 2024 SN - 1550-4131 ER - TY - JOUR AB - Precision medicine is still not considered as a standard of care in obesity treatment, despite a large heterogeneity in the metabolic phenotype of individuals with obesity. One of the strongest factors influencing the variability in metabolic disease risk is adipose tissue (AT) dysfunction; however, there is little understanding of the link between distinct cell populations, cell-type-specific transcriptional programs, and disease severity. Here, we generated a comprehensive cellular map of subcutaneous and visceral AT of individuals with metabolically healthy and unhealthy obesity. By combining single-nucleus RNA-sequencing data with bulk transcriptomics and clinical parameters, we identified that mesothelial cells, adipocytes, and adipocyte-progenitor cells exhibit the strongest correlation with metabolic disease. Furthermore, we uncovered cell-specific transcriptional programs, such as the transitioning of mesothelial cells to a mesenchymal phenotype, that are involved in uncoupling obesity from metabolic disease. Together, these findings provide valuable insights by revealing biological drivers of clinical endpoints. AU - Reinisch, I.* AU - Ghosh, A.* AU - Noé, F.* AU - Sun, W.* AU - Dong, H.* AU - Leary, P.* AU - Dietrich, A.* AU - Hoffmann, A. AU - Blüher, M. AU - Wolfrum, C.* C1 - 72860 C2 - 56751 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa SP - 640-655.e4 TI - Unveiling adipose populations linked to metabolic health in obesity. JO - Cell Metab. VL - 37 IS - 3 PB - Cell Press PY - 2024 SN - 1550-4131 ER - TY - JOUR AB - Adipose tissue can recruit catabolic adipocytes that utilize chemical energy to dissipate heat. This process occurs either by uncoupled respiration through uncoupling protein 1 (UCP1) or by utilizing ATP-dependent futile cycles (FCs). However, it remains unclear how these pathways coexist since both processes rely on the mitochondrial membrane potential. Utilizing single-nucleus RNA sequencing to deconvolute the heterogeneity of subcutaneous adipose tissue in mice and humans, we identify at least 2 distinct subpopulations of beige adipocytes: FC-adipocytes and UCP1-beige adipocytes. Importantly, we demonstrate that the FC-adipocyte subpopulation is highly metabolically active and utilizes FCs to dissipate energy, thus contributing to thermogenesis independent of Ucp1. Furthermore, FC-adipocytes are important drivers of systemic energy homeostasis and linked to glucose metabolism and obesity resistance in humans. Taken together, our findings identify a noncanonical thermogenic adipocyte subpopulation, which could be an important regulator of energy homeostasis in mammals. AU - Wang, T.* AU - Sharma, A.K.* AU - Wu, C.* AU - Maushart, C.I.* AU - Ghosh, A.* AU - Yang, W.* AU - Stefanicka, P.* AU - Kovanicova, Z.* AU - Ukropec, J.* AU - Zhang, J.* AU - Arnold, M.* AU - Klug, M.* AU - de Bock, K.* AU - Schneider, U.* AU - Popescu, C.* AU - Zheng, B.* AU - Ding, L.* AU - Long, F.* AU - Dewal, R.S.* AU - Moser, C.* AU - Sun, W.* AU - Dong, H.* AU - Takes, M.* AU - Suelberg, D.* AU - Mameghani, A.* AU - Nocito, A.* AU - Zech, C.J.* AU - Chirindel, A.* AU - Wild, D.* AU - Burger, I.A.* AU - Schön, M.R.* AU - Dietrich, A.* AU - Gao, M.* AU - Heine, M.* AU - Sun, Y.* AU - Vargas-Castillo, A.* AU - Søberg, S.* AU - Scheele, C.* AU - Balaz, M.* AU - Blüher, M. AU - Betz, M.J.* AU - Spiegelman, B.M.* AU - Wolfrum, C.* C1 - 71387 C2 - 56090 TI - Single-nucleus transcriptomics identifies separate classes of UCP1 and futile cycle adipocytes. JO - Cell Metab. VL - 36 PY - 2024 SN - 1550-4131 ER - TY - JOUR AB - Brown adipose tissue (BAT) regulates systemic metabolism by releasing signaling lipids. N6-methyladeno- sine (m6A) is the most prevalent and abundant post-transcriptional mRNA modification and has been reported to regulate BAT adipogenesis and energy expenditure. Here, we demonstrate that the absence of m6A methyltransferase-like 14 (METTL14) modifies the BAT secretome to improve systemic insulin sensitivity independent of UCP1. Using lipidomics, we identify prostaglandin E2 (PGE2) and prostaglandin F2a (PGF2a) as BAT-secreted insulin sensitizers. PGE2 and PGF2a inversely correlate with insulin sensitivity in humans and protect mice from high-fat-diet-induced insulin resistance by suppressing specific AKT phosphatases. Mechanistically, METTL14-mediated m6A promotes the decay of PTGES2 and CBR1, the genes encoding PGE2 and PGF2a biosynthesis enzymes, in brown adipocytes via YTHDF2/3. Consistently, BAT-specific knockdown of Ptges2 or Cbr1 reverses the insulin-sensitizing effects in M14KO mice. Overall, these findings reveal a novel biological mechanism through which m6A-dependent regulation of the BAT secretome regulates systemic insulin sensitivity. AU - Xiao, L.* AU - De Jesus, D.F.* AU - Ju, C.* AU - Wei, J.B.* AU - Hu, J.* AU - DiStefano-Forti, A.* AU - Tsuji, T.* AU - Cero, C.* AU - Maennistoe, V.* AU - Manninen, S.M.* AU - Wei, S.* AU - Ijaduola, O.* AU - Blüher, M. AU - Cypess, A.M.* AU - Pihlajamaeki, J.* AU - Tseng, Y.-T.* AU - He, C.* AU - Kulkarni, R.N.* C1 - 72713 C2 - 56709 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa SP - 2207–2227 TI - m6A mRNA methylation in brown fat regulates systemic insulin sensitivity via an inter-organ prostaglandin signaling axis independent of UCP1. JO - Cell Metab. VL - 36 IS - 10 PB - Cell Press PY - 2024 SN - 1550-4131 ER - TY - JOUR AB - Muscle-residing regulatory T cells (Tregs) control local tissue integrity and function. However, the molecular interface connecting Treg-based regulation with muscle function and regeneration remains largely unexplored. Here, we show that exercise fosters a stable induction of highly functional muscle-residing Tregs with increased expression of amphiregulin (Areg), EGFR, and ST2. Mechanistically, we find that mice lacking IL6Rα on T cells (TKO) harbor significant reductions in muscle Treg functionality and satellite and fibro-adipogenic progenitor cells, which are required for muscle regeneration. Using exercise and sarcopenia models, IL6Rα TKO mice demonstrate deficits in Tregs, their functional maturation, and a more pronounced decline in muscle mass. Muscle injury models indicate that IL6Rα TKO mice have significant disabilities in muscle regeneration. Treg gain of function restores impaired muscle repair in IL6Rα TKO mice. Of note, pharmacological IL6R blockade in WT mice phenocopies deficits in muscle function identified in IL6Rα TKO mice, thereby highlighting the clinical implications of the findings. AU - Becker, M. AU - Joseph, S.S. AU - Garcia-Carrizo, F.* AU - Tom, R.Z. AU - Opaleva, D. AU - Serr, I. AU - Tschöp, M.H. AU - Schulz, T.* AU - Hofmann, S.M. AU - Daniel, C. C1 - 68230 C2 - 54777 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa SP - 1736-1751.e7 TI - Regulatory T cells require IL6 receptor alpha signaling to control skeletal muscle function and regeneration. JO - Cell Metab. VL - 35 IS - 10 PB - Cell Press PY - 2023 SN - 1550-4131 ER - TY - JOUR AB - The incretin system is an essential metabolic axis that regulates postprandial metabolism. The two incretin peptides that enable this effect are the glucose-dependent insulinotropic polypeptide (GIP) and the glucagon-like peptide 1 (GLP-1), which have cognate receptors (GIPR and GLP-1R) on islet β cells as well as in other tissues. Pharmacologic engagement of the GLP-1R is a proven strategy for treating hyperglycemia in diabetes and reducing body weight. Tirzepatide is the first monomeric peptide with dual activity at both incretin receptors now available for clinical use, and in clinical trials it has shown unprecedented effects to reduce blood glucose and body weight. Here, we discuss the foundational science that led to the development of monomeric multi-incretin receptor agonists, culminating in the development of tirzepatide. We also look to the future of this field and comment on how the concept of multi-receptor agonists will continue to progress for the treatment of metabolic disease. AU - Campbell, J.E.* AU - Müller, T.D. AU - Finan, B.* AU - DiMarchi, R.D.* AU - Tschöp, M.H. AU - D'Alessio, D.A.* C1 - 67992 C2 - 54470 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa SP - 1519-1529 TI - GIPR/GLP-1R dual agonist therapies for diabetes and weight loss-chemistry, physiology, and clinical applications. JO - Cell Metab. VL - 35 IS - 9 PB - Cell Press PY - 2023 SN - 1550-4131 ER - TY - JOUR AB - There has been an intense focus to uncover the molecular mechanisms by which fasting triggers the adaptive cellular responses in the major organs of the body. Here, we show that in mice, hepatic S-adenosylmethionine (SAMe)-the principal methyl donor-acts as a metabolic sensor of nutrition to fine-tune the catabolic-fasting response by modulating phosphatidylethanolamine N-methyltransferase (PEMT) activity, endoplasmic reticulum-mitochondria contacts, β-oxidation, and ATP production in the liver, together with FGF21-mediated lipolysis and thermogenesis in adipose tissues. Notably, we show that glucagon induces the expression of the hepatic SAMe-synthesizing enzyme methionine adenosyltransferase α1 (MAT1A), which translocates to mitochondria-associated membranes. This leads to the production of this metabolite at these sites, which acts as a brake to prevent excessive β-oxidation and mitochondrial ATP synthesis and thereby endoplasmic reticulum stress and liver injury. This work provides important insights into the previously undescribed function of SAMe as a new arm of the metabolic adaptation to fasting. AU - Capelo-Diz, A.* AU - Lachiondo-Ortega, S.* AU - Fernández-Ramos, D.* AU - Cañas-Martín, J.* AU - Goikoetxea-Usandizaga, N.* AU - Serrano-Maciá, M.* AU - Gonzalez-Rellan, M.J.* AU - Mosca, L.* AU - Blazquez-Vicens, J.* AU - Tinahones-Ruano, A.* AU - Fondevila, M.F.* AU - Buyan, M.* AU - Delgado, T.C.* AU - Gutierrez de Juan, V.* AU - Ayuso-García, P.* AU - Sánchez-Rueda, A.* AU - Velasco-Avilés, S.* AU - Fernández-Susavila, H.* AU - Riobello-Suárez, C.* AU - Dziechciarz, B.* AU - Montiel-Duarte, C.* AU - Lopitz-Otsoa, F.* AU - Bizkarguenaga, M.* AU - Bilbao-García, J.* AU - Bernardo-Seisdedos, G.* AU - Senra, A.* AU - Soriano-Navarro, M.* AU - Millet, O.* AU - Díaz-Lagares, * AU - Crujeiras, A.B.* AU - Bao-Caamano, A.* AU - Cabrera, D.* AU - van Liempd, S.* AU - Tamayo-Carro, M.* AU - Borzacchiello, L.* AU - Gomez-Santos, B.* AU - Buqué, X.* AU - Sáenz de Urturi, D.* AU - González-Romero, F.* AU - Simon, J.* AU - Rodríguez-Agudo, R.* AU - Ruiz, A.* AU - Matute, C.* AU - Beiroa, D.* AU - Falcón-Pérez, J.M.* AU - Aspichueta, P.* AU - Rodríguez-Cuesta, J.* AU - Porcelli, M.* AU - Pajares, M.A.* AU - Ameneiro, C.* AU - Fidalgo, M.* AU - Aransay, A.M.* AU - Lama-Díaz, T.* AU - Blanco, M.G.* AU - López, M.* AU - Villa-Bellosta, R.* AU - Müller, T.D. AU - Nogueiras, R.* AU - Woodhoo, A.* AU - Martínez-Chantar, M.L.* AU - Varela-Rey, M.* C1 - 68042 C2 - 54520 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa SP - 1373-1389.e8 TI - Hepatic levels of S-adenosylmethionine regulate the adaptive response to fasting. JO - Cell Metab. VL - 35 IS - 8 PB - Cell Press PY - 2023 SN - 1550-4131 ER - TY - JOUR AB - Until menopause, women have a lower propensity to develop metabolic diseases than men, suggestive of a protective role for sex hormones. Although a functional synergy between central actions of estrogens and leptin has been demonstrated to protect against metabolic disturbances, the underlying cellular and molecular mechanisms mediating this crosstalk have remained elusive. By using a series of embryonic, adult-onset, and tissue/cell-specific loss-of-function mouse models, we document an unprecedented role of hypothalamic Cbp/P300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 1 (Cited1) in mediating estradiol (E2)-dependent leptin actions that control feeding specifically in pro-opiomelanocortin (Pomc) neurons. We reveal that within arcuate Pomc neurons, Cited1 drives leptin's anorectic effects by acting as a co-factor converging E2 and leptin signaling via direct Cited1-ERα-Stat3 interactions. Together, these results provide new insights on how melanocortin neurons integrate endocrine inputs from gonadal and adipose axes via Cited1, thereby contributing to the sexual dimorphism in diet-induced obesity. AU - Gonzales García, I. AU - Garcia-Clavé, E. AU - Cebrian Serrano, A. AU - Le Thuc, O. AU - Contreras, R. AU - Xu, Y. AU - Gruber, T. AU - Schriever, S.C. AU - Legutko, B. AU - Lintelmann, J. AU - Adamski, J. AU - Wurst, W. AU - Müller, T.D. AU - Woods, S.C.* AU - Pfluger, P.T. AU - Tschöp, M.H. AU - Fisette, A. AU - García-Cáceres, C. C1 - 67748 C2 - 54058 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa SP - 438-455.e7 TI - Estradiol regulates leptin sensitivity to control feeding via hypothalamic Cited1. JO - Cell Metab. VL - 35 IS - 3 PB - Cell Press PY - 2023 SN - 1550-4131 ER - TY - JOUR AB - Fibroblast growth factor 21 (FGF21) is generally known as a stress-induced metabolic regulator with enormous therapeutic potential to treat metabolic diseases, but a more specific role of FGF21 concerns physiological handling of alcohol in mammals. In this issue of Cell Metabolism, Choi et al. demonstrate that FGF21 mediates the recovery from alcohol intoxication by directly activating noradrenergic neurons in mice, thus advancing our knowledge on FGF21 biology and further diversifying its therapeutic potential. AU - Jastroch, M.* AU - Keipert, S.* AU - Tschöp, M.H. C1 - 67749 C2 - 54059 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa SP - 377-379 TI - Protection from alcohol intoxication: Must be FGF21 to enter. JO - Cell Metab. VL - 35 IS - 3 PB - Cell Press PY - 2023 SN - 1550-4131 ER - TY - JOUR AB - Non-alcoholic fatty liver disease (NAFLD) is not only a consequence of insulin resistance, but it is also an important cause of insulin resistance and major non-communicable diseases (NCDs). The close relationship of NAFLD with visceral obesity obscures the role of fatty liver from visceral adiposity as the main pathomechanism of insulin resistance and NCDs. To overcome this limitation, in analogy to the concept of adipokines, in 2008 we introduced the term hepatokines to describe the role of fetuin-A in metabolism. Since then, several other hepatokines were tested for their effects on metabolism. Here we address the dysregulation of hepatokines in people with NAFLD. Then, we discuss pathophysiological mechanisms of cardiometabolic diseases specifically related to NAFLD by focusing on hepatokine-related organ crosstalk. Finally, we propose how the determination of major hepatokines and adipokines can be used for pathomechanism-based clustering of insulin resistance in NAFLD and visceral obesity to better implement precision medicine in clinical practice. AU - Stefan, N. AU - Schick, F. AU - Birkenfeld, A.L. AU - Häring, H.-U. AU - White, M.F.* C1 - 67408 C2 - 54149 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa SP - 236-252 TI - The role of hepatokines in NAFLD. JO - Cell Metab. VL - 35 IS - 2 PB - Cell Press PY - 2023 SN - 1550-4131 ER - TY - JOUR AB - The hypothalamus is key in the control of energy balance. However, strategies targeting hypothalamic neurons have failed to provide viable options to treat most metabolic diseases. Conversely, the role of astrocytes in systemic metabolic control has remained largely unexplored. Here, we show that obesity promotes anatomically restricted remodeling of hypothalamic astrocyte activity. In the paraventricular nucleus (PVN) of the hypothalamus, chemogenetic manipulation of astrocytes results in bidirectional control of neighboring neuron activity, autonomic outflow, glucose metabolism, and energy balance. This process recruits a mechanism involving the astrocytic control of ambient glutamate levels, which becomes defective in obesity. Positive or negative chemogenetic manipulation of PVN astrocyte Ca2+ signals, respectively, worsens or improves metabolic status of diet-induced obese mice. Collectively, these findings highlight a yet unappreciated role for astrocytes in the direct control of systemic metabolism and suggest potential targets for anti-obesity strategy. AU - Herrera Moro Chao, D.* AU - Kirchner, M.K.* AU - Pham, C.* AU - Foppen, E.* AU - Denis, R.G.P.* AU - Castel, J.* AU - Morel, C.* AU - Montalban, E.* AU - Hassouna, R.* AU - Bui, L.C.* AU - Renault, J.* AU - Mouffle, C.* AU - García-Cáceres, C. AU - Tschöp, M.H. AU - Li, D.* AU - Martin, C.* AU - Stern, J.E.* AU - Luquet, S.H.* C1 - 66349 C2 - 52798 SP - 1532-1547.e6 TI - Hypothalamic astrocytes control systemic glucose metabolism and energy balance. JO - Cell Metab. VL - 34 IS - 10 PY - 2022 SN - 1550-4131 ER - TY - JOUR AB - Fasting metabolism and immunity are tightly linked; however, it is largely unknown how immune cells contribute to metabolic homeostasis during fasting in healthy subjects. Here, we combined cell-type-resolved genomics and computational approaches to map crosstalk between hepatocytes and liver macrophages during fasting. We identified the glucocorticoid receptor (GR) as a key driver of fasting-induced reprogramming of the macrophage secretome including fasting-suppressed cytokines and showed that lack of macrophage GR impaired induction of ketogenesis during fasting as well as endotoxemia. Mechanistically, macrophage GR suppressed the expression of tumor necrosis factor (TNF) and promoted nuclear translocation of hepatocyte GR to activate a fat oxidation/ketogenesis-related gene program, cooperatively induced by GR and peroxisome proliferator-activated receptor alpha (PPARα) in hepatocytes. Together, our results demonstrate how resident liver macrophages directly influence ketogenesis in hepatocytes, thereby also outlining a strategy by which the immune system can set the metabolic tone during inflammatory disease and infection. AU - Loft, A. AU - Schmidt, S.F. AU - Caratti, G.* AU - Stifel, U.* AU - Havelund, J.F.* AU - Sekar, R. AU - Kwon, Y. AU - Sulaj, A.* AU - Chow, K.K. AU - Alfaro, A.J. AU - Schwarzmayr, T. AU - Rittig, N.* AU - Svart, M.* AU - Tsokanos, F.-F. AU - Maida, A. AU - Blutke, A. AU - Feuchtinger, A. AU - Møller, N.* AU - Blüher, M. AU - Nawroth, P.* AU - Szendrödi, J.* AU - Færgeman, N.J.* AU - Zeigerer, A. AU - Tuckermann, J.* AU - Herzig, S. C1 - 64245 C2 - 51925 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa SP - 473-486.e9 TI - A macrophage-hepatocyte glucocorticoid receptor axis coordinates fasting ketogenesis. JO - Cell Metab. VL - 34 IS - 3 PB - Cell Press PY - 2022 SN - 1550-4131 ER - TY - JOUR AB - Tissue sensitivity and response to exercise vary according to the time of day and alignment of circadian clocks, but the optimal exercise time to elicit a desired metabolic outcome is not fully defined. To understand how tissues independently and collectively respond to timed exercise, we applied a systems biology approach. We mapped and compared global metabolite responses of seven different mouse tissues and serum after an acute exercise bout performed at different times of the day. Comparative analyses of intra- and inter-tissue metabolite dynamics, including temporal profiling and blood sampling across liver and hindlimb muscles, uncovered an unbiased view of local and systemic metabolic responses to exercise unique to time of day. This comprehensive atlas of exercise metabolism provides clarity and physiological context regarding the production and distribution of canonical and novel time-dependent exerkine metabolites, such as 2-hydroxybutyrate (2-HB), and reveals insight into the health-promoting benefits of exercise on metabolism. AU - Sato, S.* AU - Dyar, K.A. AU - Treebak, J.T.* AU - Jepsen, S.L.* AU - Ehrlich, A.M.* AU - Ashcroft, S.P.* AU - Trost, K.* AU - Kunzke, T. AU - Prade, V.M. AU - Small, L.* AU - Basse, A.L.* AU - Schönke, M.* AU - Chen, S.* AU - Samad, M.* AU - Baldi, P.* AU - Barrès, R.* AU - Walch, A.K. AU - Moritz, T.* AU - Holst, J.J.* AU - Lutter, D. AU - Zierath, J.R.* AU - Sassone-Corsi, P.* C1 - 64061 C2 - 51814 SP - 329-345.e8 TI - Atlas of exercise metabolism reveals time-dependent signatures of metabolic homeostasis. JO - Cell Metab. VL - 34 IS - 2 PY - 2022 SN - 1550-4131 ER - TY - JOUR AB - During mammalian energy homeostasis, the glucagon receptor (Gcgr) plays a key role in regulating both glucose and lipid metabolisms. However, the mechanisms by which these distinct signaling arms are differentially regulated remain poorly understood. Using a Cy5-glucagon agonist, we show that the endosomal protein Vps37a uncouples glucose production from lipid usage downstream of Gcgr signaling by altering intracellular receptor localization. Hepatocyte-specific knockdown of Vps37a causes an accumulation of Gcgr in endosomes, resulting in overactivation of the cAMP/PKA/p-Creb signaling pathway to gluconeogenesis without affecting β-oxidation. Shifting the receptor back to the plasma membrane rescues the differential signaling and highlights the importance of the spatiotemporal localization of Gcgr for its metabolic effects. Importantly, since Vps37a knockdown in animals fed with a high-fat diet leads to hyperglycemia, although its overexpression reduces blood glucose levels, these data reveal a contribution of endosomal signaling to metabolic diseases that could be exploited for treatments of type 2 diabetes. AU - Sekar, R. AU - Motzler, K. AU - Kwon, Y. AU - Novikoff, A. AU - Jülg, J.* AU - Najafi, B. AU - Wang, S. AU - Seitz, S. AU - Hass, D, AU - Gancheva, S.* AU - Kahl, S.* AU - Yang, B.* AU - Finan, B.* AU - Schwarz, K.* AU - Okun, J.G.* AU - Roden, M.* AU - Blüher, M. AU - Müller, T.D. AU - Krahmer, N. AU - Behrends, C.* AU - Plettenburg, O. AU - Miaczynska, M.* AU - Herzig, S. AU - Zeigerer, A. C1 - 66487 C2 - 52822 SP - 1824-1842.e9 TI - Vps37a regulates hepatic glucose production by controlling glucagon receptor localization to endosomes. JO - Cell Metab. VL - 34 IS - 11 PY - 2022 SN - 1550-4131 ER - TY - JOUR AB - In response to cold exposure, thermogenic adipocytes internalize large amounts of fatty acids after lipoprotein lipase-mediated hydrolysis of triglyceride-rich lipoproteins (TRL) in the capillary lumen of brown adipose tissue (BAT) and white adipose tissue (WAT). Here, we show that in cold-exposed mice, vascular endothelial cells in adipose tissues endocytose substantial amounts of entire TRL particles. These lipoproteins subsequently follow the endosomal-lysosomal pathway, where they undergo lysosomal acid lipase (LAL)-mediated processing. Endothelial cell-specific LAL deficiency results in impaired thermogenic capacity as a consequence of reduced recruitment of brown and brite/beige adipocytes. Mechanistically, TRL processing by LAL induces proliferation of endothelial cells and adipocyte precursors via beta-oxidation-dependent production of reactive oxygen species, which in turn stimulates hypoxia-inducible factor-1α-dependent proliferative responses. In conclusion, this study demonstrates a physiological role for TRL particle uptake into BAT and WAT and establishes endothelial lipoprotein processing as an important determinant of adipose tissue remodeling during thermogenic adaptation. AU - Fischer, A.W.* AU - Jaeckstein, M.Y.* AU - Gottschling, K.* AU - Heine, M.* AU - Sass, F.* AU - Mangels, N.* AU - Schlein, C.* AU - Worthmann, A.* AU - Bruns, O.T. AU - Yuan, Y.* AU - Zhu, H.* AU - Chen, O.* AU - Ittrich, H.* AU - Nilsson, S.K.* AU - Stefanicka, P.* AU - Ukropec, J.* AU - Balaz, M.* AU - Dong, H.* AU - Sun, W.* AU - Reimer, R.* AU - Scheja, L.* AU - Heeren, J.* C1 - 61011 C2 - 49671 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa SP - 547-564.e7 TI - Lysosomal lipoprotein processing in endothelial cells stimulates adipose tissue thermogenic adaptation. JO - Cell Metab. VL - 33 IS - 3 PB - Cell Press PY - 2021 SN - 1550-4131 ER - TY - JOUR AB - Pathologies of the micro- and macrovascular systems are a hallmark of the metabolic syndrome, which can lead to chronically elevated blood pressure. However, the underlying pathomechanisms involved still need to be clarified. Here, we report that an obesity-associated increase in serum leptin triggers the select expansion of the micro-angioarchitecture in pre-autonomic brain centers that regulate hemodynamic homeostasis. By using a series of cell- and region-specific loss- and gain-of-function models, we show that this pathophysiological process depends on hypothalamic astroglial hypoxia-inducible factor 1α-vascular endothelial growth factor (HIF1α-VEGF) signaling downstream of leptin signaling. Importantly, several distinct models of HIF1α-VEGF pathway disruption in astrocytes are protected not only from obesity-induced hypothalamic angiopathy but also from sympathetic hyperactivity or arterial hypertension. These results suggest that hyperleptinemia promotes obesity-induced hypertension via a HIF1α-VEGF signaling cascade in hypothalamic astrocytes while establishing a novel mechanistic link that connects hypothalamic micro-angioarchitecture with control over systemic blood pressure. AU - Gruber, T. AU - Pan, C. AU - Contreras, R. AU - Wiedemann, T. AU - Morgan, D.A.* AU - Skowronski, A.A.* AU - Lefort, S. AU - De Bernardis Murat, C. AU - Le Thuc, O. AU - Legutko, B. AU - Ruiz Ojeda, F.J. AU - Fuente-Fernández, M.* AU - García-Villalón, A.L.* AU - González-Hedström, D.* AU - Huber, M. AU - Szigeti-Buck, K.* AU - Müller, T.D. AU - Ussar, S. AU - Pfluger, P.T. AU - Woods, S.C.* AU - Ertürk, A. AU - LeDuc, C.A.* AU - Rahmouni, K.* AU - Granado, M.* AU - Horvath, T.L.* AU - Tschöp, M.H. AU - García-Cáceres, C. C1 - 61938 C2 - 50530 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa SP - 1155-1170.e10 TI - Obesity-associated hyperleptinemia alters the gliovascular interface of the hypothalamus to promote hypertension. JO - Cell Metab. VL - 33 IS - 6 PB - Cell Press PY - 2021 SN - 1550-4131 ER - TY - JOUR AB - Hexokinases (HK) catalyze the first step of glycolysis limiting its pace. HK2 is highly expressed in gut epithelium, contributes to immune responses, and is upregulated during inflammation. We examined the microbial regulation of HK2 and its impact on inflammation using mice lacking HK2 in intestinal epithelial cells (Hk2ΔIEC). Hk2ΔIEC mice were less susceptible to acute colitis. Analyzing the epithelial transcriptome from Hk2ΔIEC mice during colitis and using HK2-deficient intestinal organoids and Caco-2 cells revealed reduced mitochondrial respiration and epithelial cell death in the absence of HK2. The microbiota strongly regulated HK2 expression and activity. The microbially derived short-chain fatty acid (SCFA) butyrate repressed HK2 expression via histone deacetylase 8 (HDAC8) and reduced mitochondrial respiration in wild-type but not in HK2-deficient Caco-2 cells. Butyrate supplementation protected wild-type but not Hk2ΔIEC mice from colitis. Our findings define a mechanism how butyrate promotes intestinal homeostasis and suggest targeted HK2-inhibition as therapeutic avenue for inflammation. AU - Hinrichsen, F.* AU - Hamm, J.* AU - Westermann, M.* AU - Schröder, L.* AU - Shima, K.* AU - Mishra, N.* AU - Walker, A. AU - Sommer, N.* AU - Klischies, K.* AU - Prasse, D.* AU - Zimmermann, J.* AU - Kaiser, S.* AU - Bordoni, D.* AU - Fazio, A.* AU - Marinos, G.* AU - Laue, G.* AU - Imm, S.* AU - Tremaroli, V.* AU - Basic, M.* AU - Häsler, R.* AU - Schmitz, R.A.* AU - Krautwald, S.* AU - Wolf, A.* AU - Stecher, B.* AU - Schmitt-Kopplin, P. AU - Kaleta, C.* AU - Rupp, J.* AU - Bäckhed, F.* AU - Rosenstiel, P.* AU - Sommer, F.* C1 - 63735 C2 - 51495 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa SP - 2355-2366.e8 TI - Microbial regulation of hexokinase 2 links mitochondrial metabolism and cell death in colitis. JO - Cell Metab. VL - 33 IS - 12 PB - Cell Press PY - 2021 SN - 1550-4131 ER - TY - JOUR AB - Liver fibrosis is a strong predictor of long-term mortality in individuals with metabolic-associated fatty liver disease; yet, the mechanisms underlying the progression from the comparatively benign fatty liver state to advanced non-alcoholic steatohepatitis (NASH) and liver fibrosis are incompletely understood. Using cell-type-resolved genomics, we show that comprehensive alterations in hepatocyte genomic and transcriptional settings during NASH progression, led to a loss of hepatocyte identity. The hepatocyte reprogramming was under tight cooperative control of a network of fibrosis-activated transcription factors, as exemplified by the transcription factor Elf-3 (ELF3) and zinc finger protein GLIS2 (GLIS2). Indeed, ELF3- and GLIS2-controlled fibrosis-dependent hepatokine genes targeting disease-associated hepatic stellate cell gene programs. Thus, interconnected transcription factor networks not only promoted hepatocyte dysfunction but also directed the intra-hepatic crosstalk necessary for NASH and fibrosis progression, implying that molecular "hub-centered" targeting strategies are superior to existing mono-target approaches as currently used in NASH therapy. AU - Loft, A. AU - Alfaro, A.J. AU - Schmidt, S.F. AU - Pedersen, F.B.* AU - Terkelsen, M.K.* AU - Puglia, M.* AU - Chow, K.K. AU - Feuchtinger, A. AU - Troullinaki, M. AU - Maida, A. AU - Wolff, G. AU - Sakurai, M. AU - Berutti, R. AU - Ekim Üstünel, B. AU - Nawroth, P.P. AU - Ravnskjaer, K.* AU - Diaz, M.B. AU - Blagoev, B.* AU - Herzig, S. C1 - 62521 C2 - 50903 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa SP - 1685-1700.e9 TI - Liver-fibrosis-activated transcriptional networks govern hepatocyte reprogramming and intra-hepatic communication. JO - Cell Metab. VL - 33 IS - 8 PB - Cell Press PY - 2021 SN - 1550-4131 ER - TY - JOUR AB - Skeletal and glycemic traits have shared etiology, but the underlying genetic factors remain largely unknown. To identify genetic loci that may have pleiotropic effects, we studied Genome-wide association studies (GWASs) for bone mineral density and glycemic traits and identified a bivariate risk locus at 3q21. Using sequence and epigenetic modeling, we prioritized an adenylate cyclase 5 (ADCY5) intronic causal variant, rs56371916. This SNP changes the binding affinity of SREBP1 and leads to differential ADCY5 gene expression, altering the chromatin landscape from poised to repressed. These alterations result in bone- and type 2 diabetes-relevant cell-autonomous changes in lipid metabolism in osteoblasts and adipocytes. We validated our findings by directly manipulating the regulator SREBP1, the target gene ADCY5, and the variant rs56371916, which together imply a novel link between fatty acid oxidation and osteoblast differentiation. Our work, by systematic functional dissection of pleiotropic GWAS loci, represents a framework to uncover biological mechanisms affecting pleiotropic traits. AU - Sinnott-Armstrong, N.* AU - Sousa, I.S.* AU - Laber, S.* AU - Rendina-Ruedy, E.* AU - Nitter Dankel, S.E.* AU - Ferreira, T.* AU - Mellgren, G.* AU - Karasik, D.* AU - Rivas, M.* AU - Pritchard, J.* AU - Guntur, A.R.* AU - Cox, R.D.* AU - Lindgren, C.M.* AU - Hauner, H. AU - Sallari, R.* AU - Rosen, C.J.* AU - Hsu, Y.H.* AU - Lander, E.S.* AU - Kiel, D.P.* AU - Claussnitzer, M.* C1 - 61197 C2 - 50095 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa SP - 615-628.e13 TI - A regulatory variant at 3q21.1 confers an increased pleiotropic risk for hyperglycemia and altered bone mineral density. JO - Cell Metab. VL - 33 IS - 3 PB - Cell Press PY - 2021 SN - 1550-4131 ER - TY - JOUR AB - Wound healing is a coordinated process that initially relies on pro-inflammatory macrophages, followed by a pro-resolution function of these cells. Changes in cellular metabolism likely dictate these distinct activities, but the nature of these changes has been unclear. Here, we profiled early- versus late-stage skin wound macrophages in mice at both the transcriptional and functional levels. We found that glycolytic metabolism in the early phase is not sufficient to ensure productive repair. Instead, by combining conditional disruption of the electron transport chain with deletion of tgcqmitochondrial aspartyl-tRNA synthetase, followed by single-cell sequencing analysis, we found that a subpopulation of early-stage wound macrophages are marked by mitochondrial ROS (mtROS) production and HIF1α stabilization, which ultimately drives a pro-angiogenic program essential for timely healing. In contrast, late-phase, pro-resolving wound macrophages are marked by IL-4Rα-mediated mitochondrial respiration and mitohormesis. Collectively, we identify changes in mitochondrial metabolism as a critical control mechanism for macrophage effector functions during wound healing. AU - Willenborg, S.* AU - Sanin, D.E.* AU - Jais, A. AU - Ding, X.* AU - Ulas, T.* AU - Nüchel, J.* AU - Popović, M.* AU - MacVicar, T.* AU - Langer, T.* AU - Schultze, J.L.* AU - Gerbaulet, A.* AU - Roers, A.* AU - Pearce, E.J.* AU - Brüning, J.C.* AU - Trifunovic, A.* AU - Eming, S.A.* C1 - 63436 C2 - 51434 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa SP - 2398-2414.e9 TI - Mitochondrial metabolism coordinates stage-specific repair processes in macrophages during wound healing. JO - Cell Metab. VL - 33 IS - 12 PB - Cell Press PY - 2021 SN - 1550-4131 ER - TY - JOUR AB - Uncertainty exists as to whether the glucose-dependent insulinotropic polypeptide receptor (GIPR) should be activated or inhibited for the treatment of obesity. Gipr was recently demonstrated in hypothalamic feeding centers, but the physiological relevance of CNS Gipr remains unknown. Here we show that HFD-fed CNS-Gipr KO mice and humanized (h)GIPR knockin mice with CNS-hGIPR deletion show decreased body weight and improved glucose metabolism. In DIO mice, acute central and peripheral administration of acyl-GIP increases cFos neuronal activity in hypothalamic feeding centers, and this coincides with decreased body weight and food intake and improved glucose handling. Chronic central and peripheral administration of acyl-GIP lowers body weight and food intake in wild-type mice, but shows blunted/absent efficacy in CNS-Gipr KO mice. Also, the superior metabolic effect of GLP-1/GIP co-agonism relative to GLP-1 is extinguished in CNS-Gipr KO mice. Our data hence establish a key role of CNS Gipr for control of energy metabolism. AU - Zhang, Q. AU - Delessa, C.T.* AU - Augustin, R.* AU - Bakhti, M. AU - Collden, G. AU - Drucker, D.J.* AU - Feuchtinger, A. AU - García-Cáceres, C. AU - Grandl, G. AU - Harger, A. AU - Herzig, S. AU - Hofmann, S.M. AU - Holleman, C.L. AU - Jastroch, M.* AU - Keipert, S.* AU - Kleinert, M. AU - Knerr, P.J.* AU - Kulaj, K. AU - Legutko, B. AU - Lickert, H. AU - Liu, X. AU - Luippold, G.* AU - Lutter, D. AU - Malogajski, E. AU - Tarquis Medina, M. AU - Mowery, S.A.* AU - Blutke, A. AU - Perez-Tilve, D.* AU - Salinno, C. AU - Sehrer, L. AU - DiMarchi, R.D.* AU - Tschöp, M.H. AU - Stemmer, K. AU - Finan, B.* AU - Wolfrum, C.* AU - Müller, T.D. C1 - 61315 C2 - 49909 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa SP - 833-844.e5 TI - The glucose-dependent insulinotropic polypeptide (GIP) regulates body weight and food intake via CNS-GIPR signaling. JO - Cell Metab. VL - 33 IS - 4 PB - Cell Press PY - 2021 SN - 1550-4131 ER - TY - JOUR AB - Mitochondrial dysfunction is a hallmark of heart disease. Nicolas-Avila et al. (2020) now find that cardiomyocytes eject dysfunctional mitochondria in exopher vesicles, which require elimination by specialized heart-resident macrophages, altogether supporting proper heart function. AU - Bartelt, A. AU - Weber, C.* C1 - 60253 C2 - 49724 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa SP - 512-513 TI - Mitochondrial ejection for cardiac protection: The Macrophage Connection. JO - Cell Metab. VL - 32 IS - 4 PB - Cell Press PY - 2020 SN - 1550-4131 ER - TY - JOUR AB - Energy-dense food alters dopaminergic (DA) transmission in the mesocorticolimbic (MCL) system and can promote reward dysfunctions, compulsive feeding, and weight gain. Yet the mechanisms by which nutrients influence the MCL circuitry remain elusive. Here, we show that nutritional triglycerides (TGs), a conserved post-prandial metabolic signature among mammals, can be metabolized within the MCL system and modulate DA-associated behaviors by gating the activity of dopamine receptor subtype 2 (DRD2)-expressing neurons through a mechanism that involves the action of the lipoprotein lipase (LPL). Further, we show that in humans, postprandial TG excursions modulate brain responses to food cues in individuals carrying a genetic risk for reduced DRD2 signaling. Collectively, these findings unveil a novel mechanism by which dietary TGs directly alter signaling in the reward circuit to regulate behavior, thereby providing a new mechanistic basis by which energy-rich diets may lead to (mal)adaptations in DA signaling that underlie reward deficit and compulsive behavior. AU - Berland, C. AU - Montalban, E.* AU - Perrin, E.* AU - Di Miceli, M.* AU - Nakamura, Y.* AU - Martinat, M.* AU - Sullivan, M.* AU - Davis, X.S.* AU - Shenasa, M.A.* AU - Martin, C.* AU - Tolu, S.* AU - Marti, F.* AU - Caille, S.* AU - Castel, J.* AU - Perez, S.* AU - Salinas, C.G.* AU - Morel, C.* AU - Hecksher-Sørensen, J.* AU - Cador, M.* AU - Fioramonti, X.* AU - Tschöp, M.H. AU - Layé, S.* AU - Venance, L.* AU - Faure, P.* AU - Hnasko, T.S.* AU - Small, D.M.* AU - Gangarossa, G.* AU - Luquet, S.H.* C1 - 58822 C2 - 48437 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa SP - 773-790 TI - Circulating triglycerides gate dopamine-associated behaviors through DRD2-expressing neurons. JO - Cell Metab. VL - 31 IS - 4 PB - Cell Press PY - 2020 SN - 1550-4131 ER - TY - JOUR AB - There is a general consensus that overconsumption of sugar-sweetened beverages contributes to the prevalence of obesity and related comorbidities such as type 2 diabetes (T2D). Whether a similar relationship exists for no- or low-calorie "diet'' drinks is a subject of intensive debate and controversy. Here, we demonstrate that consuming seven sucralose-sweetened beverages with, but not without, a carbohydrate over 10 days decreases insulin sensitivity in healthy human participants, an effect that correlates with reductions in midbrain, insular, and cingulate responses to sweet, but not sour, salty, or savory, taste as assessed with fMRI. Taste perception was unaltered and consuming the carbohydrate alone had no effect. These findings indicate that consumption of sucralose in the presence of a carbohydrate rapidly impairs glucose metabolism and results in longer-term decreases in brain, but not perceptual sensitivity to sweet taste, suggesting dysregulation of gut-brain control of glucose metabolism. AU - Dalenberg, J.R.* AU - Patel, B.P.* AU - Denis, R.* AU - Veldhuizen, M.G.* AU - Nakamura, Y.* AU - Vinke, P.C.* AU - Luquet, S.* AU - Small, D.M. C1 - 58535 C2 - 48255 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa SP - 493-502 TI - Short-term consumption of sucralose with, but not without, carbohydrate impairs neural and metabolic sensitivity to sugar in humans. JO - Cell Metab. VL - 31 IS - 3 PB - Cell Press PY - 2020 SN - 1550-4131 ER - TY - JOUR AB - The gut microbiota plays an important role for the absorption of nutrients and the maintenance of metabolism, potentially impacting the development of human metabolic disorders such as obesity and type 2 diabetes. In this issue of Cell Metabolism, Krisko et al. (2020) demonstrate that the gut microbiota regulates glucose homeostasis solely via hepatic gluconeogenesis and not via thermogenic adipose tissue as suggested previously. AU - Jastroch, M.* AU - Ussar, S. AU - Keipert, S.* C1 - 58532 C2 - 48256 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa SP - 443-444 TI - Gut microbes controlling blood sugar: No fire required! JO - Cell Metab. VL - 31 IS - 3 PB - Cell Press PY - 2020 SN - 1550-4131 ER - TY - JOUR AB - Obesity is genetically heterogeneous with monogenic and complex polygenic forms. Using exome and targeted sequencing in 2,737 severely obese cases and 6,704 controls, we identified three genes (PHIP, DGKI, andZMYM4) with an excess burden of very rare predicted deleterious variants in cases. In cells, we found that nuclear PHIP (pleckstrin homology domain interacting protein) directly enhances transcription of pro-opiomelanocortin (POMC), a neuropeptide that suppresses appetite. Obesity-associated PHIP variants repressed POMC transcription. Our demonstration that PHIP is involved in human energy homeostasis through transcriptional regulation of central melanocortin signaling has potential diagnostic and therapeutic implications for patients with obesity and developmental delay. Additionally, we found an excess burden of predicted deleterious variants involving genes nearest to loci from obesity genome-wide association studies. Genes and gene sets influencing obesity with variable penetrance provide compelling evidence for a continuum of causality in the genetic architecture of obesity, and explain some of its missing heritability. AU - Marenne, G.* AU - Hendricks, A.E.* AU - Perdikari, A.* AU - Bounds, R.* AU - Payne, F.* AU - Keogh, J.M.* AU - Lelliott, C.J.* AU - Henning, E.* AU - Pathan, S.* AU - Ashford, S.* AU - Bochukova, E.G.* AU - Mistry, V.* AU - Daly, A.* AU - Hayward, C.* AU - Wareham, N.J.* AU - O'Rahilly, S.* AU - Langenberg, C.* AU - Wheeler, E.* AU - Zeggini, E. AU - Farooqi, I.S.* AU - Barroso, I.* C1 - 59263 C2 - 48771 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa SP - 1107-1119 TI - Exome sequencing identifies genes and gene sets contributing to severe childhood obesity, linking PHIP variants to repressed POMC transcription. JO - Cell Metab. VL - 31 IS - 6 PB - Cell Press PY - 2020 SN - 1550-4131 ER - TY - JOUR AB - Cachexia is a devastating, non-curable condition in many cancer patients that is marked by severe wasting of the muscle and fat tissue. Its prevention has been hampered by an insufficient knowledge of the underlying molecular mechanism(s) that lead to its pathogenesis. Suriben et al. (2020) now report the development and characterization of an antagonistic antibody for the previously identified GDF15-GFRAL axis that efficiently blocks tumor-induced body wasting in experimental animals. Cachexia is a devastating, non-curable condition in many cancer patients that is marked by severe wasting of the muscle and fat tissue. Its prevention has been hampered by an insufficient knowledge of the underlying molecular mechanism(s) that lead to its pathogenesis. Suriben et al. (2020) now report the development and characterization of an antagonistic antibody for the previously identified GDF15-GFRAL axis that efficiently blocks tumor-induced body wasting in experimental animals. AU - Rohm, M. AU - Herzig, S. C1 - 59981 C2 - 49715 SP - 331-333 TI - An antibody attack against body wasting in cancer. JO - Cell Metab. VL - 32 IS - 3 PY - 2020 SN - 1550-4131 ER - TY - JOUR AB - Acute or chronic cellular stress resulting from aberrant metabolic and biochemical processes may trigger a pervasive non-apoptotic form of cell death, generally known as ferroptosis. Ferroptosis is unique among the different cell death modalities, as it has been mostly linked to pathophysiological conditions and because several metabolic pathways, such as (seleno)thiol metabolism, fatty acid metabolism, iron handling, mevalonate pathway, and mitochondrial respiration, directly impinge on the cells’ sensitivity toward lipid peroxidation and ferroptosis. Additionally, key cellular redox systems, such as selenium-dependent glutathione peroxidase 4 and the NAD(P)H/ferroptosis suppressor protein-1/ubiquinone axis, are at play that constantly surveil and neutralize oxidative damage to cellular membranes. Since this form of cell death emerges to be the root cause of a number of diseases and since it offers various pharmacologically tractable nodes for therapeutic intervention, there has been overwhelming interest in the last few years aiming for a better molecular understanding of the ferroptotic death process. AU - Zheng, J. AU - Conrad, M. C1 - 60684 C2 - 49429 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa SP - 920-937 TI - The metabolic underpinnings of ferroptosis. JO - Cell Metab. VL - 32 IS - 6 PB - Cell Press PY - 2020 SN - 1550-4131 ER - TY - JOUR AB - We studied sex differences in over 50 cardio-metabolic traits in a panel of 100 diverse inbred strains of mice. The results clearly showed that the effects of sex on both clinical phenotypes and gene expression depend on the genetic background. In support of this, genetic loci associated with the traits frequently showed sex specificity. For example, Lyplal1, a gene implicated in human obesity, was shown to underlie a sex-specific locus for diet induced obesity. Global gene expression analyses of tissues across the panel implicated adipose tissue "beiging" and mitochondrial functions in the sex differences. Isolated mitochondria showed gene-bysex interactions in oxidative functions, such that some strains (C57BL/6J) showed similar function between sexes, whereas others (DBA/2J and A/J) showed increased function in females. Reduced adipose mitochondria! function in males as compared to females was associated with increased susceptibility to obesity and insulin resistance. Gonadectomy studies indicated that gonadal hormones acting in a tissue-specific manner were responsible in part for the sex differences. AU - Norheim, F.* AU - Hasin-Brumshtein, Y.* AU - Vergnes, L.* AU - Chella Krishnan, K.* AU - Pan, C.* AU - Seldin, M.M.* AU - Hui, S.T.* AU - Mehrabian, M.* AU - Zhou, Z.* AU - Gupta, S.* AU - Parks, B.W.* AU - Walch, A.K. AU - Reue, K.* AU - Hofmann, S.M. AU - Arnold, A.P.* AU - Lusis, A.J.* C1 - 55134 C2 - 46246 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa SP - 932-949.e4 TI - Gene-by-sex interactions in mitochondrial functions and cardio-metabolic traits. JO - Cell Metab. VL - 29 IS - 4 PB - Cell Press PY - 2019 SN - 1550-4131 ER - TY - JOUR AB - Due to the implication of altered metabolism in a large spectrum of tissue function and disease, assessment of metabolic processes becomes essential in managing health. In this regard, imaging can play a critical role in allowing observation of biochemical and physiological processes. Nuclear imaging methods, in particular positron emission tomography, have been widely employed for imaging metabolism but are mainly limited by the use of ionizing radiation and the sensing of only one parameter at each scanning session. Observations in healthy individuals or longitudinal studies of disease could markedly benefit from non-ionizing, multi-parameter imaging methods. We therefore focus this review on progress with the non-ionizing radiation methods of MRI, hyperpolarized magnetic resonance and magnetic resonance spectroscopy, chemical exchange saturation transfer, and emerging optoacoustic (photoacoustic) imaging. We also briefly discuss the role of nuclear and optical imaging methods for research and clinical protocols. AU - Ntziachristos, V. AU - Pleitez, M.A. AU - Aime, S.* AU - Brindle, K.M.* C1 - 54440 C2 - 45583 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa SP - 518-538 TI - Emerging technologies to image tissue metabolism. JO - Cell Metab. VL - 29 IS - 3 PB - Cell Press PY - 2019 SN - 1550-4131 ER - TY - JOUR AB - Progressive decline of pancreatic beta cell function is central to the pathogenesis of type 2 diabetes. Protein phosphorylation regulates glucose-stimulated insulin secretion from beta cells, but how signaling networks are remodeled in diabetic islets in vivo remains unknown. Using high-sensitivity mass spectrometry-based proteomics, we quantified 6,500 proteins and 13,000 phosphopeptides in islets of obese diabetic mice and matched controls, revealing drastic remodeling of key kinase hubs and signaling pathways. Integration with a literature-derived signaling network implicated GSK3 kinase in the control of the beta cell-specific transcription factor PDX1. Deep phosphoproteomic analysis of human islets chronically treated with high glucose demonstrated a conserved glucotoxicity-dependent role of GSK3 kinase in regulating insulin secretion. Remarkably, the ability of beta cells to secrete insulin in response to glucose was rescued almost completely by pharmacological inhibition of GSK3. Thus, our resource enables investigation of mechanisms and drug targets in type 2 diabetes. AU - Sacco, F.* AU - Seelig, A. AU - Humphrey, S.J.* AU - Krahmer, F.* AU - Volta, F. AU - Reggio, A.* AU - Marchetti, P.* AU - Gerdes, J.M. AU - Mann, M.* C1 - 55705 C2 - 46522 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa SP - 1422-1432.e3 TI - Phosphoproteomics reveals the GSK3-PDX1 axis as a key pathogenic signaling node in diabetic islets. JO - Cell Metab. VL - 29 IS - 6 PB - Cell Press PY - 2019 SN - 1550-4131 ER - TY - JOUR AB - Skin affections after sulfur mustard (SM) exposure include erythema, blister formation and severe inflammation. An antidote or specific therapy does not exist. Anti-inflammatory compounds as well as substances counteracting SM-induced cell death are under investigation. In this study, we investigated the benzylisoquinoline alkaloide berberine (BER), a metabolite in plants like berberis vulgaris, which is used as herbal pharmaceutical in Asian countries, against SM toxicity using a well-established in vitro approach. Keratinocyte (HaCaT) mono-cultures (MoC) or HaCaT/THP-1 co-cultures (CoC) were challenged with 100, 200 or 300 mM SM for 1 h. Post-exposure, both MoC and CoC were treated with 10, 30 or 50 mu M BER for 24 h. At that time, supernatants were collected and analyzed both for interleukine (IL) 6 and 8 levels and for content of adenylate-kinase (AK) as surrogate marker for cell necrosis. Cells were lysed and nucleosome formation as marker for late apoptosis was assessed. In parallel, AK in cells was determined for normalization purposes. BER treatment did not influence necrosis, but significantly decreased apoptosis. Anti-inflammatory effects were moderate, but also significant, primarily in CoC. Overall, BER has protective effects against SM toxicity in vitro. Whether this holds true should be evaluated in future in vivo studies. AU - Lu, T.T.* AU - Heyne, S.* AU - Dror, E.* AU - Casas, E.* AU - Leonhardt, L.* AU - Boenke, T.* AU - Yang, C.-H.* AU - Sagar* AU - Arrigoni, L.* AU - Dalgaard, K.* AU - Teperino, R. AU - Enders, L.* AU - Selvaraj, M.* AU - Ruf, M.* AU - Raja, S.J.* AU - Xie, H.* AU - Boenisch, U.* AU - Orkin, S.H.* AU - Lynn, F.C.* AU - Hoffman, B.G.* AU - Grün, D.* AU - Vavouri, T.* AU - Lempradl, A.M.* AU - Pospisilik, J.A.* C1 - 53515 C2 - 44635 CY - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland SP - 1294-1308.e7 TI - The polycomb-dependent epigenome controls beta cell dysfunction, dedifferentiation, and diabetes. JO - Cell Metab. VL - 27 IS - 6 PB - Elsevier Ireland Ltd PY - 2018 SN - 1550-4131 ER - TY - JOUR AB - The molecular causes of type 2 diabetes (T2D) are not well understood. Both type 1 diabetes (T1D) and T2D are characterized by impaired insulin signaling and hyperglycemia. From analogy to T1D, insulin resistance and hyperglycemia are thought to also play causal roles in T2D. Recent clinical studies, however, found that T2D patients treated to maintain glycemia below the diabetes definition threshold (HbA(1c) < 6.5%) still develop diabetic complications. This suggests additional insulin-and glucose-independent mechanisms could be involved in T2D progression and/or initiation. T2D patients have elevated levels of the metabolite methylglyoxal (MG). We show here, using Drosophila glyoxalase 1 knockouts, that animals with elevated methylglyoxal recapitulate several core aspects of T2D: insulin resistance, obesity, and hyperglycemia. Thus elevated MG could constitute one root cause of T2D, suggesting that the molecular causes of elevated MG warrant further study. AU - Moraru, A.* AU - Wiederstein, J.* AU - Pfaff, D. AU - Fleming, T. AU - Miller, A.K.* AU - Nawroth, P.P. AU - Teleman, A.A.* C1 - 53212 C2 - 44521 CY - Cambridge SP - 926-934.e8 TI - Elevated levels of the reactive metabolite methylglyoxal recapitulate progression of type 2 diabetes. JO - Cell Metab. VL - 27 IS - 4 PB - Cell Press PY - 2018 SN - 1550-4131 ER - TY - JOUR AB - Metabolism is a fundamental process of life. However, non-invasive measurement of local tissue metabolism is limited today by a deficiency in adequate tools for in vivo observations. We designed a multi-modular platform that explored the relation between local tissue oxygen consumption, determined by label-free optoacoustic measurements of hemoglobin, and concurrent indirect calorimetry obtained during metabolic activation of brown adipose tissue (BAT). By studying mice and humans, we show how video-rate handheld multi-spectral optoacoustic tomography (MSOT) in the 700-970 nm spectral range enables non-invasive imaging of BAT activation, consistent with positron emission tomography findings. Moreover, we observe BAT composition differences between healthy and diabetic tissues. The study consolidates hemoglobin as a principal label-free biomarker for longitudinal non-invasive imaging of BAT morphology and bioenergetics in situ. We also resolve water and fat components in volunteers, and contrast MSOT readouts with magnetic resonance imaging data. AU - Reber, J. AU - Willershäuser, M.* AU - Karlas, A. AU - Paul-Yuan, K. AU - Diot, G. AU - Franz, D.* AU - Fromme, T.* AU - Ovsepian, S.V. AU - Bézière, N. AU - Dubikovskaya, E.* AU - Karampinos, D.C.* AU - Holzapfel, C.* AU - Hauner, H.* AU - Klingenspor, M.* AU - Ntziachristos, V. C1 - 53071 C2 - 44343 CY - Cambridge SP - 689-701.e4 TI - Non-invasive measurement of brown fat metabolism based on optoacoustic imaging of hemoglobin gradients. JO - Cell Metab. VL - 27 IS - 3 PB - Cell Press PY - 2018 SN - 1550-4131 ER - TY - JOUR AB - Activation of energy expenditure in thermogenic fat is a promising strategy to improve metabolic health, yet the dynamic processes that evoke this response are poorly understood. Here we show that synthesis of the mitochondrial phospholipid cardiolipin is indispensable for stimulating and sustaining thermogenic fat function. Cardiolipin biosynthesis is robustly induced in brown and beige adipose upon cold exposure. Mimicking this response through overexpression of cardiolipin synthase (Crls1) enhances energy consumption in mouse and human adipocytes. Crls1 deficiency in thermogenic adipocytes diminishes inducible mitochondrial uncoupling and elicits a nuclear transcriptional response through endoplasmic reticulum stress-mediated retrograde communication. Cardiolipin depletion in brown and beige fat abolishes adipose thermogenesis and glucose uptake, which renders animals insulin resistant. We further identify a rare human CRLS1 variant associated with insulin resistance and show that adipose CRLS1 levels positively correlate with insulin sensitivity. Thus, adipose cardiolipin has a powerful impact on organismal energy homeostasis through thermogenic fat bioenergetics. AU - Sustarsic, E.G.* AU - Ma, T.* AU - Lynes, M.D.* AU - Larsen, M.* AU - Karavaeva, I.* AU - Havelund, J.F.* AU - Nielsen, C.H.* AU - Jedrychowski, M.P.* AU - Moreno-Torres, M.* AU - Lundh, M.* AU - Plucinska, K.* AU - Jespersen, N.Z.* AU - Grevengoed, T.J.* AU - Kramar, B.* AU - Peics, J.* AU - Hansen, J.B.* AU - Shamsi, F.* AU - Forss, I.* AU - Neess, D.* AU - Keipert, S. AU - Wang, J.* AU - Stohlmann, K.* AU - Brandslund, I.* AU - Christensen, C.* AU - Jørgensen, M.E.* AU - Linneberg, A.* AU - Pedersen, O.* AU - Kiebish, M.A.* AU - Qvortrup, K.* AU - Han, X.* AU - Pedersen, B.K.* AU - Jastroch, M. AU - Mandrup, S.* AU - Kjær, A.* AU - Gygi, S.P.* AU - Hansen, T.* AU - Gillum, M.P.* AU - Grarup, N.* AU - Emanuelli, B.* AU - Nielsen, S.* AU - Scheele, C.* AU - Tseng, Y.H.* AU - Færgeman, N.J.* AU - Gerhart-Hines, Z.* C1 - 53603 C2 - 44924 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa SP - 159-+ TI - Cardiolipin synthesis in brown and beige fat mitochondria is essential for systemic energy homeostasis. JO - Cell Metab. VL - 28 IS - 1 PB - Cell Press PY - 2018 SN - 1550-4131 ER - TY - JOUR AB - The processes contributing to β cell dysfunction in type 2 diabetes (T2D) are uncertain, largely because it is difficult to access β cells in their intact immediate environment. We examined the pathophysiology of β cells under T2D progression directly in pancreatic tissues. We used MALDI imaging of Langerhans islets (LHIs) within mouse tissues or from human tissues to generate in situ-omics data, which we supported with in vitro experiments. Molecular interaction networks provided information on functional pathways and molecules. We found that stearoylcarnitine accumulated in β cells, leading to arrest of insulin synthesis and energy deficiency via excessive β-oxidation and depletion of TCA cycle and oxidative phosphorylation metabolites. Acetylcarnitine and an accumulation of N-acyl taurines, a group not previously detected in β cells, provoked insulin secretion. Thus, β cell dysfunction results from enhanced insulin secretion combined with an arrest of insulin synthesis. AU - Aichler, M. AU - Borgmann, D.M. AU - Krumsiek, J. AU - Buck, A. AU - MacDonald, P.E.* AU - Fox, J.E.M.* AU - Lyon, J.* AU - Light, P.E.* AU - Keipert, S. AU - Jastroch, M. AU - Feuchtinger, A. AU - Müller, N.S. AU - Sun, N. AU - Palmer, A.* AU - Alexandrov, T.* AU - Hrabě de Angelis, M. AU - Neschen, S. AU - Tschöp, M.H. AU - Walch, A.K. C1 - 51273 C2 - 42866 CY - Cambridge SP - 1334-1347.e4 TI - N-acyl taurines and acylcarnitines cause an imbalance in insulin synthesis and secretion provoking β cell dysfunction in type 2 diabetes. JO - Cell Metab. VL - 25 IS - 6 PB - Cell Press PY - 2017 SN - 1550-4131 ER - TY - JOUR AB - Unimolecular dual incretins derived from hybridized glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) sequences have demonstrated synergistic reduction of adiposity in animal models and reductions of hyperglycemia in short-duration human trials. Here, we extend the characterization of NNC0090-2746 (also known as RG7697), a fatty-acylated dual agonist possessing in vitro balanced GIPR and GLP-1R agonism. In this 12-week, randomized, placebo-controlled, double-blind phase 2a trial, patients with type 2 diabetes inadequately controlled with metformin received 1.8 mg of NNC0090-2746 or placebo subcutaneously once daily. Liraglutide 1.8 mg (Victoza), starting with 2-week dose escalation, was administered subcutaneously once daily as an open-label reference arm. Measurements were collected at regular intervals after randomization. NNC0090-2746 significantly improved glycemic control and reduced body weight compared with placebo. Total cholesterol, alone among a range of lipid parameters, and leptin were both significantly reduced compared with placebo. Treatment with NNC0090-2746 was generally safe and well tolerated. AU - Frias, J.P.* AU - Bastyr, E.J.* AU - Vignati, L.* AU - Tschöp, M.H. AU - Schmitt, C.* AU - Owen, K.R.* AU - Christensen, R.H.* AU - DiMarchi, R.D.* C1 - 51669 C2 - 43391 SP - 343-352.e2 TI - The sustained effects of a dual GIP/GLP-1 receptor agonist, NNC0090-2746, in patients with type 2 diabetes. JO - Cell Metab. VL - 26 IS - 2 PY - 2017 SN - 1550-4131 ER - TY - JOUR AB - Obesity and type 2 diabetes are associated with metabolic defects and adipose tissue inflammation. Foxp3(+) regulatory T cells (Tregs) control tissue homeostasis by counteracting local inflammation. However, if and how T cells interlink environmental influences with adipocyte function remains unknown. Here, we report that enhancing sympathetic tone by cold exposure, beta3-adrenergic receptor (ADRB3) stimulation or a short-term high-calorie diet enhances Treg induction in vitro and in vivo. CD4(+) T cell proteomes revealed higher expression of Foxp3 regulatory networks in response to cold or ADRB3 stimulation in vivo reflecting Treg induction. Specifically, Ragulator-interacting protein C17orf59, which limits mTORC1 activity, was upregulated in CD4(+) T cells by either ADRB3 stimulation or cold exposure, suggesting contribution to Treg induction. By loss- and gain-of-function studies, including Treg depletion and transfers in vivo, we demonstrated that a T cell-specific Stat6/Pten axis links cold exposure or ADRB3 stimulation with Foxp3(+) Treg induction and adipose tissue function. Our findings offer a new mechanistic model in which tissue-specific Tregs maintain adipose tissue function. AU - Kälin, S. AU - Becker, M. AU - Ott, V. AU - Serr, I. AU - Hosp, F.* AU - Mollah, M.M.H. AU - Keipert, S. AU - Lamp, D. AU - Rohner-Jeanrenaud, F.* AU - Flynn, V.K. AU - Scherm, M.G. AU - Nascimento, L.F.R. AU - Gerlach, K.* AU - Popp, V.* AU - Dietzen, S.* AU - Bopp, T.* AU - Krishnamurthy, P.* AU - Kaplan, M.H.* AU - Serrano, M.* AU - Woods, S.C.* AU - Tripal, P.* AU - Palmisano, R.* AU - Jastroch, M. AU - Blüher, M.* AU - Wolfrum, C.* AU - Weigmann, B.* AU - Ziegler, A.-G. AU - Mann, M.* AU - Tschöp, M.H. AU - Daniel, C. C1 - 51831 C2 - 43493 SP - 475-492.e7 TI - A Stat6/Pten axis links regulatory T cells with adipose tissue function. JO - Cell Metab. VL - 26 IS - 3 PY - 2017 SN - 1550-4131 ER - TY - JOUR AB - Brown adipose tissue (BAT)-dependent thermogenesis and its suggested augmenting hormone, FGF21, are potential therapeutic targets in current obesity and diabetes research. Here, we studied the role of UCP1 and FGF21 for metabolic homeostasis in the cold and dissected underlying molecular mechanisms using UCP1-FGF21 double-knockout mice. We report that neither UCP1 nor FGF21, nor even compensatory increases of FGF21 serum levels in UCP1 knockout mice, are required for defense of body temperature or for maintenance of energy metabolism and body weight. Remarkably, cold-induced browning of inguinal white adipose tissue (iWAT) is FGF21 independent. Global RNA sequencing reveals major changes in response to UCP1- but not FGF21-ablation in BAT, iWAT, and muscle. Markers of mitochondrial failure and inflammation are observed in BAT, but in particular the enhanced metabolic reprogramming in iWAT supports the thermogenic role of UCP1 and excludes an important thermogenic role of endogenous FGF21 in normal cold acclimation. AU - Keipert, S. AU - Kutschke, M. AU - Ost, M.* AU - Schwarzmayr, T. AU - van Schothorst, E.M.* AU - Lamp, D. AU - Brachthäuser, L. AU - Hamp, I. AU - Mazibuko-Mbeje, S. AU - Hartwig, S.* AU - Lerch, S.* AU - Graf, E. AU - Plettenburg, O. AU - Neff, F. AU - Tschöp, M.H. AU - Jastroch, M. C1 - 51643 C2 - 43511 SP - 437-446.e5 TI - Long-term cold adaptation does not require FGF21 or UCP1. JO - Cell Metab. VL - 26 IS - 2 PY - 2017 SN - 1550-4131 ER - TY - JOUR AB - The macromolecular mechanics of GLP-1 with its cell surface receptor came into focus as two landmark publications recently published in Nature collectively herald advancement in structure-based design for a receptor class of great therapeutic importance (Jazayeri et al., 2017; Zhang et al., 2017). AU - Mayer, J.P.* AU - Tschöp, M.H. AU - DiMarchi, R.D.* C1 - 51666 C2 - 43484 SP - 289-291 TI - Once blind, now we see GLP-1 molecular action. JO - Cell Metab. VL - 26 IS - 2 PY - 2017 SN - 1550-4131 ER - TY - JOUR AB - Chronic inflammation has been proposed to contribute to the pathogenesis of diet-induced obesity. However, scarce therapeutic options are available to treat obesity and the associated immunometabolic complications. Glucocorticoids are routinely employed for the management of inflammatory diseases, but their pleiotropic nature leads to detrimental metabolic side effects. We developed a glucagon-like peptide-1 (GLP-1)-dexamethasone co-agonist in which GLP-1 selectively delivers dexamethasone to GLP-1 receptor-expressing cells. GLP-1-dexamethasone lowers body weight up to 25% in obese mice by targeting the hypothalamic control of feeding and by increasing energy expenditure. This strategy reverses hypothalamic and systemic inflammation while improving glucose tolerance and insulin sensitivity. The selective preference for GLP-1 receptor bypasses deleterious effects of dexamethasone on glucose handling, bone integrity, and hypothalamus-pituitary-adrenal axis activity. Thus, GLP-1-directed glucocorticoid pharmacology represents a safe and efficacious therapy option for diet-induced immunometabolic derangements and the resulting obesity. AU - Quarta, C. AU - Clemmensen, C. AU - Zhu, Z.* AU - Yang, B.* AU - Joseph, S.S. AU - Lutter, D. AU - Yi, C.X.* AU - Graf, E. AU - García-Cáceres, C. AU - Legutko, B. AU - Fischer, K. AU - Brommage, R. AU - Zizzari, P.* AU - Franklin, B.S.* AU - Krueger, M.* AU - Koch, M.* AU - Vettorazzi, S.* AU - Li, P.* AU - Hofmann, S.M. AU - Bakhti, M. AU - Bastidas-Ponce, A. AU - Lickert, H. AU - Strom, T.M. AU - Gailus-Durner, V. AU - Bechmann, I.* AU - Perez-Tilve, D.* AU - Tuckermann, J.P.* AU - Hrabě de Angelis, M. AU - Sandoval, D.A.* AU - Cota, D.* AU - Latz, E.* AU - Seeley, R.J.* AU - Müller, T.D. AU - DiMarchi, R.D.* AU - Finan, B. AU - Tschöp, M.H. C1 - 51988 C2 - 43606 CY - Cambridge SP - 620-632.e6 TI - Molecular integration of incretin and glucocorticoid action reverses immunometabolic dysfunction and obesity. JO - Cell Metab. VL - 26 IS - 4 PB - Cell Press PY - 2017 SN - 1550-4131 ER - TY - JOUR AB - The prospective cohort study, named PURE, found that in >135,000 participants from 18 countries, nutritive carbohydrates increase human mortality, whereas dietary fat reduces it, requesting a fundamental change of current nutritional guidelines. Experimental evidence from animal models provides synergizing mechanistic concepts as well as pharmacological options to mimic low-carb or ketogenic diets. AU - Ravichandran, M.* AU - Grandl, G. AU - Ristow, M.* C1 - 52051 C2 - 43673 CY - Cambridge SP - 585-587 TI - Dietary carbohydrates impair healthspan and promote mortality. JO - Cell Metab. VL - 26 IS - 4 PB - Cell Press PY - 2017 SN - 1550-4131 ER - TY - JOUR AB - Breast tumor recurrence and metastasis represent the main causes of cancer-related death in women, and treatments are still lacking. Here, we define the lipogenic enzyme acetyl-CoA carboxylase (ACC) 1 as a key player in breast cancer metastasis. ACC1 phosphorylation was increased in invading cells both in murine and human breast cancer, serving as a point of convergence for leptin and transforming growth factor (TGF) β signaling. ACC1 phosphorylation was mediated by TGFβ-activated kinase (TAK) 1, and ACC1 inhibition was indispensable for the elevation of cellular acetyl-CoA, the subsequent increase in Smad2 transcription factor acetylation and activation, and ultimately epithelial-mesenchymal transition and metastasis induction. ACC1 deficiency worsened tumor recurrence upon primary tumor resection in mice, and ACC1 phosphorylation levels correlated with metastatic potential in breast and lung cancer patients. Given the demonstrated effectiveness of anti-leptin receptor antibody treatment in halting ACC1-dependent tumor invasiveness, our work defines a "metabolocentric" approach in metastatic breast cancer therapy. AU - Rios Garcia, M. AU - Steinbauer, B.* AU - Srivastava, K.* AU - Singhal, M.* AU - Mattijssen, F. AU - Maida, A. AU - Christian, S.* AU - Hess-Stumpp, H.* AU - Augustin, H.G.* AU - Müller-Decker, K.* AU - Nawroth, P.P. AU - Herzig, S. AU - Berriel Diaz, M. C1 - 52183 C2 - 43827 CY - Cambridge SP - 1–14.e1–e5 TI - Acetyl-CoA carboxylase 1-dependent protein acetylation controls breast cancer metastasis and recurrence. JO - Cell Metab. VL - 26 IS - 6 PB - Cell Press PY - 2017 SN - 1550-4131 ER - TY - JOUR AB - A BMI in the normal range associates with a decreased risk of cardiometabolic disease and all-cause mortality. However, not all subjects in this BMI range have this low risk. Compared to people who are of normal weight and metabolically healthy, subjects who are of normal weight but metabolically unhealthy (∼20% of the normal weight adult population) have a greater than 3-fold higher risk of all-cause mortality and/or cardiovascular events. Here we address to what extent major risk phenotypes determine metabolic health in lean compared to overweight and obese people and provide support for the existence of a lipodystrophy-like phenotype in the general population. Furthermore, we highlight the molecular mechanisms that induce this phenotype. Finally, we propose strategies as to how this knowledge could be implemented in the prevention and treatment of cardiometabolic diseases in different stages of adiposity in routine clinical practice. AU - Stefan, N. AU - Schick, F. AU - Häring, H.-U. C1 - 51670 C2 - 43331 SP - 292-300 TI - Causes, characteristics, and consequences of metabolically unhealthy normal weight in humans. JO - Cell Metab. VL - 26 IS - 2 PB - Elsevier PY - 2017 SN - 1550-4131 ER - TY - JOUR AB - Signaling by the corticotropin-releasing factor receptor type 1 (CRFR1) plays an important role in mediating the autonomic response to stressful challenges. Multiple hypothalamic nuclei regulate sympathetic outflow. Although CRFR1 is highly expressed in the arcuate nucleus (Arc) of the hypothalamus, the identity of these neurons and the role of CRFR1 here are presently unknown. Our studies show that nearly half of Arc-CRFR1 neurons coexpress agouti-related peptide (AgRP), half of which originate from POMC precursors. Arc-CRFR1 neurons are innervated by CRF neurons in the hypothalamic paraventricular nucleus, and CRF application decreases AgRP(+)CRFR1(+) neurons' excitability. Despite similar anatomy in both sexes, only female mice selectively lacking CRFR1 in AgRP neurons showed a maladaptive thermogenic response to cold and reduced hepatic glucose production during fasting. Thus, CRFR1, in a subset of AgRP neurons, plays a regulatory role that enables appropriate sympathetic nervous system activation and consequently protects the organism from hypothermia and hypoglycemia. AU - Kuperman, Y.* AU - Weiss, M.* AU - Dine, J.* AU - Staikin, K.* AU - Golani, O.* AU - Ramot, A.* AU - Nahum, T.* AU - Kühne, C.* AU - Shemesh, Y.* AU - Wurst, W. AU - Harmelin, A.* AU - Deussing, J.M.* AU - Eder, M.* AU - Chen, A.* C1 - 48661 C2 - 41263 CY - Cambridge SP - 1185-1199 TI - CRFR1 in AgRP neurons modulates sympathetic nervous system activity to adapt to cold stress and fasting. JO - Cell Metab. VL - 23 IS - 6 PB - Cell Press PY - 2016 SN - 1550-4131 ER - TY - JOUR AB - Pro-opiomelanocortin deficiency is a rare cause of severe intractable obesity. Two patients have experienced dramatic weight loss in response to setmelanotide, a melanocortin-4 receptor activator. The drug has potential in broader populations, but caution is warranted as it may act at other melanocortin receptors. AU - Müller, T.D. AU - Tschöp, M.H. AU - O'Rahilly, S.* C1 - 49171 C2 - 41690 CY - Cambridge SP - 194-195 TI - Metabolic precision medicines: Curing POMC deficiency. JO - Cell Metab. VL - 24 IS - 2 PB - Cell Press PY - 2016 SN - 1550-4131 ER - TY - JOUR AB - Type 2 diabetes is associated with increased risk of malignancies, whereas antidiabetic interventions like physical exercise or metformin reduce cancer incidence. A recent publication shows that one diabetes treatment approach, namely incretin-related DPP4 inhibitors, increases metastatic capacity by activating the antioxidant transcription factor NRF2 to decrease reactive oxygen species (ROS) levels. AU - Tschöp, M.H. AU - Stumvoll, M.* AU - Ristow, M.* C1 - 48824 C2 - 41454 CY - Cambridge SP - 959-960 TI - Opposing effects of antidiabetic interventions on malignant growth and metastasis. JO - Cell Metab. VL - 23 IS - 6 PB - Cell Press PY - 2016 SN - 1550-4131 ER - TY - JOUR AB - Many complex diseases have historically proven to be defiant to the best mono-therapeutic approaches. Several examples of combination therapies have largely overcome such challenges, notably for the treatment of severe hypertension and tuberculosis. Obesity and its consequences, such as type 2 diabetes, have proven to be equally resistant to therapeutic approaches based on single medicines. Proper management of type 2 diabetes often requires adjunctive medications, and the recent registration of a few compound mixtures has set the precedent for combinatorial treatment of obesity. On the other hand, double or triple therapeutic combinations are more difficult to advance to regulatory approval than single molecules. More recently, several classes of novel unimolecular combination therapeutics have emerged with superior efficacy than currently prescribed options and pose the potential to reverse obesity and type 2 diabetes. Here, we summarize the discovery, pre-clinical validation, and first clinical test of such peptide hormone poly-agonist drug candidates. AU - Tschöp, M.H. AU - Finan, B. AU - Clemmensen, C. AU - Gelfanov, V.* AU - Perez-Tilve, D.* AU - Müller, T.D. AU - DiMarchi, R.D.* C1 - 49077 C2 - 41597 CY - Cambridge SP - 51-62 TI - Unimolecular polypharmacy for treatment of diabetes and obesity. JO - Cell Metab. VL - 24 IS - 1 PB - Cell Press PY - 2016 SN - 1550-4131 ER - TY - JOUR AB - Obesity, insulin resistance, and related pathologies are associated with immune-mediated chronic inflammation. Kit mutant mice are protected from diet-induced obesity and associated co-morbidities, and this phenotype has previously been attributed to their lack of mast cells. We performed a comprehensive metabolic analysis of Kit-dependent Kit(W/Wv) and Kit-independent Cpa3(Cre/+) mast-cell-deficient mouse strains, employing diet-induced or genetic (Lep(Ob/Ob) background) models of obesity. Our results show that mast cell deficiency, in the absence of Kit mutations, plays no role in the regulation of weight gain or insulin resistance. Moreover, we provide evidence that the metabolic phenotype observed in Kit mutant mice, while independent of mast cells, is immune regulated. Our data underscore the value of definitive mast cell deficiency models to conclusively test the involvement of this enigmatic cell in immune-mediated pathologies and identify Kit as a key hematopoietic factor in the pathogenesis of metabolic syndrome. AU - Gutierrez, D.A.* AU - Muralidhar, S.* AU - Feyerabend, T.B.* AU - Herzig, S. AU - Rodewald, H.R.* C1 - 44804 C2 - 37040 CY - Cambridge SP - 678-691 TI - Hematopoietic Kit deficiency, rather than lack of mast cells, protects mice from obesity and insulin resistance. JO - Cell Metab. VL - 21 IS - 5 PB - Cell Press PY - 2015 SN - 1550-4131 ER - TY - JOUR AB - Canonical protein phosphatase 3/calcineurin signaling is central to numerous physiological processes. Here we provide evidence that calcineurin plays a pivotal role in controlling systemic energy and body weight homeostasis. Knockdown of calcineurin in Drosophila melanogaster led to a decrease in body weight and energy stores, and increased energy expenditure. In mice, global deficiency of catalytic subunit Ppp3cb, and tissue-specific ablation of regulatory subunit Ppp3r1 from skeletal muscle, but not adipose tissue or liver, led to protection from high-fat-diet-induced obesity and comorbid sequelæ. Ser637 hyperphosphorylation of dynamin-related protein 1 (Drp1) in skeletal muscle of calcineurin-deficient mice was associated with mitochondrial elongation into power-cable-shaped filaments and increased mitochondrial respiration, but also with attenuated exercise performance. Our data suggest that calcineurin acts as highly conserved pivot for the adaptive metabolic responses to environmental changes such as high-fat, high-sugar diets or exercise. AU - Pfluger, P.T. AU - Kabra, D.G. AU - Aichler, M. AU - Schriever, S.C. AU - Pfuhlmann, K. AU - Casquero García, V. AU - Lehti, M.* AU - Weber, J.* AU - Kutschke, M. AU - Rozman, J. AU - Elrod, J.W.* AU - Hevener, A.L.* AU - Feuchtinger, A. AU - Hrabě de Angelis, M. AU - Walch, A.K. AU - Rollmann, S.M.* AU - Aronow, B.J.* AU - Müller, T.D. AU - Perez-Tilve, D.* AU - Jastroch, M. AU - de Luca, M.* AU - Molkentin, J.D.* AU - Tschöp, M.H. C1 - 46877 C2 - 39009 SP - 838-850 TI - Calcineurin links mitochondrial elongation with energy metabolism. JO - Cell Metab. VL - 22 IS - 5 PY - 2015 SN - 1550-4131 ER - TY - JOUR AB - Replenishing the lost or dysfunctional insulin-producing β cell mass in diabetic patients could slow down or reverse disease progression. Kondegowda et al. (2015) now show that osteoprotegerin and denosumab, inhibitors of the receptor activator of the NF-κB Ligand (RANKL) pathway and osteoclast activation, stimulate human β cell proliferation and therefore possess therapeutic potential. AU - Schmitz, F. AU - Roscioni, S. AU - Lickert, H. C1 - 45386 C2 - 37337 CY - Cambridge SP - 58-59 TI - Repurposing an osteoporosis drug for β cell regeneration in diabetic patients. JO - Cell Metab. VL - 22 IS - 1 PB - Cell Press PY - 2015 SN - 1550-4131 ER - TY - JOUR AB - Obesity, diabetes, and metabolic syndrome result from complex interactions between genetic and environmental factors, including the gut microbiota. To dissect these interactions, we utilized three commonly used inbred strains of mice-obesity/diabetes-prone C57Bl/6J mice, obesity/diabetes-resistant 129S1/SvImJ from Jackson Laboratory, and obesity-prone but diabetes-resistant 129S6/SvEvTac from Taconic-plus three derivative lines generated by breeding these strains in a new, common environment. Analysis of metabolic parameters and gut microbiota in all strains and their environmentally normalized derivatives revealed strong interactions between microbiota, diet, breeding site, and metabolic phenotype. Strain-dependent and strain-independent correlations were found between specific microbiota and phenotypes, some of which could be transferred to germ-free recipient animals by fecal transplantation. Environmental reprogramming of microbiota resulted in 129S6/SvEvTac becoming obesity resistant. Thus, development of obesity/metabolic syndrome is the result of interactions between gut microbiota, host genetics, and diet. In permissive genetic backgrounds, environmental reprograming of microbiota can ameliorate development of metabolic syndrome. AU - Ussar, S. AU - Griffin, N.W.* AU - Bezy, O.* AU - Fujisaka, S.* AU - Vienberg, S.* AU - Softic, S.* AU - Deng, L.* AU - Bry, L.* AU - Gordon, J.I.* AU - Kahn, C.R.* C1 - 46626 C2 - 37653 CY - Cambridge SP - 516-530 TI - Interactions between gut microbiota, host genetics and diet modulate the predisposition to obesity and metabolic syndrome. JO - Cell Metab. VL - 22 IS - 3 PB - Cell Press PY - 2015 SN - 1550-4131 ER - TY - JOUR AB - How circulating signals of hunger and satiety enter the brain to reach neurons that govern energy balance has long remained a matter of controversy and speculation. Balland et al. (2014) now elucidate molecular mechanisms by which a highly specialized hypothalamic glial cell regulates transport of leptin across the blood-brain barrier. AU - Gao, Y. AU - Tschöp, M.H. AU - Luquet, S.* C1 - 30748 C2 - 33843 CY - Cambridge SP - 173-175 TI - Hypothalamic tanycytes: Gatekeepers to metabolic control. JO - Cell Metab. VL - 19 IS - 2 PB - Cell Press PY - 2014 SN - 1550-4131 ER - TY - JOUR AB - The c-Jun NH(2)-terminal kinase (JNK) is a critical determinant of obesity-associated inflammation and glucose intolerance. The upstream mechanisms controlling this pathway are still unknown. Here we report that the levels of the PB1 domain-containing adaptor NBR1 correlated with the expression of proinflammatory molecules in adipose tissue from human patients with metabolic syndrome, suggesting that NBR1 plays a key role in adipose-tissue inflammation. We also show that NBR1 inactivation in the myeloid compartment impairs the function, M1 polarization, and chemotactic activity of macrophages; prevents inflammation of adipose tissue; and improves glucose tolerance in obese mice. Furthermore, we demonstrate that an interaction between the PB1 domains of NBR1 and the mitogen-activated kinase kinase 3 (MEKK3) enables the formation of a signaling complex required for the activation of JNK. Together, these discoveries identify an NBR1-MEKK3 complex as a key regulator of JNK signaling and adipose tissue inflammation in obesity. AU - Hernandez, E.D.* AU - Lee, S.J.* AU - Kim, J.Y.* AU - Duran, A.* AU - Linares, J.F.* AU - Yajima, T.* AU - Müller, T.D. AU - Tschöp, M.H. AU - Smith, S.R.* AU - Diaz-Meco, M.T.* AU - Moscat, J.* C1 - 31799 C2 - 34786 CY - Cambridge SP - 499-511 TI - A macrophage NBR1-MEKK3 complex triggers JNK-mediated adipose tissue inflammation in obesity. JO - Cell Metab. VL - 20 IS - 3 PB - Cell Press PY - 2014 SN - 1550-4131 ER - TY - JOUR AB - Millions of diabetic patients are waiting for better treatment options, ideally by replenishing the lost or dysfunctional insulin-producing β cell mass. Yi et al. (2013) now identify Betatrophin, a hormone that specifically increases β cell proliferation with promising therapeutic potential. AU - Lickert, H. C1 - 27767 C2 - 32804 SP - 5-6 TI - Betatrophin fuels β cell proliferation: First step toward regenerative therapy? JO - Cell Metab. VL - 18 IS - 1 PB - Cell Press PY - 2013 SN - 1550-4131 ER - TY - JOUR AB - Accumulating evidence suggests that changes in the metabolic signature of astrocytes underlie their response to neuroinflammation, but how proinflammatory stimuli induce these changes is poorly understood. By monitoring astrocytes following acute cortical injury, we identified a differential and region-specific remodeling of their mitochondrial network: while astrocytes within the penumbra of the lesion undergo mitochondrial elongation, those located in the core-the area invaded by proinflammatory cells-experience transient mitochondrial fragmentation. In brain slices, proinflammatory stimuli reproduced localized changes in mitochondrial dynamics, favoring fission over fusion. This effect was triggered by Drp1 phosphorylation and ultimately resulted in reduced respiratory capacity. Furthermore, maintenance of the mitochondrial architecture critically depended on the induction of autophagy. Deletion of Atg7, required for autophagosome formation, prevented the reestablishment of tubular mitochondria, leading to marked reactive oxygen species accumulation and cell death. Thus, our data reveal autophagy to be essential for regenerating astrocyte mitochondrial networks during inflammation. AU - Motori, E.* AU - Puyal, J.* AU - Toni, N.* AU - Ghanem, A.* AU - Angeloni, C.* AU - Malaguti, M.* AU - Cantelli-Forti, G.* AU - Berninger, B.* AU - Conzelmann, K.K.* AU - Götz, M. AU - Winklhofer, K.F.* AU - Hrelia, S.* AU - Bergami, M.* C1 - 28932 C2 - 33585 SP - 844-859 TI - Inflammation-induced alteration of astrocyte mitochondrial dynamics requires autophagy for mitochondrial network maintenance. JO - Cell Metab. VL - 18 IS - 6 PY - 2013 SN - 1550-4131 ER - TY - JOUR AB - The opioid system plays a pivotal role in how our brain regulates hedonic components of ingestive behavior. Duraffourd et al. (2012) add the gut to this opioid landscape, demonstrating direct activation of periportal mu-opioid receptors by food-derived opioid peptides (nutropioids), and a gut-brain feedback spiral that culminates in enhanced satiety. AU - Pfluger, P.T. AU - Schriever, S.C. AU - Tschöp, M.H. C1 - 8565 C2 - 30181 SP - 137-139 TI - Nutropioids, hedonism in the gut? JO - Cell Metab. VL - 16 IS - 2 PB - Cell Press PY - 2012 SN - 1550-4131 ER - TY - JOUR AU - Pihlajamäki, J.* AU - Lerin, C.* AU - Kaminska, D.* AU - Venesmaa, S.* AU - Itkonen, P.* AU - Boes, T.* AU - Floß, T. AU - Schroeder, J.* AU - Dearie, F.* AU - Crunkhorn, S.* AU - Burak, F.* AU - Jimenez-Chillaron, J.C.* AU - Kuulasmaa, T.* AU - Miettinen, P.* AU - Park, P.J.* AU - Nasser, I.* AU - Zhao, Z.W.* AU - Zhang, Z.Y.* AU - Xu, Y.* AU - Wurst, W. AU - Ren, H.M.* AU - Morris, A.J.* AU - Stamm, S.* AU - Goldfine, A.B.* AU - Laakso, M.* AU - Patti, M.E.* C1 - 8024 C2 - 29971 SP - 267-269 TI - SFRS10-A splicing factor gene reduced in human obesity? Response. JO - Cell Metab. VL - 15 IS - 3 PB - Cell Press PY - 2012 SN - 1550-4131 ER - TY - JOUR AB - Alternative mRNA splicing provides transcript diversity and may contribute to human disease. We demonstrate that expression of several genes regulating RNA processing is decreased in both liver and skeletal muscle of obese humans. We evaluated a representative splicing factor, SFRS10, downregulated in both obese human liver and muscle and in high-fat-fed mice, and determined metabolic impact of reduced expression. SFRS10-specific siRNA induces lipogenesis and lipid accumulation in hepatocytes. Moreover, Sfrs10 heterozygous mice have increased hepatic lipogenic gene expression, VLDL secretion, and plasma triglycerides. We demonstrate that LPIN1, a key regulator of lipid metabolism, is a splicing target of SFRS10; reduced SFRS10 favors the lipogenic β isoform of LPIN1. Importantly, LPIN1β-specific siRNA abolished lipogenic effects of decreased SFRS10 expression. Together, our results indicate that reduced expression of SFRS10, as observed in tissues from obese humans, alters LPIN1 splicing, induces lipogenesis, and therefore contributes to metabolic phenotypes associated with obesity. AU - Pihlajamäki, J.* AU - Lerin, C.* AU - Itkonen, P.* AU - Boes, T.* AU - Floß, T. AU - Schroeder, J.* AU - Dearie, F.* AU - Crunkhorn, S.* AU - Burak, F.* AU - Jimenez-Chillaron, J.C.* AU - Kuulasmaa, T.* AU - Miettinen, P.* AU - Park, P.J.* AU - Nasser, I.* AU - Zhao, Z.* AU - Zhang, Z.* AU - Xu, Y.* AU - Wurst, W. AU - Ren, H.* AU - Morris, A.J.* AU - Stamm, S.* AU - Goldfine, A.B.* AU - Laakso, M.* AU - Patti, M.E.* C1 - 6477 C2 - 28775 SP - 208-218 TI - Expression of the splicing factor gene SFRS10 is reduced in human obesity and contributes to enhanced lipogenesis. JO - Cell Metab. VL - 14 IS - 2 PB - Elsevier PY - 2011 SN - 1550-4131 ER - TY - JOUR AB - Oxidative stress in conjunction with glutathione depletion has been linked with various acute and chronic degenerative disorders, yet the molecular mechanisms have remained unclear. In contrast to the belief that oxygen radicals are detrimental to cells and tissues by unspecific oxidation of essential biomolecules, we now demonstrate that oxidative stress is sensed and transduced by glutathione peroxidase 4 (GPx4) into a-yet-unrecognized cell-death pathway. Inducible GPx4 inactivation in mice and cells revealed 12/15-lipoxygenase-derived lipid peroxidation as specific downstream event, triggering apoptosis-inducing factor (AIF)-mediated cell death. Cell death could be entirely prevented either by alpha-tocopherol (alpha-Toc), 12/15-lipoxygenase inhibitors, or siRNA-mediated AIF silencing. Accordingly, 12/15-/ipoxygenase-deficient cells were highly resistant to glutathione depletion. Neuron-specific GPx4 depletion caused neurodegeneration in vivo and ex vivo, highlighting the importance of this pathway in neuronal cells. Since oxidative stress is common in the etiology of many human disorders, the identified pathway reveals promising targets for future therapies. AU - Seiler, A. AU - Schneider, M. AU - Förster, H. AU - Roth, S.* AU - Wirth, E.K.* AU - Culmsee, C.* AU - Plesnila, N.* AU - Kremmer, E.* AU - Radmark, O. AU - Wurst, W. AU - Bornkamm, G.W. AU - Schweizer, U.* AU - Conrad, M. C1 - 1413 C2 - 25921 SP - 237-248 TI - Glutathione peroxidase 4 senses and translates oxidative stress into 12/15-lipoxygenase dependent- and AIF-Mediated cell death. JO - Cell Metab. VL - 8 IS - 3 PB - Cell Press PY - 2008 SN - 1550-4131 ER -