TY - JOUR AB - BACKGROUND: For characterizing health states, fat distribution is more informative than overall body size. We used population-based whole-body magnetic resonance imaging (MRI) to identify distinct body composition subphenotypes and characterize associations with cardiovascular disease (CVD) risk. METHODS: Bone marrow, visceral, subcutaneous, cardiac, renal, hepatic, skeletal muscle and pancreatic adipose tissue were measured by MRI in n = 299 individuals from the population-based KORA cohort. Body composition subphenotypes were identified by data-driven k-means clustering. CVD risk was calculated by established scores. RESULTS: We identified five body composition subphenotypes, which differed substantially in CVD risk factor distribution and CVD risk. Compared to reference subphenotype I with favorable risk profile, two high-risk phenotypes, III&V, had a 3.8-fold increased CVD risk. High-risk subphenotype III had increased bone marrow and skeletal muscle fat (26.3 % vs 11.4 % in subphenotype I), indicating ageing effects, whereas subphenotype V showed overall high fat contents, and particularly elevated pancreatic fat (25.0 % vs 3.7 % in subphenotype I), indicating metabolic impairment. Subphenotype II had a 2.7-fold increased CVD risk, and an unfavorable fat distribution, probably smoking-related, while BMI was only slightly elevated. Subphenotype IV had a 2.8-fold increased CVD risk with comparably young individuals, who showed high blood pressure and hepatic fat (17.7 % vs 3.0 % in subphenotype I). CONCLUSIONS: Whole-body MRI can identify distinct body composition subphenotypes associated with different degrees of cardiometabolic risk. Body composition profiling may enable a more comprehensive risk assessment than individual fat compartments, with potential benefits for individualized prevention. AU - Grune, E. AU - Nattenmüller, J.* AU - Kiefer, L.S.* AU - Machann, J. AU - Peters, A. AU - Bamberg, F.* AU - Schlett, C.L.* AU - Rospleszcz, S. C1 - 72921 C2 - 56818 CY - 1600 John F Kennedy Boulevard, Ste 1800, Philadelphia, Pa 19103-2899 Usa TI - Subphenotypes of body composition and their association with cardiometabolic risk - Magnetic resonance imaging in a population-based sample. JO - Metabolism VL - 164 PB - W B Saunders Co-elsevier Inc PY - 2025 SN - 0026-0495 ER - TY - JOUR AB - BACKGROUND AND AIMS: Adipose tissue function is integral to systemic metabolic homeostasis. Excessive adipose tissue growth is associated with development of chronic low-grade inflammation and whole body dysmetabolism. The cell metabolic pathways regulating adipose tissue growth and homeostasis are little understood. Here we studied the role of polyamine metabolism in adipose tissue (patho)physiology. METHODS: We generated mice with global and adipocyte progenitor (AP)-specific Antizyme inhibitor 2 (AZIN2) deficiency and performed diet-induced obesity studies. APs were isolated from the subcutaneous and gonadal adipose tissue of mice and cultured. RESULTS: Polyamine metabolism components, including AZIN2, were highly expressed in APs and their expression in the adipose tissue was downregulated with obesity. IL4 induced Azin2 expression in APs. AZIN2 facilitated polyamine synthesis and acetylation, and regulated total acetyl-CoA levels in APs. AZIN2 deficiency upregulated histone acetylation in genes related to lipid metabolism. Azin2-/- APs committed more efficiently to adipogenesis in vivo and in vitro, and were more prone to senescence compared to wild-type counterparts. Upon diet-induced obesity, global and AP-specific AZIN2 deficiency in mice provoked AP depletion, adipocyte hypertrophy, obesity, inflammation, glucose intolerance and insulin resistance. In human adipose tissue, AZIN2 expression strongly correlated with expression of progenitor markers. CONCLUSIONS: Altogether, we identified AZIN2 as a novel AP marker that regulates AP fate and preserves adipose tissue health. AU - Mund, C.* AU - Sinha, A.* AU - Aderhold, A.* AU - Mateska, I.* AU - Hagag, E.* AU - Traikov, S.* AU - Gercken, B.* AU - Soto, A.* AU - Pollock, J.* AU - Arndt, L.* AU - Wölk, M.* AU - Werner, N.* AU - Fodelianaki, G.* AU - Subramanian, P.* AU - Chung, K.J.* AU - Grossklaus, S.* AU - Langner, M.* AU - Elgendy, M.* AU - Grinenko, T.* AU - Wielockx, B.* AU - Dahl, A.* AU - Gericke, M.* AU - Blüher, M.* AU - Coskun, Ü. AU - Voehringer, D.* AU - Fedorova, M.* AU - Peitzsch, M.* AU - Murray, P.J.* AU - Chavakis, T. AU - Alexaki, V.I.* C1 - 75301 C2 - 57930 CY - 1600 John F Kennedy Boulevard, Ste 1800, Philadelphia, Pa 19103-2899 Usa TI - A key role of polyamine metabolism in adipose tissue homeostasis that regulates obesity. JO - Metabolism VL - 172 PB - W B Saunders Co-elsevier Inc PY - 2025 SN - 0026-0495 ER - TY - JOUR AU - Ribas Latre, A. AU - Heiker, J.T. C1 - 74205 C2 - 57367 CY - 1600 John F Kennedy Boulevard, Ste 1800, Philadelphia, Pa 19103-2899 Usa TI - Reply to: Reconsidering KLK7's role in adipose inflammation: Letter to the editor. JO - Metabolism VL - 169 PB - W B Saunders Co-elsevier Inc PY - 2025 SN - 0026-0495 ER - TY - JOUR AB - Obesity is a major health problem associated with global metabolic dysfunction and increased inflammation. It is thus critical to identify the mechanisms underlying the crosstalk between immune cells and adipose tissue that drive cardiovascular and metabolic dysfunction in obesity. Expression of the kallikrein-related serine protease 7 (KLK7) in adipose tissue is linked to inflammation and insulin resistance in high fat diet (HFD)-fed mice. Here, we engineered mice with a macrophage-specific KLK7 knockout (KLK7MKO) to investigate how KLK7 loss impacts immune cell function and obesity-related pathology. Compared to control mice, we observed lower levels of systemic inflammation, with less infiltration and activation of inflammatory macrophages in HFD-fed KLK7MKO mice, particularly in the epididymal adipose tissue. Mechanistically, we uncover that Klk7 deficiency reduces pro-inflammatory gene expression in macrophages and restricts their migration through higher cell adhesion, hallmark features of macrophages in obese conditions. Importantly, through analyses of 1143 human visceral adipose tissue samples, we uncover that KLK7 expression is associated with pathways controlling cellular migration and inflammatory gene expression. In addition, serum KLK7 levels were strongly correlated with circulating inflammatory markers in a second cohort of 60 patients with obesity and diabetes. Our work uncovers the pro-inflammatory role of KLK7 in controlling inflammatory macrophage polarization and infiltration in visceral obesity, thereby contributing to metabolic disease. Thus, targeting KLK7 to control immune cell activation may dissociate adipose dysfunction from obesity, thereby representing an alternative obesity therapy. AU - Ribas Latre, A. AU - Hoffmann, A. AU - Gebhardt, C. AU - Weiner, J.* AU - Arndt, L.* AU - Raulien, N.* AU - Gericke, M.* AU - Ghosh, A.* AU - Krause, K.* AU - Klöting, N. AU - Pfluger, P.T. AU - Sheikh, B. AU - Ebert, T.* AU - Tönjes, A.* AU - Stumvoll, M. AU - Wolfrum, C.* AU - Blüher, M. AU - Wagner, U.* AU - Vendrell, J.* AU - Fernández-Veledo, S.* AU - Heiker, J.T. C1 - 73798 C2 - 57232 CY - 1600 John F Kennedy Boulevard, Ste 1800, Philadelphia, Pa 19103-2899 Usa TI - The serine protease KLK7 promotes immune cell infiltration in visceral adipose tissue in obesity. JO - Metabolism VL - 168 PB - W B Saunders Co-elsevier Inc PY - 2025 SN - 0026-0495 ER - TY - JOUR AB - OBJECTIVE: Individuals at increased risk of type 2 diabetes have recently been classified into six prediabetes clusters, which stratify the risk of progression to diabetes and diabetes complications. Clusters 1, 2 and 4 are low-risk clusters while clusters 3, 5 and 6 are high-risk clusters; individuals in cluster 6 have an elevated risk of nephropathy and all-cause mortality despite delayed onset of diabetes. The urinary peptidome classifiers CKD273 (chronic kidney disease, CKD), HF2 (heart failure, HF) and CAD238 (coronary artery disease, CAD) are based on unique urinary peptide patterns and have shown potential for identifying individuals at risk for CKD and cardiovascular pathologies. This observational study investigates whether peptidome classifiers can differentiate complication risks across the prediabetes clusters and if a novel combination of peptides can distinguish high-risk from low-risk prediabetes clusters. METHODS: Urine peptidome analysis was performed on spot urine samples from individuals across 6 prediabetes clusters (n = 249) and 19 individuals with screen-detected diabetes (study cohorts at University Hospital Tübingen, Germany from 11/2004 to 11/2012). Predefined urinary classifiers were calculated for each participant. Lasso regression analysis was used to identify an optimal combination of peptides distinguishing low- Schlesinger et al. (2022), Wagner et al. (2021) [1,2,4] and high-risk (Rooney et al., 2021; Wagner, 2023; Latosinska et al., 2021 [3,5,6]) clusters. RESULTS: The predefined urinary peptidome classifiers CKD273, HF2 and CAD238 differed significantly across prediabetes clusters, particularly with elevated values in cluster 6 compared to the healthiest cluster 2. CKD273, HF2 and CAD238 were inversely associated with insulin sensitivity indexes. Machine Learning identified a combination of 112 urinary peptides that differentiated low-risk from high-risk prediabetes clusters (AUC-ROC 0.868 (95 % CI 0.755-0.981)). CONCLUSIONS: Urinary peptidome classifiers support the increased risk of CKD and suggest an elevated risk of heart failure and coronary artery disease in the high-risk prediabetes cluster 6. Urine peptidomics show promising potential as a tool for identifying high-risk prediabetes individuals and guiding early preventive interventions. AU - Schork, A. AU - Fritsche, A. AU - Schleicher, E.D.* AU - Peter, A.* AU - Heni, M. AU - Stefan, N. AU - Jumpertz von Schwartzenberg, R. AU - Guthoff, M. AU - Mischak, H.* AU - Siwy, J.* AU - Birkenfeld, A.L. AU - Wagner, R. C1 - 73578 C2 - 57116 CY - 1600 John F Kennedy Boulevard, Ste 1800, Philadelphia, Pa 19103-2899 Usa TI - Differential risk assessment in persons at risk of type 2 diabetes using urinary peptidomics. JO - Metabolism VL - 167 PB - W B Saunders Co-elsevier Inc PY - 2025 SN - 0026-0495 ER - TY - JOUR AB - BACKGROUND: High 1-h-post-load plasma glucose (1 h-PG) is an early diabetes risk marker. We hypothesized that isolated high 1 h-PG represents an intermediate state between normal glucose regulation (NGR) and impaired glucose regulation (IGR) and is amendable to greater lifestyle intervention (LI) benefit. METHODS: In the Tübingen Lifestyle Intervention Program, 317 people with either NGR, IGR or isolated high 1 h-PG without IGR underwent LI for 9 months to achieve ≥5 % weight loss. RESULTS: Before LI initiation, insulin sensitivity and β-cell function declined progressively from NGR (n = 106) to high 1 h-PG (n = 96) and to IGR (n = 115). Visceral adipose tissue (VAT) volume and liver fat content increased from NGT to high 1 h-PG and to IGR. LI improved insulin sensitivity and ß-cell function in the high 1 h-PG group to levels observed in NGR together with a marked reduction in hepatic fat content. Compared to the IGR group, T2D risk was reduced by 80 % (37-96 %, p = 0.005) in the high 1 h-PG group during a 12-year follow-up period. The odds of remission to complete normoglycemia were doubled in the high 1 h-PG group compared to the IGR group (2.18 [1.13-4.28], p = 0.021). CONCLUSION: High 1 h-PG indicates an intermediate metabolic state with pathophysiological changes more severe than in NGR but milder than in IGR. In people with high 1 h-PG, LI significantly improved insulin sensitivity and β-cell function and reduced ectopic lipid deposition and the risk of developing T2D compared to IGR. These findings highlight the value of 1 h-PG as a clinically useful biomarker, providing a critical window for early intervention to reverse core metabolic defects driving prediabetes and T2D. AU - Wang, Y. AU - Sandforth, A. AU - Jumpertz von Schwartzenberg, R. AU - Ganslmeier, M. AU - Cheng, Y. AU - Sandforth, L. AU - Katzenstein, S. AU - Machann, J. AU - Schick, F. AU - Kantartzis, K. AU - Preissl, H. AU - Fritsche, A. AU - Stefan, N. AU - Bergman, M.* AU - Birkenfeld, A.L. C1 - 75967 C2 - 58288 CY - 1600 John F Kennedy Boulevard, Ste 1800, Philadelphia, Pa 19103-2899 Usa SP - 7 TI - Lifestyle intervention is more effective in high 1-hour post-load glucose than in prediabetes for restoring β-cell function, reducing ectopic fat, and preventing type 2 diabetes. JO - Metabolism VL - 174 PB - W B Saunders Co-elsevier Inc PY - 2025 SN - 0026-0495 ER - TY - JOUR AB - BACKGROUND: Steatotic liver disease (SLD) is characterized by excessive accumulation of lipids in the liver. It is associated with elevated risk of hepatic and cardiometabolic diseases, as well as mental disorders such as depression. Previous studies revealed global gray matter reduction in SLD. To investigate a possible shared neurobiology with depression, we examined liver-fat-related regional gray matter alterations in SLD and its most significant clinical subgroup metabolic dysfunction-associated steatotic liver disease (MASLD). METHODS: We analyzed regional cortical thickness and area obtained from brain MRI in 29,051 participants in UK Biobank. Liver fat amount was computed as proton density fat fraction (PDFF) from liver MRI scans. We examined the relationship between brain structure and PDFF, adjusting for sociodemographic, physical, lifestyle, and environmental factors, as well as alcohol intake and a spectrum of cardiometabolic covariates. Finally, we compared patterns of brain alterations in SLD/MASLD and major depressive disorder (MDD) using previously published results. RESULTS: PDFF-related gray matter alterations were region-specific, involving both increases and decreases in cortical thickness, and increased cortical area. In several regions, PDFF effects on gray matter could also be attributed to cardiometabolic covariates. However, PDFF was consistently associated with lower cortical thickness in middle and superior temporal areas and higher cortical thickness in pericalcarine and right frontal pole areas. PDFF-related alterations for the SLD and the MASLD group correlated with those observed in MDD (Pearson r = 0.45-0.54, p < 0.01). CONCLUSION: These findings suggest the presence of shared biological mechanisms linking MDD to SLD and MASLD. They might explain the well-known elevated risk of depression in these groups and support early lifestyle interventions and treatment of metabolic risk factors for the successful management of the interconnected diseases depression and SLD/MASLD. AU - Arold, D.* AU - Bornstein, S.R. AU - Perakakis, N. AU - Ehrlich, S.* AU - Bernardoni, F.* C1 - 71400 C2 - 56108 CY - 1600 John F Kennedy Boulevard, Ste 1800, Philadelphia, Pa 19103-2899 Usa TI - Regional gray matter changes in steatotic liver disease provide a neurobiological link to depression: A cross-sectional UK biobank cohort study. JO - Metabolism VL - 159 PB - W B Saunders Co-elsevier Inc PY - 2024 SN - 0026-0495 ER - TY - JOUR AB - In Wilson disease (WD), liver copper (Cu) excess, caused by mutations in the ATPase Cu transporting beta (ATP7B), has been extensively studied. In contrast, in the gastrointestinal tract, responsible for dietary Cu uptake, ATP7B malfunction is poorly explored. We therefore investigated gut biopsies from WD patients and compared intestines from two rodent WD models and from human ATP7B knock-out intestinal cells to their respective wild-type controls. We observed gastrointestinal (GI) inflammation in patients, rats and mice lacking ATP7B. Mitochondrial alterations and increased intestinal leakage were observed in WD rats, Atp7b-/- mice and human ATP7B KO Caco-2 cells. Proteome analyses of intestinal WD homogenates revealed profound alterations of energy and lipid metabolism. The intestinal damage in WD animals and human ATP7B KO cells did not correlate with absolute Cu elevations, but likely reflects intracellular Cu mislocalization. Importantly, Cu depletion by the high-affinity Cu chelator methanobactin (MB) restored enterocyte mitochondria, epithelial integrity, and resolved gut inflammation in WD rats and human WD enterocytes, plausibly via autophagy-related mechanisms. Thus, we report here before largely unrecognized intestinal damage in WD, occurring early on and comprising metabolic and structural tissue damage, mitochondrial dysfunction, and compromised intestinal barrier integrity and inflammation, that can be resolved by high-affinity Cu chelation treatment. AU - Fontes, A. AU - Pierson, H.* AU - Bierła, J.B.* AU - Eberhagen, C. AU - Kinschel, J.* AU - Akdogan, B. AU - Rieder, T.* AU - Sailer, J.* AU - Reinold, Q.* AU - Cielecka-Kuszyk, J.* AU - Szymanska, S.* AU - Neff, F.* AU - Steiger, K.* AU - Seelbach, O.* AU - Zibert, A.* AU - Schmidt, H.H.* AU - Hauck, S.M. AU - von Toerne, C. AU - Michalke, B. AU - Semrau, J.D.* AU - DiSpirito, A.M.* AU - Ramalho-Santos, J.* AU - Kroemer, G.* AU - Polishchuk, R.S.* AU - Azul, A.M.* AU - DiSpirito, A.* AU - Socha, P.* AU - Lutsenko, S.* AU - Zischka, H. C1 - 71097 C2 - 55912 CY - 1600 John F Kennedy Boulevard, Ste 1800, Philadelphia, Pa 19103-2899 Usa TI - Copper impairs the intestinal barrier integrity in Wilson disease. JO - Metabolism VL - 158 PB - W B Saunders Co-elsevier Inc PY - 2024 SN - 0026-0495 ER - TY - JOUR AB - Metabolic dysfunction-associated steatotic liver disease (MASLD) poses a significant and ever-increasing health and economic burden worldwide. Substantial epidemiological evidence shows that MASLD is a multisystem disease that is associated not only with liver-related complications but is also associated with an increased risk of developing cardiometabolic comorbidities and extrahepatic cancers (principally gastrointestinal [GI] cancers). GI cancers account for a quarter of the global cancer incidence and a third of cancer-related deaths. In this narrative review, we provide an overview of the literature on (a) the epidemiological data on the risk of non-liver GI cancers in MASLD, (b) the putative mechanisms by which MASLD (and factors linked with MASLD) may increase this risk, and (c) the possible pharmacotherapies beneficially affecting both MASLD and extrahepatic GI cancer risk. There are multiple potential pathophysiological mechanisms by which MASLD may increase extrahepatic GI cancer risk. Although further studies are needed, the current evidence supports a possible extrahepatic carcinogenic role for MASLD, regardless of obesity and diabetes status, thus highlighting the potential role of tailoring cancer screening for individuals with MASLD. Although there are conflicting data in the literature, aspirin, statins and metformin appear to exert some chemo-preventive effects against GI cancer. AU - Mantovani, A.* AU - Lonardo, A.* AU - Stefan, N. AU - Targher, G.* C1 - 71522 C2 - 56233 CY - 1600 John F Kennedy Boulevard, Ste 1800, Philadelphia, Pa 19103-2899 Usa TI - Metabolic dysfunction-associated steatotic liver disease and extrahepatic gastrointestinal cancers. JO - Metabolism VL - 160 PB - W B Saunders Co-elsevier Inc PY - 2024 SN - 0026-0495 ER - TY - JOUR AB - Leptin has been established as the prototype adipose tissue secreted hormone and as a major regulator of several human physiology functions. Here, we are primarily reviewing the findings from studies in humans involving leptin administration. We are describing the metabolic, endocrine and immunologic effects of leptin replacement in conditions of leptin deficiency, such as short-term fasting in healthy individuals, relative energy deficiency in sports (REDS), congenital leptin deficiency (CLD), generalized (GL) and partial lipodystrophy (PL), HIV-associated lipodystrophy (HIV-L) and of leptin treatment in conditions of leptin excess (common obesity, type 2 diabetes, steatotic liver disease). We are comparing the results with the findings from preclinical models and present the main conclusions regarding the role of leptin in human physiology, pathophysiology and therapeutics. We conclude that, in conditions of energy deficiency, leptin substitution effectively reduces body weight and fat mass through reduction of appetite, it improves hypertriglyceridemia, insulin resistance and hepatic steatosis (especially in GL and PL), it restores neuroendocrine function (especially the gonadotropic axis), it regulates adaptive immune system cell populations and it improves bone health. On the contrary, leptin treatment in conditions of leptin excess, such as common obesity and type 2 diabetes, does not improve any metabolic abnormalities. Strategies to overcome leptin tolerance/resistance in obesity and type 2 diabetes have provided promising results in animal studies, which should though be tested in humans in randomized clinical trials. AU - Perakakis, N. AU - Mantzoros, C.S.* C1 - 72220 C2 - 56492 TI - Leptin in humans: Evidence from clinical studies and current and future clinical applications. JO - Metabolism VL - 161 PY - 2024 SN - 0026-0495 ER - TY - JOUR AB - BACKGROUND: Cancer cachexia (CCx) presents a multifaceted challenge characterized by negative protein and energy balance and systemic inflammatory response activation. While previous CCx studies predominantly focused on mouse models or human body fluids, there's an unmet need to elucidate the molecular inter-organ cross-talk underlying the pathophysiology of human CCx. METHODS: Spatial metabolomics were conducted on liver, skeletal muscle, subcutaneous and visceral adipose tissue, and serum from cachectic and control cancer patients. Organ-wise comparisons were performed using component, pathway enrichment and correlation network analyses. Inter-organ correlations in CCx altered pathways were assessed using Circos. Machine learning on tissues and serum established classifiers as potential diagnostic biomarkers for CCx. RESULTS: Distinct metabolic pathway alteration was detected in CCx, with adipose tissues and liver displaying the most significant (P ≤ 0.05) metabolic disturbances. CCx patients exhibited increased metabolic activity in visceral and subcutaneous adipose tissues and liver, contrasting with decreased activity in muscle and serum compared to control patients. Carbohydrate, lipid, amino acid, and vitamin metabolism emerged as highly interacting pathways across different organ systems in CCx. Muscle tissue showed decreased (P ≤ 0.001) energy charge in CCx patients, while liver and adipose tissues displayed increased energy charge (P ≤ 0.001). We stratified CCx patients by severity and metabolic changes, finding that visceral adipose tissue is most affected, especially in cases of severe cachexia. Morphometric analysis showed smaller (P ≤ 0.05) adipocyte size in visceral adipose tissue, indicating catabolic processes. We developed tissue-based classifiers for cancer cachexia specific to individual organs, facilitating the transfer of patient serum as minimally invasive diagnostic markers of CCx in the constitution of the organs. CONCLUSIONS: These findings support the concept of CCx as a multi-organ syndrome with diverse metabolic alterations, providing insights into the pathophysiology and organ cross-talk of human CCx. This study pioneers spatial metabolomics for CCx, demonstrating the feasibility of distinguishing cachexia status at the organ level using serum. AU - Sun, N. AU - Krauss, T.* AU - Seeliger, C.* AU - Kunzke, T. AU - Stöckl, B. AU - Feuchtinger, A. AU - Zhang, C.-Y. AU - Voss, A. AU - Heisz, S.* AU - Prokopchuk, O.* AU - Martignoni, M.E.* AU - Janssen, K.P.* AU - Claussnitzer, M.* AU - Hauner, H.* AU - Walch, A.K. C1 - 71781 C2 - 56289 CY - 1600 John F Kennedy Boulevard, Ste 1800, Philadelphia, Pa 19103-2899 Usa TI - Inter-organ cross-talk in human cancer cachexia revealed by spatial metabolomics. JO - Metabolism VL - 161 PB - W B Saunders Co-elsevier Inc PY - 2024 SN - 0026-0495 ER - TY - JOUR AB - BACKGROUND: The capacity of a polyphenol-enriched diet to modulate the epigenome in vivo is partly unknown. Given the beneficial metabolic effects of a Mediterranean (MED) diet enriched in polyphenols and reduced in red/processed meat (green-MED), as previously been proven by the 18-month DIRECT PLUS randomized controlled trial, we analyzed the effects of the green-MED diet on methylome and transcriptome levels to highlight molecular mechanisms underlying the observed metabolic improvements. METHODS: Our study included 260 participants (baseline BMI = 31.2 kg/m2, age = 5 years) of the DIRECT PLUS trial, initially randomized to one of the intervention arms: A. healthy dietary guidelines (HDG), B. MED (440 mg polyphenols additionally provided by walnuts), C. green-MED (1240 mg polyphenols additionally provided by walnuts, green tea, and Mankai: green duckweed shake). Blood methylome and transcriptome of all study subjects were analyzed at baseline and after completing the 18-month intervention using Illumina EPIC and RNA sequencing technologies. RESULTS: A total of 1573 differentially methylated regions (DMRs; false discovery rate (FDR) < 5 %) were found in the green-MED compared to the MED (177) and HDG (377) diet participants. This corresponded to 1753 differentially expressed genes (DEGs; FDR < 5 %) in the green-MED intervention compared to MED (7) and HDG (738). Consistently, the highest number (6 %) of epigenetic modulating genes was transcriptionally changed in subjects participating in the green-MED intervention. Weighted cluster network analysis relating transcriptional and phenotype changes among participants subjected to the green-MED intervention identified candidate genes associated with serum-folic acid change (all P < 1 × 10-3) and highlighted one module including the KIR3DS1 locus, being negatively associated with the polyphenol changes (e.g. P < 1 × 10-4), but positively associated with the MRI-assessed superficial subcutaneous adipose area-, weight- and waist circumference- 18-month change (all P < 0.05). Among others, this module included the DMR gene Cystathionine Beta-Synthase, playing a major role in homocysteine reduction. CONCLUSIONS: The green-MED high polyphenol diet, rich in green tea and Mankai, renders a high capacity to regulate an individual's epigenome. Our findings suggest epigenetic key drivers such as folate and green diet marker to mediate this capacity and indicate a direct effect of dietary polyphenols on the one‑carbon metabolism. AU - Hoffmann, A. AU - Meir, A.Y.* AU - Hagemann, T. AU - Czechowski, P. AU - Müller, L.* AU - Engelmann, B.* AU - Haange, S.B.* AU - Rolle-Kampczyk, U.* AU - Tsaban, G.* AU - Zelicha, H.* AU - Rinott, E.* AU - Kaplan, A.* AU - Shelef, I.* AU - Stumvoll, M. AU - Blüher, M. AU - Liang, L.* AU - Ceglarek, U.* AU - Isermann, B.* AU - von Bergen, M.* AU - Kovacs, P.* AU - Keller, M. AU - Shai, I.* C1 - 67886 C2 - 54364 CY - 1600 John F Kennedy Boulevard, Ste 1800, Philadelphia, Pa 19103-2899 Usa TI - A polyphenol-rich green Mediterranean diet enhances epigenetic regulatory potential: The DIRECT PLUS randomized controlled trial. JO - Metabolism VL - 145 PB - W B Saunders Co-elsevier Inc PY - 2023 SN - 0026-0495 ER - TY - JOUR AB - OBJECTIVES: Recent studies suggested obesity to be a possible risk factor for COVID-19 disease in the wake of the coronavirus (SARS-CoV-2) infection. However, the causality and especially the role of body fat distribution in this context is still unclear. Thus, using a univariable as well as multivariable two-sample Mendelian randomization (MR) approach, we investigated for the first time the causal impact of body composition on the susceptibility and severity of COVID-19. METHODS: As indicators of overall and abdominal obesity we considered the measures body mass index (BMI), waist circumference (WC), and trunk fat ratio (TFR). Summary statistics of genome-wide association studies (GWASs) for these body composition measures were drawn from the GIANT consortium and UK Biobank, while for susceptibility and severity due to COVID-19 disease data from the COVID-19 Host Genetics Initiative was used. For the COVID-19 cohort neither age nor gender was available. Total and direct causal effect estimates were calculated using Single Nucleotide Polymorphisms (SNPs), sensitivity analyses were done applying several robust MR techniques and mediation effects of type 2 diabetes (T2D) and cardiovascular diseases (CVD) were investigated within multivariable MR analyses. RESULTS: Genetically predicted BMI was strongly associated with both, susceptibility (OR = 1.31 per 1 SD increase; 95% CI: 1.15-1.50; P-value = 7.3·10-5) and hospitalization (OR = 1.62 per 1 SD increase; 95% CI: 1.33-1.99; P-value = 2.8·10-6) even after adjustment for genetically predicted visceral obesity traits. These associations were neither mediated substantially by T2D nor by CVD. Finally, total but not direct effects of visceral body fat on outcomes could be detected. CONCLUSIONS: This study provides strong evidence for a causal impact of overall obesity on the susceptibility and severity of COVID-19 disease. The impact of abdominal obesity was weaker and disappeared after adjustment for BMI. Therefore, obese people should be regarded as a high-risk group. Future research is necessary to investigate the underlying mechanisms linking obesity with COVID-19. AU - Freuer, D. AU - Linseisen, J. AU - Meisinger, C. C1 - 61476 C2 - 50281 CY - 1600 John F Kennedy Boulevard, Ste 1800, Philadelphia, Pa 19103-2899 Usa TI - Impact of body composition on COVID-19 susceptibility and severity: A two-sample multivariable Mendelian randomization study. JO - Metabolism VL - 118 PB - W B Saunders Co-elsevier Inc PY - 2021 SN - 0026-0495 ER - TY - JOUR AB - AIMS/HYPOTHESIS: Besides insulin resistance, type 2 diabetes associates with decreased hepatic insulin clearance (HIC). We now tested for causal relationship of HIC to liver fat accumulation or features of the metabolic syndrome. METHODS: HIC was derived from oral glucose tolerance tests with the "Oral C-peptide and Insulin Minimal Models" (n = 3311). Liver fat was quantified by magnetic resonance spectroscopy (n = 1211). Mendelian Randomization was performed using established single nucleotide polymorphisms (SNPs; 115 for liver fat, 155 alanine-aminotransferase, 37 insulin sensitivity, 37 insulin secretion, 72 fasting insulin, 5285 BMI, 163 visceral fat, 270 waist circumference, 442 triglycerides, 620 HDL-Cholesterol, 193C-reactive protein, 53 lipodystrophy-like phenotypes). RESULTS: HIC associated inversely with liver fat (p < 0.003) and insulin sensitivity (p < 0.0001). Both liver fat and HIC were independently associated with insulin sensitivity (p < 0.0001). Neither liver fat nor alanine-aminotransferase were causally linked to HIC, as indicated by Mendelian Randomization (Nliver fat = 1054, NHIC = 2254; Nalanine aminotranferase = 1985, NHIC = 2251). BMI-related SNPs were causally associated with HIC (NBMI = 2772, NHIC = 2259, p < 0.001) but not waist circumference-SNPs (NSNPs-waist circumference = 2751, NHIC = 2280). Genetically determined insulin sensitivity was not causally related to HIC (Ninsulin sensitivity = 2752, NHIC = 2286). C-reactive protein and HDL were causally associated with HIC, with higher C-reactive protein and lower HDL leading to higher HIC (NC-reactive protein = 2660, NHIC = 2240; NHDL = 2694, NHIC = 2275). CONCLUSIONS: This Mendelian Randomization analysis does not support a causal link between hepatic steatosis and HIC. Other components of the metabolic syndrome seem to compensate peripheral hyperinsulinemia by increasing hepatic insulin extraction. AU - Lamprinou, A. AU - Willmann, C. AU - Machann, J. AU - Schick, F. AU - Eckstein, S.S. AU - Man, C.D.* AU - Visentin, R.* AU - Birkenfeld, A.L. AU - Peter, A. AU - Stefan, N. AU - Häring, H.-U. AU - Fritsche, A. AU - Heni, M. AU - Wagner, R. C1 - 61843 C2 - 50198 CY - 1600 John F Kennedy Boulevard, Ste 1800, Philadelphia, Pa 19103-2899 Usa TI - Determinants of hepatic insulin clearance - results from a Mendelian Randomization study. JO - Metabolism VL - 119 PB - W B Saunders Co-elsevier Inc PY - 2021 SN - 0026-0495 ER - TY - JOUR AB - Background: Deficiency in the leptin-leptin receptor (LEPR) axis leads to severe, and potentially treatable, obesity in humans. To guide clinical decision-making, the functional relevance of variants in the LEPR gene needs to be carefully investigated. Cases and methods: We characterized the functional impact of LEPR variants identified in two patients with severe early-onset obesity (1: compound heterozygous for the novel variant p.Tyr411del and p.Trp664Arg; 2: heterozygous for p.Arg612His) by investigating leptin-mediated signaling, leptin binding, receptor expression on cell surfaces, and receptor dimerization and activation for either wild-type and/or mutant LEPR. Results: Leptin-induced STAT3-phosphorylation was blunted the novel p.Tyr411del or the p.Trp664Arg variant and mildly reduced with the p.Arg612His variant. Computational structure prediction suggested impaired leptin binding for all three LEPR variants. Experimentally, reduced leptin binding of all mutant proteins was due to diminished LEPR expression on the cell surface, with the p.Trp664Arg mutations being the most affected. Considering the heterozygosity in our patients, we assessed the heterodimerization capacity with the wild-type LEPR, which was retained for the p.Tyr411del and p.Arg612His variants. Finally, mimicking (compound) heterozygosity, we confirmed abolished STAT3-phosphorylation for the variant combination [p.Tyr411del + p.Trp664Arg] as found in patient 1, whereas it was retained for [p.Arg612His + wilde type] as found in patient 2. Conclusions: The novel p.Tyr411del mutation causes complete loss of function alone (and combined with p.Trp664Arg) and is likely the cause for the early onset obesity, qualifying the patient for pharmacologic treatment. Heterozygosity for the p.Arg612His variant, however, appears unlikely to be solely responsible for the phenotype. AU - Voigtmann, F.* AU - Wolf, P.* AU - Landgraf, K.* AU - Stein, R. AU - Kratzsch, J.* AU - Schmitz, S.* AU - Abou Jamra, R.* AU - Blüher, M. AU - Meiler, J.* AU - Beck-Sickinger, A.G.* AU - Kiess, W.* AU - Körner, A.* C1 - 60884 C2 - 49572 CY - 1600 John F Kennedy Boulevard, Ste 1800, Philadelphia, Pa 19103-2899 Usa TI - Identification of a novel leptin receptor (LEPR) variant and proof of functional relevance directing treatment decisions in patients with morbid obesity. JO - Metabolism VL - 116 PB - W B Saunders Co-elsevier Inc PY - 2021 SN - 0026-0495 ER - TY - JOUR AB - Background: An adequate metabolic and hormonal response to the switch from rest to exercise is critical for the health benefits of exercise interventions. Previous work suggests that this response is impaired with overweight/obesity but the specific differences between overweight/obese and lean individuals remain unclear. Methods: We compared glucose and non-esterified fatty acid (NEFA) regulation and the changes of key homeostatic hormones during 45 min of moderate exercise between 17 overweight/obese and 28 lean premenopausal women. For this comparison, we implemented an exercise protocol at 60% of individual peak oxygen uptake, with frequent blood sampling and under fasting conditions. Results: We found that at the same exercise intensity in the overweight/obese and the lean group of women, the metabolic and hormonal response differed. In contrast to the lean group, the overweight/obese group portrayed an activation in the stress axis (adrenocorticotropic hormone (ACTH)/cortisol) and a lower growth hormone (hGH) response and exercise-increase of plasma NEFA. Both groups, however, displayed increased insulin sensitivity during exercise that was accompanied by a normalization of the elevated fasting glucose in the overweight/obese group after 15–20 min. Conclusion: We conclude that the response to exercise in overweight/obese subjects indeed differs from that in lean individuals. Additionally, we demonstrate that exercise can elicit beneficial (improved glucose regulation) and unwanted effects (stress axis activation) in overweight/obese subjects at the same time. This second finding suggests that exercise interventions for overweight/obese subjects need careful consideration of intensity and dose in order to achieve the intended results and avoid acute, undesired reactions. AU - Gar, C. AU - Rottenkolber, M. AU - Haenelt, M.* AU - Potzel, A. AU - Kern-Matschilles, S. AU - Then, C. AU - Seissler, J. AU - Bidlingmaier, M.* AU - Lechner, A. C1 - 58869 C2 - 48632 CY - 1600 John F Kennedy Boulevard, Ste 1800, Philadelphia, Pa 19103-2899 Usa TI - Altered metabolic and hormonal responses to moderate exercise in overweight/obesity. JO - Metabolism VL - 107 PB - W B Saunders Co-elsevier Inc PY - 2020 SN - 0026-0495 ER - TY - JOUR AB - Background: Adaptive thermogenesis during prolonged energy deficit refers to the greater than expected reduction in energy expenditure (EE) independent of concomitant loss of metabolically active body mass.Objective: As inter-individual variability in the magnitude of adaptive thermogenesis may influence the extent of energy deficit thereby predicting the amount of weight reduction, we investigated whether early adaptive thermogenesis is a determinant of weight loss after 6 weeks of daily 50% caloric restriction in an inpatient setting.Design and methods: The current study reports the results of an exploratory, secondary analysis in overweight but otherwise healthy subjects (n=11, 7 men, 35 +/- 9y, BMI 40 +/- 7 kg/m(2), body fat 633 +/- 5.3%). Body composition and 24-h EL (24hEE) measurement in a whole-room indirect calorimeter were used to calculate the magnitude of adaptive thermogenesis while on caloric restriction after 1, and 6 weeks. Energy deficit during caloric restriction was quantified via food, stool, and urine bomb calorimetry. Fasting hormonal concentrations (FF4, FT3 FGF21, leptin) were obtained at baseline and at weeks 3 and 6 during caloric restriction.Results: The magnitude of adaptive thermogenesis in 24hEE after 1 week of caloric restriction was 178 137 kcal/day (mean +/- SD), was overall stable during and following caloric restriction, and demonstrated remarkable intra-individual consistency. A relatively greater decrease in 24hEE of 100 kcal/d after 1 week of caloric restriction was associated on average with reduced energy deficit by 8195 kcal over 6 weeks and predicted 2.0 kg less weight loss, of which 0.5 kg was fat mass, after 6 weeks. No correlations were found between hormonal concentrations and weight loss.Conclusions: The extent of weight loss is influenced by the magnitude of adaptive thermogenesis in the early stage of caloric restriction. Although these results need replication in larger study groups with adequate statistical power, targeting adaptive thermogenesis may help to optimize long-term interventions in obesity therapy. Published by Elsevier Inc. AU - Heinitz, S. AU - Hollstein, T.* AU - Ando, T.* AU - Walter, M.* AU - Basolo, A.* AU - Krakoff, J.* AU - Votruba, S.B.* AU - Piaggi, P.* C1 - 59684 C2 - 49012 CY - 1600 John F Kennedy Boulevard, Ste 1800, Philadelphia, Pa 19103-2899 Usa TI - Early adaptive thermogenesis is a determinant of weight loss after six weeks of caloric restriction in overweight subjects. JO - Metabolism VL - 110 PB - W B Saunders Co-elsevier Inc PY - 2020 SN - 0026-0495 ER - TY - JOUR AB - Objective: Ectopic fat accumulation in the pancreas in response to obesity and its implication on the onset of type 2 diabetes remain poorly understood. Intermittent fasting (IF) is known to improve glucose homeostasis and insulin resistance. However, the effects of IF on fat in the pancreas and beta-cell function remain largely unknown. Our aim was to evaluate the impact of IF on pancreatic fat accumulation and its effects on islet function.Methods: New Zealand Obese (NZO) mice were fed a high-fat diet ad libitum (NZO-AL) or fasted every other day (intermittent fasting, NZO-IF) and pancreatic fat accumulation, glucose homoeostasis, insulin sensitivity, and islet function were determined and compared to ad libitum-fed B6.V-Lep(ob/ob) (ob/ob) mice. To investigate the crosstalk of pancreatic adipocytes and islets, co-culture experiments were performed.Results: NZO-IF mice displayed better glucose homeostasis and lower fat accumulation in both the pancreas (-32%) and the liver (-35%) than NZO-AL mice. Ob/ob animals were insulin-resistant and had low fat in the pancreas but high fat in the liver. NZO-AL mice showed increased fat accumulation in both organs and exhibited an impaired islet function. Co-culture experiments demonstrated that pancreatic adipocytes induced a hypersecretion of insulin and released higher levels of free fatty adds than adipocytes of inguinal white adipose tissue.Conclusions: These results suggest that pancreatic fat participates in diabetes development, but can be prevented by IF. AU - Quiclet, C.* AU - Dittberner, N.* AU - Gässler, A.* AU - Stadion, M.* AU - Gerst, F. AU - Helms, A.* AU - Baumeier, C.* AU - Schulz, T.J. AU - Schürmann, A.* C1 - 56093 C2 - 46812 CY - 1600 John F Kennedy Boulevard, Ste 1800, Philadelphia, Pa 19103-2899 Usa SP - 9-17 TI - Pancreatic adipocytes mediate hypersecretion of insulin in diabetes-susceptible mice. JO - Metabolism VL - 97 PB - W B Saunders Co-elsevier Inc PY - 2019 SN - 0026-0495 ER - TY - JOUR AB - BACKGROUND: The activation of hepatic stellate cells (HSCs) plays a crucial role in liver fibrosis, however the role of HSCs is less understood in hepatic insulin resistance. Since in the liver cGMP-dependent protein kinase I (cGKI) was detected in HSC but not in hepatocytes, and cGKI-deficient mice that express cGKI selectively in smooth muscle but not in other cell types (cGKI-SM mice) displayed hepatic insulin resistance, we hypothesized that cGKI modulates HSC activation and insulin sensitivity. MATERIALS AND METHODS: To study stellate cell activation in cGKI-SM mice, retinol storage and gene expression were studied. Moreover, in the human stellate cell line LX2, the consequences of cGKI-silencing on gene expression were investigated. Finally, cGKI expression was examined in human liver biopsies covering a wide range of liver fat content. RESULTS: Retinyl-ester concentrations in the liver of cGKI-SM mice were lower compared to wild-type animals, which was associated with disturbed expression of genes involved in retinol metabolism and inflammation. cGKI-silenced LX2 cells showed an mRNA expression profile of stellate cell activation, altered matrix degradation and activated chemokine expression. On the other hand, activation of LX2 cells suppressed cGKI expression. In accordance with this finding, in human liver biopsies, we observed a negative correlation between cGKI mRNA and liver fat content. CONCLUSIONS: These results suggest that the lack of cGKI possibly leads to stellate cell activation, which stimulates chemokine expression and activates inflammatory processes, which could disturb hepatic insulin sensitivity. AU - Frankó, A. AU - Kovarova, M. AU - Feil, S.* AU - Feil, R.* AU - Wagner, R. AU - Heni, M. AU - Königsrainer, A.* AU - Ruoß, M.* AU - Nüssler, A.K.* AU - Weigert, C. AU - Häring, H.-U. AU - Lutz, S.Z. AU - Peter, A. C1 - 54253 C2 - 45451 SP - 22-30 TI - cGMP-dependent protein kinase I (cGKI) modulates human hepatic stellate cell activation. JO - Metabolism VL - 88 PY - 2018 SN - 0026-0495 ER - TY - JOUR AB - OBJECTIVE: A proportion of type 2 diabetes cases arise from normal-weight individuals who can therefore be considered to be "metabolically unhealthy normal-weight" (MUH-NW). It remains unclear which factors account for this access risk. Our aims were to identify risk factors for type 2 diabetes in normal-weight individuals and to compare the strengths of their associations with type 2 diabetes to that observed in overweight and obese participants. METHODS: A case-cohort, including 2027 sub-cohort participants and 706 incident type 2 cases, was designed within the population-based European Prospective Investigation into Cancer and Nutrition Potsdam study. Adjusted means and relative frequencies of anthropometric, lifestyle and biochemical risk factors were calculated in groups stratified by BMI and incident diabetes status. Cox regressions were applied to evaluate associations between these variables and diabetes risk stratified by BMI category. RESULTS: MUH-NW individuals were characterized by known diabetes risk factors, e.g. they were significantly more likely to be male, former smokers, hypertensive, and less physically active compared to normal-weight individuals without incident diabetes. Higher waist circumference (women: 75.5 vs. 73.1cm; men: 88.0 vs. 85.1cm), higher HbA1c (6.1 vs. 5.3%), higher triglycerides (1.47 vs. 1.11mmol/l), and higher levels of high sensitive C-reactive protein (0.81 vs. 0.51mg/l) as well as lower levels of HDL-cholesterol (1.28 vs. 1.49mmol/l) and adiponectin (6.32 vs. 8.25μg/ml) characterized this phenotype. Stronger associations with diabetes among normal-weight participants compared to overweight and obese (p for interaction<0.05) were observed for height, waist circumference, former smoking, and hypertension. CONCLUSIONS: Normal-weight individuals who develop diabetes have higher levels of diabetes risk factors, however, frequently still among the normal range. Still, hypertension, elevated HbA1c and lifestyle risk factors might be useful indicators of risk. AU - Eckel, N.* AU - Mühlenbruch, K.* AU - Meidtner, K.* AU - Boeing, H.* AU - Stefan, N. AU - Schulze, M.B.* C1 - 44347 C2 - 36825 CY - Philadelphia SP - 862-871 TI - Characterization of metabolically unhealthy normal-weight individuals: Risk factors and their associations with type 2 diabetes. JO - Metabolism VL - 64 IS - 8 PB - W B Saunders Co-elsevier Inc PY - 2015 SN - 0026-0495 ER - TY - JOUR AB - BACKGROUND: Walnut consumption is associated with reduced risk of coronary heart disease (CHD). OBJECTIVE: We assessed the effect of walnuts on lipid and glucose metabolism, adipokines, inflammation and endothelial function in healthy Caucasian men and postmenopausal women ≥50years old. DESIGN: Forty subjects (mean±SEM: age 60±1years, BMI 24.9±0.6kg/m2; 30 females) were included in a controlled, cross-over study and randomized to receive first a walnut-enriched (43g/d) and then a Western-type (control) diet or vice-versa, with each lasting 8weeks and separated by a 2-week wash-out. At the beginning and end of each diet phase, measurements of fasting values, a mixed meal test and an assessment of postprandial endothelial function (determination of microcirculation by peripheral artery tonometry) were conducted. Area under the curve (AUC), incremental AUC (iAUC) and treatment×time interaction (shape of the curve) were evaluated for postprandial triglycerides, VLDL-triglycerides, chylomicron-triglycerides, glucose and insulin. RESULTS: Compared with the control diet, the walnut diet significantly reduced non-HDL-cholesterol (walnut vs. control: -10±3 vs. -3±2mg/dL; p=0.025) and apolipoprotein-B (-5.0±1.3 vs. -0.2±1.1mg/dL; p=0.009) after adjusting for age, gender, BMI and diet sequence. Total cholesterol showed a trend toward reduction (p=0.073). Fasting VLDL-cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides and glucose, insulin, HOMA-IR, and HbA1c did not change significantly. Similarly, fasting adipokines, C-reactive protein, biomarkers of endothelial dysfunction, postprandial lipid and glucose metabolism and endothelial function were unaffected. CONCLUSION: Daily consumption of 43g of walnuts for 8weeks significantly reduced non-HDL-cholesterol and apolipoprotein-B, which may explain in part the epidemiological observation that regular walnut consumption decreases CHD risk. AU - Wu, L.* AU - Piotrowski, K.* AU - Rau, T.T.* AU - Waldmann, E.* AU - Broedl, U.C.* AU - Demmelmair, H.* AU - Koletzko, B.* AU - Stark, R.G. AU - Nagel, J.M.* AU - Mantzoros, C.S.* AU - Parhofer, K.G.* C1 - 29156 C2 - 30827 CY - Philadelphia SP - 382-391 TI - Walnut-enriched diet reduces fasting non-HDL-cholesterol and apolipoprotein B in healthy Caucasian subjects: A randomized controlled cross-over clinical trial. JO - Metabolism VL - 63 IS - 3 PB - W B Saunders Co-elsevier Inc PY - 2014 SN - 0026-0495 ER - TY - JOUR AB - Objective. Obstructive respiratory diseases, mainly the chronic obstructive pulmonary disease (COPD) and asthma, are associated with functional polymorphisms of xenobiotic-metabolizing enzymes (XMEs). To date, association for obstructive bronchitis has not been described. Material/Methods. In this study, we investigated the genotypes from 26 functional polymorphisms of 20 XMEs in children (n, 1028) at the age of 6 years from the German prospective birth cohort study (LISAplus) and analyzed the associations between genotypes and obstructive bronchitis. Results. For the first time, we found noteworthy gene disease associations for the functional PON1 M55L and EPHX1 H139R polymorphisms and gene environment associations for the functional COMT V158M and NQO1 P1875 polymorphisms after stratification for maternal active smoking behaviour during pregnancy. The noteworthy associations were substantiated by the biological findings that all the risk genotypes belong to genes involved in oxidative stress and code for proteins with a fast enzymatic activity or concomitantly appear in common estrogene-metabolizing pathway (COMT, NQO1). Conclusion. The oxidative stress has to be taken into account in mechanism of the obstructive bronchitis in early childhood. The risk genotypes may serve as risk factors for respiratory obstruction rather than for signs of COPD or asthma. AU - Bauer, M.* AU - Gräbsch, C.* AU - Schlink, U.* AU - Klopp, N. AU - Illig, T. AU - Krämer, U.* AU - von Berg, A.* AU - Schaaf, B.* AU - Borte, M.* AU - Heinrich, J. AU - Herbarth, O.* AU - Lehmann, I.* AU - Roder, S.* C1 - 11542 C2 - 30720 SP - 1771-1779 TI - Genetic association between obstructive bronchitis and enzymes of oxidative stress. JO - Metabolism VL - 61 IS - 12 PB - Elsevier PY - 2012 SN - 0026-0495 ER - TY - JOUR AB - Tissue availability of polyunsaturated fatty acids (PUFAs) depends on dietary intake and metabolic turnover and has a major impact on human health. Strong associations between variants in the human genes fatty acid desaturase 1 (FADS1, encoding Delta-5 desaturase) and fatty acid desaturase 2 (FADS2, encoding Delta-6 desaturase) and blood levels of PUFAs and long-chain PUFAs (LC-PUFAs) have been reported. The most significant associations and the highest proportion of genetically explained variability (28%) were found for arachidonic acid (20:4n-6), the main precursor of eicosanoids. Subjects carrying the minor alleles of several single nucleotide polymorphisms had a lower prevalence of allergic rhinitis and atopic eczema. Therefore, blood levels of PUFAs and LC-PUFAs are influenced not only by diet, but to a large extent also by genetic variants common in a European population. These findings have been replicated in independent populations. Depending on genetic variants, requirements of dietary PUFA or LC-PUFA intakes to achieve comparable biological effects may differ. We recommend including analyses of FADS1 and FADS2 polymorphism in future cohort and intervention studies addressing biological effects of PUFAs and LC-PUFAs. AU - Glaser, C.* AU - Heinrich, J. AU - Koletzko, B.* C1 - 342 C2 - 27353 SP - 993-999 TI - Role of FADS1 and FADS2 polymorphisms in polyunsaturated fatty acid metabolism. JO - Metabolism VL - 59 IS - 7 PB - Elsevier PY - 2010 SN - 0026-0495 ER - TY - JOUR AB - The natural anti-inflammatory protein interleukin-1 receptor antagonist (IL-1Ra) inhibits the activity of IL-1 and is associated with vascular injury and metabolic disorders. We analyzed genetic and nongenetic determinants of the IL-1Ra phenotype. Fifteen haplotype-tagging single nucleotide polymorphisms (SNPs) in the IL-1α (IL1A), IL-1β (IL1B), and IL-1 receptor antagonist (IL-1RN) genes were determined in the Health 2000 survey (n = 6771) and European myocardial infarction (MI) survivors (n = 972). Three SNPs were genotyped in the FINRISK97 (FR97) study (n = 7222). We found 3 IL1RN variants that were associated with the IL-1Ra phenotype in the study populations and remained significant after Bonferroni correction with increasing significance in meta-analysis (P values for rs3213448,rs315952, rs315949, respectively: 5.5 x 10(-11), 1.5 x 10(-11), and 4.0 x 10(-14)). Minor allele of the rare IL1B variant rs1143642 was associated with decreased IL-1Ra levels in the Health 2000 and FR97 populations, and the association strengthened in the meta-analysis (P = 9.4 x 10(-7)). The proportion of variance explained by the IL1RN variant was larger in MI survivors (5.0%) than in the unselected population (0.5%). Body mass index was the strongest nongenetic predictor of the IL-1Ra phenotype, explaining 11.8% of the variance in Health 2000, 18.1% in FR97, and 25% in MI survivors. In conclusion, 3 IL1RN SNPs and 1 IL1B variant were determining IL-1Ra phenotype independently of body mass index and other metabolic phenotypes. The proportion of phenotypic variation in IL-1Ra explained by the genetic variants was, however, modest compared with the proportion explained by the body mass index. AU - Luotola, K.* AU - Pietila, A.* AU - Alanne, M.* AU - Lanki, T.* AU - Loo, B.M.* AU - Jula, A.* AU - Perola, M.* AU - Peters, A. AU - Zeller, T.* AU - Blankenberg, S.* AU - Salomaa, V.* C1 - 1477 C2 - 27543 SP - 1520-1527 TI - Genetic variation of the interleukin-1 family and nongenetic factors determining the interleukin-1 receptor antagonist phenotypes. JO - Metabolism VL - 59 IS - 10 PB - Elsevier PY - 2010 SN - 0026-0495 ER -