Background Recent evidence indicates that insulin resistance (IR) in obesity may develop independently in different organs, representing different etiologies toward type 2 diabetes and other cardiometabolic diseases. The aim of this study was to investigate whether IR in the liver and IR in skeletal muscle are associated with distinct metabolic profiles. Methods This study includes baseline data from 634 adults with overweight or obesity (BMI ≥ 27 kg/m 2 ) (≤65 years; 63% women) without diabetes of the European Diogenes Study. Hepatic insulin resistance index (HIRI) and muscle insulin sensitivity index (MISI), were derived from a five-point OGTT. At baseline 17 serum metabolites were identified and quantified by nuclearmagnetic-resonance spectroscopy. Linear mixed model analyses (adjusting for center, sex, body mass index (BMI), waist-to-hip ratio) were used to associate HIRI and MISI with these metabolites. In an independent sample of 540 participants without diabetes (BMI ≥ 27 kg/m 2 ; 40-65 years; 46% women) of the Maastricht Study, an observational prospective population-based cohort study, 11 plasma metabolites and a seven-point OGTT were available for validation. Results Both HIRI and MISI were associated with higher levels of valine, isoleucine, oxo-isovaleric acid, alanine, lactate, and triglycerides, and lower levels of glycine (all p < 0.05). HIRI was also associated with higher levels of leucine, hydroxyisobutyrate, tyrosine, proline, creatine, and n-acetyl and lower levels of acetoacetate and 3-OH-butyrate (all p < 0.05). Except for valine, these results were replicated for all available metabolites in the Maastricht Study. Conclusions In persons with obesity without diabetes, both liver and muscle IR show a circulating metabolic profile of elevated (branched-chain) amino acids, lactate, and triglycerides, and lower glycine levels, but only liver IR associates with lower ketone body levels and elevated ketogenic amino acids in circulation, suggestive of decreased ketogenesis. This knowledge might enhance developments of more targeted tissue-specific interventions to prevent progression to more severe disease stages.

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Obesity-related insulin resistance (IR) may develop in multiple organs, representing various etiologies for cardiometabolic diseases. We identified abdominal subcutaneous adipose tissue (ScAT) transcriptome profiles in liver or muscle IR by means of RNA sequencing in overweight or obese participants of the Diet, Obesity, and Genes (DiOGenes) (NCT00390637, ClinicalTrials.gov) cohort (n = 368). Tissue-specific IR phenotypes were derived from a 5-point oral glucose tolerance test. Hepatic and muscle IR were characterized by distinct abdominal ScAT transcriptome profiles. Genes related to extracellular remodeling were upregulated in individuals with primarily hepatic IR, while genes related to inflammation were upregulated in individuals with primarily muscle IR. In line with this, in two independent cohorts, the Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) (n = 325) and the Maastricht Study (n = 685), an increased systemic low-grade inflammation profile was specifically related to muscle IR but not to liver IR. We propose that increased ScAT inflammatory gene expression may translate into an increased systemic inflammatory profile, linking ScAT inflammation to the muscle IR phenotype. These distinct IR phenotypes may provide leads for more personalized prevention of cardiometabolic diseases.

Highlights d Multiomics analyses of adipose tissue and skeletal muscle in BMI-discordant twins d Excess body weight downregulates mitochondrial pathways in both tissues d Excess body weight upregulates proinflammatory pathways in both tissues d Adipose tissue alterations are associated with metabolic health in acquired obesity

Context Mitochondria are essential for cellular energy homeostasis, yet their role in subcutaneous adipose tissue (SAT) during different types of weight-loss interventions remains unknown. Objective Investigate how SAT mitochondria change following diet-induced and bariatric surgery-induced weight-loss interventions in four independent weight-loss studies. Design/Setting The DiOGenes study is a European multicenter dietary intervention with an 8-week low caloric diet (LCD; 800 kcal/d; n=261) and 6-month weight maintenance (n=121) period. The Kuopio Obesity Surgery study (KOBS) is a Roux-en-Y gastric bypass (RYGB) surgery study (n=172) with a 1-year follow-up. We associated weight-loss percentage with global and 2210 mitochondria-related RNA transcripts in linear regression analysis adjusted for age and sex. We repeated these analyses in two studies. The Finnish CRYO study has a 6-week LCD (800–1000 kcal/d; n=19) and a 10.5-month follow-up. The Swedish DEOSH study is a RYGB surgery study with a 2-year (n=49) and 5-year (n=37) follow-up. Results Diet-induced weight loss led to a significant transcriptional downregulation of oxidative phosphorylation (DiOGenes; Ingenuity Pathway Analyses (IPA) z-scores: -8.7 following LCD, -4.4 following weight maintenance; CRYO: IPA z-score: -5.6, all p&lt;0.001), while upregulation followed surgery-induced weight loss (KOBS: IPA z-score: 1.8, p&lt;0.001; in DEOSH: IPA z-scores: 4.0 following 2 years, 0.0 following 5 years). We confirmed an upregulated oxidative phosphorylation at the proteomics level following surgery (IPA z-score: 3.2, p&lt;0.001). Conclusions Differentially regulated SAT mitochondria-related gene expressions suggest qualitative alterations between weight-loss interventions, providing insights into the potential molecular mechanistic targets for weight-loss success.

Introduction/hypothesis Disturbances in skeletal muscle fatty acid (FA) handling may contribute to the development and progression of whole-body insulin resistance (IR). In this study, we compared fasting and postprandial skeletal muscle FA handling in individuals with varying degrees of IR. Methods Seventy-four overweight/obese participants (62 men) were divided into two groups based on the HOMA-IR median (3.35). Fasting and postprandial skeletal muscle FA handling were determined by combining the forearm muscle balance technique with stable isotopes. , respectively, p = 0.045). Although no differences in skeletal muscle TAG, diacylglycerol, NEFA content and FSR were present between groups, the high-IR group showed increased saturation of the intramuscular NEFA pool (p = 0.039). This was accompanied by lower muscle GPAT1 (also known as GPAM) expression (p = 0.050).Conclusions/interpretation Participants with high-IR demonstrated increased postprandial skeletal muscle VLDL-TAG extraction and higher saturation of the intramuscular NEFA pool vs individuals with mild-IR. These data support the involvement of disturbances in skeletal muscle FA handling in the progression of whole-body IR.

Subcutaneous AT does not appear prone to enhanced meal-derived fatty acid uptake after weight loss, nor were fatty acid uptake dynamics detected as related to weight regain.

Nicotinamide adenine dinucleotide (NAD + ) precursor nicotinamide riboside (NR) has emerged as a promising compound to improve obesity-associated mitochondrial dysfunction and metabolic syndrome in mice. However, most short-term clinical trials conducted so far have not reported positive outcomes. Therefore, we aimed to determine whether long-term NR supplementation boosts mitochondrial biogenesis and metabolic health in humans. Twenty body mass index (BMI)–discordant monozygotic twin pairs were supplemented with an escalating dose of NR (250 to 1000 mg/day) for 5 months. NR improved systemic NAD + metabolism, muscle mitochondrial number, myoblast differentiation, and gut microbiota composition in both cotwins. NR also showed a capacity to modulate epigenetic control of gene expression in muscle and adipose tissue in both cotwins. However, NR did not ameliorate adiposity or metabolic health. Overall, our results suggest that NR acts as a potent modifier of NAD + metabolism, muscle mitochondrial biogenesis and stem cell function, gut microbiota, and DNA methylation in humans irrespective of BMI.