TY - JOUR AB - Insulin resistance is a central feature of metabolic disorders such as type 2 diabetes (T2D). While studies on this disorder have largely been linked to glucose metabolism and intracellular signaling, recent advances reveal that insulin resistance extends beyond traditional glucose regulatory pathways, impacting multiple organs including the brain, contributing to cognitive dysfunction and neurodegenerative diseases such as Alzheimer's disease (AD). This opinion revisits insulin resistance through molecular, cellular, and systemic perspectives, emphasizing the intersection between peripheral and brain insulin resistance (BIR), the role of the blood-brain barrier (BBB), and emerging biomarkers. Furthermore, we integrate insights from multi-omics and neuroimaging studies to refine our understanding, advocating for a broader perspective that informs early detection and intervention in metabolic and neurodegenerative diseases. AU - Chen, W.* AU - Kullmann, S. AU - Rhea, E.M.* C1 - 74678 C2 - 57546 TI - Expanding the understanding of insulin resistance in brain and periphery. JO - Trends Endocrinol. Metab. PY - 2025 SN - 1043-2760 ER - TY - JOUR AB - Liver fibrosis and biological sex variably modulate the risks of hepatocellular carcinoma (HCC) and extrahepatic cancers (EHCs) arising in the context of metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we highlight how these variables may have implications in the setting of chemoprevention and precision medicine approaches in MASLD and guide additional research. AU - Lonardo, A.* AU - Stefan, N. AU - Mantovani, A.* C1 - 73007 C2 - 56997 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa SP - 610-613 TI - Widening research horizons on metabolic dysfunction-associated steatotic liver disease and cancer. JO - Trends Endocrinol. Metab. VL - 36 IS - 7 PB - Cell Press PY - 2025 SN - 1043-2760 ER - TY - JOUR AB - Prediabetes is a highly prevalent and increasingly common condition affecting a significant proportion of the global population. The heterogeneous nature of prediabetes presents a challenge in identifying individuals who particularly benefit from lifestyle or other therapeutic interventions aiming at preventing type 2 diabetes (T2D) and associated comorbidities. The phenotypic characteristics of individuals at risk for diabetes are associated with both specific risk profiles for progression and a differential potential to facilitate prediabetes remission and reduce the risk of future T2D. This review examines the current definition and global prevalence of prediabetes and evaluates the potential of prediabetes remission to reduce the alarming increase in the global burden of T2D. AU - Sandforth, L. AU - Kullmann, S. AU - Sandforth, A. AU - Fritsche, A. AU - Jumpertz von Schwartzenberg, R. AU - Stefan, N. AU - Birkenfeld, A.L. C1 - 73393 C2 - 57043 TI - Prediabetes remission to reduce the global burden of type 2 diabetes. JO - Trends Endocrinol. Metab. PY - 2025 SN - 1043-2760 ER - TY - JOUR AB - The past decades have witnessed the rise and fall of several, largely unsuccessful, therapeutic attempts to bring the escalating obesity pandemic to a halt. Looking back to look ahead, the field has now put its highest hopes in translating insights from how the gastrointestinal (GI) tract communicates with the brain to calibrate behavior, physiology, and metabolism. A major focus of this review is to summarize the latest advances in comprehending the neuroendocrine aspects of this so-called 'gut-brain axis' and to explore novel concepts, cutting-edge technologies, and recent paradigm-shifting experiments. These exciting insights continue to refine our understanding of gut-brain crosstalk and are poised to promote the development of additional therapeutic avenues at the dawn of a new era of antiobesity therapeutics. AU - Gruber, T.* AU - Lechner, F. AU - Krieger, J.P.* AU - García-Cáceres, C. C1 - 70787 C2 - 55746 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa SP - 42-54 TI - Neuroendocrine gut-brain signaling in obesity. JO - Trends Endocrinol. Metab. VL - 36 IS - 1 PB - Cell Press PY - 2024 SN - 1043-2760 ER - TY - JOUR AB - Unimolecular co-agonists at the GLP-1/GIP receptors have recently achieved remarkable anti-obesogenic feats; yet, in a recent Phase 1 clinical trial, Véniant and colleagues report astounding body-weight loss, and an appreciable safety profile, in participants with obesity using the GLP-1R agonist/GIPR antagonist AMG 133. AU - Novikoff, A. AU - Müller, T.D. C1 - 70707 C2 - 55921 CY - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa SP - 566-568 TI - Antagonizing GIPR adds fire to the GLP-1R flame. JO - Trends Endocrinol. Metab. VL - 35 IS - 7 PB - Cell Press PY - 2024 SN - 1043-2760 ER - TY - JOUR AB - Brown adipose tissue (BAT) is often considered as a sink for nutrients to generate heat. However, when the complex hormonal and nervous inputs and intracellular signaling networks regulating substrate utilization are considered, BAT appears much more as a tightly controlled rheostat, regulating body temperature and balancing circulating nutrient levels. Here we provide an overview of key regulatory circuits, including the diurnal rhythm, determining glucose, fatty acid, and amino acid utilization and the interdependency of these nutrients in thermogenesis. Moreover, we discuss additional factors mediating sympathetic BAT activation beyond β-adrenergic signaling and the limitations of glucose-based BAT activity measurements to foster a better understanding and interpretation of BAT activity data. AU - Onogi, Y. AU - Ussar, S. C1 - 65032 C2 - 52134 SP - 493-506 TI - Regulatory networks determining substrate utilization in brown adipocytes. JO - Trends Endocrinol. Metab. VL - 33 IS - 7 PY - 2022 SN - 1043-2760 ER - TY - JOUR AB - Lipid peroxidation (LPO) is the molecular mechanism involved in oxidative damage of cellular membranes and the hallmark of a nonapoptotic form of cell death, known as ferroptosis. This iron-dependent cell death is an emerging strategy in cancer treatment and one of the central cell death mechanisms accounting for early cell loss and organ dysfunction in both neurodegenerative disease and ischemia-reperfusion injury. Although the biological roles of LPO products have attracted considerable attention, not only for their pathological mechanisms but also for their potential clinical application as biomarkers, the existence of a common lethal lipid death signal generated during ferroptosis remains poorly explored. A better understanding of the LPO process, however, may unleash unprecedented opportunities for therapeutic intervention of as-yet incurable diseases. AU - Aldrovandi, M. AU - Fedorova, M.* AU - Conrad, M. C1 - 62027 C2 - 50576 CY - 84 Theobalds Rd, London Wc1x 8rr, England SP - 463-473 TI - Juggling with lipids, a game of Russian roulette. JO - Trends Endocrinol. Metab. VL - 32 IS - 7 PB - Elsevier Science London PY - 2021 SN - 1043-2760 ER - TY - JOUR AB - The target of rapamycin complex 2 (TORC2) was discovered in 2002 in budding yeast. Its mammalian counterpart, mTORC2, was first described in 2004. Soon thereafter it was demonstrated that mTORC2 directly phosphorylates Akt on Ser473, ending a long search for the elusive 'second' insulin-responsive Akt kinase. In this review we discuss key evidence pertaining to the subcellular localization of mTORC2, highlighting a spatial heterogeneity that relates to mTORC2 activation. We summarize current models for how growth factors (GFs), such as insulin, trigger mTORC2 activation, and we provide a comprehensive discussion focusing on a new exciting frontier, the molecular mechanisms underpinning GF-independent activation of mTORC2. AU - Knudsen, J.R.* AU - Fritzen, A.M.* AU - James, D.E.* AU - Jensen, T.E.* AU - Kleinert, M. AU - Richter, E.A.* C1 - 57344 C2 - 47719 CY - 84 Theobalds Rd, London Wc1x 8rr, England SP - 13-24 TI - Growth factor-dependent and -independent activation of mTORC2. JO - Trends Endocrinol. Metab. VL - 31 IS - 1 PB - Elsevier Science London PY - 2020 SN - 1043-2760 ER - TY - JOUR AB - Nonalcoholic fatty liver disease (NAFLD) is becoming the most common liver disorder worldwide. Specifically, nonalcoholic steatohepatitis (NASH) and fibrosis pose an enormous burden for patients and health-care systems. In the absence of approved pharmacological therapies effective lifestyle interventions for NAFLD, such as dietary strategies and exercise training are currently the therapeutic strategies of choice. This review covers the influence of macro-nutrient quality and quantity (i.e., low-carbohydrate and high-protein diets), for successful reduction of intrahepatocellular lipids (IHL). Moreover, we discuss the effectiveness of different modalities of physical exercising with and without weight loss. These lifestyle modifications not only provide strategies to reduce IHL but may also hold a still underestimatec potential to induce improvement and/or even remission of NAFLD. AU - El-Agroudy, N.N.* AU - Kurzbach, A.* AU - Rodionov, R.N.* AU - O'Sullivan, J.* AU - Roden, M.* AU - Birkenfeld, A.L. AU - Pesta, D.H.* C1 - 56763 C2 - 47291 CY - 84 Theobalds Rd, London Wc1x 8rr, England SP - 701-709 TI - Are lifestyle therapies effective for NAFLD treatment? JO - Trends Endocrinol. Metab. VL - 30 IS - 10 PB - Elsevier Science London PY - 2019 SN - 1043-2760 ER - TY - JOUR AB - Brown and brown-like adipocytes are specialized adipocytes with a high capacity to convert metabolic energy to heat. This function is not only eminent in supporting organismal thermogenesis, but may also have potential in the fight against obesity. The latter has spurred a massive interest in understanding the development and regulation of these thermogenic adipocytes. Here, we review how genome-wide studies based on next-generation sequencing have provided insight into how the chromatin and transcriptional landscapes are established in thermogenic adipocytes and how thermogenic signals can change the genomic programming of white adipocytes. Furthermore, we discuss how the integration of genomic data can be used to discover novel transcriptional pathways that may be modulated as part of therapeutic strategies for the treatment of obesity. The development and thermogenic functions of brown adipocytes are regulated by coordinated actions of many different transcription factors, cofactors, noncoding RNAs, and histone modifiers.Activation of thermogenic transcriptional regulators can change the genomic programming of white adipocytes and lead to the formation of brown-like adipocytes.Integrative genomic approaches allow deciphering of the transcriptional networks that control the development and specialized functions of thermogenic adipocytes.Integrative genomic approaches may reveal novel transcriptional pathways that can be targeted to increase the thermogenic capacity of adipocytes. AU - Loft, A. AU - Forss, I.* AU - Mandrup, S.* C1 - 50323 C2 - 42323 CY - London SP - 104-120 TI - Genome-wide insights into the development and function of thermogenic adipocytes. JO - Trends Endocrinol. Metab. VL - 28 IS - 2 PB - Elsevier Science London PY - 2017 SN - 1043-2760 ER - TY - JOUR AB - The metabolome, although very dynamic, is sufficiently stable to provide specific quantitative traits related to health and disease. Metabolomics requires balanced use of state-of-the-art study design, chemical analytics, biostatistics, and bioinformatics to deliver meaningful answers to contemporary questions in human disease research. The technology is now frequently employed for biomarker discovery and for elucidating the mechanisms underlying endocrine-related diseases. Metabolomics has also enriched genome-wide association studies (GWAS) in this area by providing functional data. The contributions of rare genetic variants to metabolome variance and to the human phenotype have been underestimated until now. AU - Tokarz, J. AU - Haid, M. AU - Cecil, A. AU - Prehn, C. AU - Artati, A. AU - Möller, G. AU - Adamski, J. C1 - 51686 C2 - 43416 CY - London SP - 705-721 TI - Endocrinology meets metabolomics: Achievements, pitfalls, and challenges. JO - Trends Endocrinol. Metab. VL - 28 IS - 10 PB - Elsevier Science London PY - 2017 SN - 1043-2760 ER - TY - JOUR AB - Air pollution affects a large proportion of the global population. Air pollutants are hypothesized to exert their effects via impaired endothelial function, elevated systemic inflammation, mitochondrial dysfunction, and oxidative stress, all of which are hallmarks of type 2 diabetes (T2D). Here we review epidemiological studies aimed at answering whether diabetes patients are more vulnerable to ambient (outdoor) air pollution exposure and whether air pollution is associated with diabetes development or other predisposing conditions for T2D. Current evidence suggests an association between air pollution exposure and T2D, but more critical analysis is warranted. Understanding the associations between air pollution exposure and the development of T2D is critical in our efforts to control sources of air pollution and their impact on the disease. AU - Thiering, E. AU - Heinrich, J. C1 - 45181 C2 - 37261 CY - London SP - 384-394 TI - Epidemiology of air pollution and diabetes. JO - Trends Endocrinol. Metab. VL - 26 IS - 7 PB - Elsevier Science London PY - 2015 SN - 1043-2760 ER -