The intestinal microbiota, consisting of an estimated 10<^>10-10<^>11 organisms, regulate physiological processes involved in digestion, metabolism, and immunity. Surprisingly, these intestinal microorganisms have been found to influence tissues that are not directly in contact with the gut, such as adipose tissue, the liver, skeletal muscle, and the brain. This interaction takes place even when intestinal barrier function is uncompromised. An increasing body of evidence suggests that bacterial membrane vesicles (bMVs), in addition to bacterial metabolites such as short-chain fatty acids, are able to mediate effects of the microbiota on these host tissues. The ability of bMVs to dissipate from the intestinal lumen into systemic circulation hereby facilitates the transport and presentation of bacterial components and metabolites to host organs. Importantly, there are indications that the interaction between bMVs and tissues or immune cells may play a role in the etiology of (chronic metabolic) disease. For example, the gut-derived bMV-mediated induction of insulin resistance in skeletal muscle cells and pro-inflammatory signaling by adipocytes possibly underlies diseases such as type 2 diabetes and obesity. Here, we review the current knowledge on bMVs in the microbiota's effects on host energy/substrate metabolism with a focus on etiological roles in the onset and progression of metabolic disease. We furthermore illustrate that vesicle production by bacterial microbiota could potentially be modulated through lifestyle intervention to improve host metabolism.

Context Abdominal obesity is associated with increased cardiometabolic disease risk, while lower body fat seems to confer protection against obesity-related complications. The functional differences between upper and lower body adipose tissue (AT) remain poorly understood.Objective We aimed to examine whether mitochondrial respiration is impaired in abdominal as compared to femoral differentiated human multipotent adipose-derived stem cells (hMADS; primary outcome) and AT in postmenopausal women.Design In this cross-sectional study, 23 postmenopausal women with normal weight or obesity were recruited at the University of Birmingham/Queen Elizabeth Hospital Birmingham (Birmingham, UK). We collected abdominal and femoral subcutaneous AT biopsies to determine mitochondrial oxygen consumption rates in differentiated abdominal and femoral hMADS. Furthermore, we assessed oxidative phosphorylation (OXPHOS) protein expression and mitochondrial DNA (mtDNA) content in abdominal and femoral AT as well as hMADS. Finally, we explored in vivo fractional oxygen extraction and carbon dioxide release across abdominal and femoral subcutaneous AT in a subgroup of the same individuals with normal weight or obesity.Results We found lower basal and maximal uncoupled mitochondrial oxygen consumption rates in abdominal compared to femoral hMADS. In line, in vivo fractional oxygen extraction and carbon dioxide release were lower across abdominal than femoral AT. OXPHOS protein expression and mtDNA content did not significantly differ between abdominal and femoral differentiated hMADS and AT.Conclusion The present findings demonstrate that in vitro mitochondrial respiration and in vivo oxygen fractional extraction are less in upper compared to lower body differentiated hMADS and AT, respectively, in postmenopausal women.

A proinflammatory adipose tissue (AT) microenvironment and systemic low‐grade inflammation may differentially affect tissue‐specific insulin sensitivity. This study investigated the relationships of abdominal subcutaneous AT (aSAT) and circulating immune cells, aSAT gene expression, and circulating inflammatory markers with liver and skeletal muscle insulin sensitivity in people with overweight and obesity.

Prolyl carboxypeptidase (PRCP) is involved in metabolic disorders by hydrolyzing anorexigenic peptides. A link between serum PRCP activity and obesity has been reported, but its origin/source is still unclear. Previously proven correlations between human serum PRCP activity and the amount of adipose tissue may suggest that adipose tissue is an important source of circulating PRCP. We investigated PRCP activity in visceral, subcutaneous adipose tissue (VAT and SCAT), skeletal muscle tissue and serum of lean and obese men with or without type 2 diabetes (T2D). Correlations between PRCP activity, metabolic and biochemical parameters and immune cell populations were assessed. PRCP activity was the highest in VAT, compared to SCAT, and was very low in skeletal muscle tissue in the overall group. Serum PRCP activity was significantly higher in T2-diabetic obese men, compared to lean and obese non-diabetic men, and was positively correlated with glycemic control. A positive correlation was observed between serum PRCP activity and VAT immune cell populations, which might indicate that circulating PRCP activity is deriving rather from the immune fraction than from adipocytes. In conclusion, PRCP activity was observed in human adipose tissue for the first time and serum PRCP activity is correlated with T2D in obese men.

Adipose tissue of metabolically compromised humans with obesity is often characterized by impaired regulation of autophagy pathway. However, data on the role of autophagy in human adipocyte lipid catabolism is scarce. Therefore, we investigated the effect of pharmacological agents (including 3-methyladenine (3MA), bafilomycin A1 (BAF), chloroquine (CQ) and lalistat-2 (L-stat), that target different stages of the autophagy pathway on lipid hydrolysis in differentiated human multipotent adipose-derived stem cells (hMADs). Glycerol and fatty acid release were measured as marker of lipid hydrolysis following starvation and β-adrenergic stimulation. Microtubule-associated protein light chain 3 ratio (LC3II/LC3I) and HSL phosphorylation (pHSL) were analyzed by Western blot. Our data indicate that pharmacological inhibition of the autophagy pathway reduced lipid hydrolysis in human adipocytes, although to a limited extent (10-15%). However, further research is needed to reveal the exact mechanism of action of these pharmacological agents and their interplay with cytosolic lipid breakdown in human adipocytes.

Adipose tissue (AT) inflammation may increase obesity-related cardiometabolic complications. Altered AT oxygen partial pressure (pO2) may impact the adipocyte inflammatory phenotype. Here, we investigated the effects of physiological pO2 levels on the inflammatory phenotype of abdominal (ABD) and femoral (FEM) adipocytes derived from postmenopausal women with normal weight (NW) or obesity (OB). Biopsies were collected from ABD and FEM subcutaneous AT in eighteen postmenopausal women (aged 50–65 years) with NW (BMI 18–25 kg/m2, n = 9) or OB (BMI 30–40 kg/m2, n = 9). We compared the effects of prolonged exposure to different physiological pO2 levels on adipokine expression and secretion in differentiated human multipotent adipose-derived stem cells. Low physiological pO2 (5% O2) significantly increased leptin gene expression/secretion in ABD and FEM adipocytes derived from individuals with NW and OB compared with high physiological pO2 (10% O2) and standard laboratory conditions (21% O2). Gene expression/secretion of IL-6, DPP-4, and MCP-1 was reduced in differentiated ABD and FEM adipocytes from individuals with OB but not NW following exposure to low compared with high physiological pO2 levels. Low physiological pO2 decreases gene expression and secretion of several proinflammatory factors in ABD and FEM adipocytes derived from individuals with OB but not NW.

Objective Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) uses the host's angiotensin-converting enzyme 2 (ACE2) as a cellular entry point. Therefore, modulating ACE2 might impact SARS-CoV-2 viral replication, shedding, and coronavirus disease 2019 (COVID-19) severity. Here, it was investigated whether the angiotensin II type 1 receptor blocker valsartan alters the expression of renin-angiotensin system (RAS) components, including ACE2, in human adipose tissue (AT) and skeletal muscle. Methods A randomized, double-blind, placebo-controlled clinical trial was performed, in which 36 participants (BMI 31.0 +/- 0.8 kg/m(2)) with impaired glucose metabolism received either valsartan or placebo for 26 weeks. Before and after 26 weeks' treatment, abdominal subcutaneous AT and skeletal muscle biopsies were obtained, and gene expression of RAS components was measured by quantitative reverse transcription polymerase chain reaction. Results Valsartan treatment did not significantly impact the expression of RAS components, including ACE2, in AT and skeletal muscle. Conclusions Given the pivotal role of ACE2 in SARS-CoV-2 spread and the clinical outcomes in COVID-19 patients, the data suggest that the putative beneficial effects of angiotensin II type 1 receptor blockers on the clinical outcomes of patients with COVID-19 may not be mediated through altered ACE2 expression in abdominal subcutaneous AT.

Objective: Recent studies suggest that hypoxia exposure may improve glucose homeostasis, but well-controlled human studies are lacking. We hypothesized that mild intermittent hypoxia (MIH) exposure decreases tissue oxygen partial pressure (pO2) and induces metabolic improvements in people who are overweight/obese. Methods: In a randomized, controlled, single-blind crossover study, 12 men who were overweight/obese were exposed to MIH (15 % O2, 3 x 2 h/day) or normoxia (21 % O2) for 7 consecutive days. Adipose tissue (AT) and skeletal muscle (SM) pO2, fasting/postprandial substrate metabolism, tissue-specific insulin sensitivity, SM oxidative capacity, and AT and SM gene/protein expression were determined. Furthermore, primary human myotubes and adipocytes were exposed to oxygen levels mimicking the hypoxic and normoxic AT and SM microenvironments. Results: MIH decreased systemic oxygen saturation (92.0 +/- 0.5 % vs 97.1 +/- 0.3, p < 0.001, respectively), AT pO2 (21.0 +/- 2.3 vs 36.5 +/- 1.5 mmHg, p < 0.001, respectively), and SM pO2 (9.5 +/- 2.2 vs 15.4 +/- 2.4 mmHg, p = 0.002, respectively) compared to normoxia. In addition, MIH increased glycolytic metabolism compared to normoxia, reflected by enhanced fasting and postprandial carbohydrate oxidation (pAUC = 0.002) and elevated plasma lactate concentrations (pAUC = 0.005). Mechanistically, hypoxia exposure increased insulin-independent glucose uptake compared to standard laboratory conditions (-50 %, p < 0.001) and physiological normoxia (-25 %, p = 0.019) through AMP-activated protein kinase in primary human myotubes but not in primary human adipocytes. MIH upregulated inflammatory/metabolic pathways and downregulated extracellular matrix-related pathways in AT but did not alter systemic inflammatory markers and SM oxidative capacity. MIH exposure did not induce significant alterations in AT (p = 0.120), hepatic (p = 0.132) and SM (p = 0.722) insulin sensitivity. Conclusions: Our findings demonstrate for the first time that 7-day MIH reduces AT and SM pO2, evokes a shift toward glycolytic metabolism, and induces adaptations in AT and SM but does not induce alterations in tissue-specific insulin sensitivity in men who are overweight/obese. Future studies are needed to investigate further whether oxygen signaling is a promising target to mitigate metabolic complications in obesity. Clinical trial registration: This study is registered at the Netherlands Trial Register (NL7120/NTR7325). (c) 2021 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Our recent in vivo human studies showed that colonic administration of sodium acetate (SA) resulted in increased circulating acetate levels, which was accompanied by increments in whole-body fat oxidation in overweight-obese men. Since skeletal muscle has a major role in whole-body fat oxidation, we aimed to investigate effects of SA on fat oxidation and underlying mechanisms in human primary skeletal muscle cells (HSkMC). We investigated the dose (0–5 mmol/L) and time (1, 4, 20, and 24 h) effect of SA on complete and incomplete endogenous and exogenous oxidation of 14C-labeled palmitate in HSkMC derived from a lean insulin sensitive male donor. Both physiological (0.1 and 0.25 mmol/L) and supraphysiological (0.5, 1 and 5 mmol/L) concentrations of SA neither increased endogenous nor exogenous fat oxidation over time in HSkMC. In addition, no effect of SA was observed on Thr172-AMPKα phosphorylation. In conclusion, our previously observed in vivo effects of SA on whole-body fat oxidation in men may not be explained via direct effects on HSkMC fat oxidation. Nevertheless, SA-mediated effects on whole-body fat oxidation may be triggered by other mechanisms including gut-derived hormones or may occur in other metabolically active tissues.

To investigate (1) the association of four VDR polymorphisms (TaqI/rs731236, ApaI/rs7975232, FokI/rs10735810, and Bsml/rs1544410) with markers of adiposity and tissue-specific insulin resistance at baseline, after weight loss and weight maintenance; (2) the effect of the VDR polymorphisms in the SAT transcriptome in overweight/obese Caucasians of the DiOGenes cohort.We included 553 adult obese individuals (mean BMI 34.8 kg/m2), men (n = 197) and women (n = 356) at baseline, following an 8-week weight loss intervention and 26 weeks weight maintenance. Genotyping was performed using an Illumina 660W-Quad SNP chip on the Illumina iScan Genotyping System. Tissue-specific IR was determined using Hepatic Insulin Resistance Index (HIRI), Muscle Insulin Sensitivity Index (MISI), and Adipose Tissue Insulin Resistance Index (Adipo-IR). Expression quantitative trait loci (eQTL) analysis was performed to determine the effect of SNPs on SAT gene expression.None of the VDR polymorphisms were associated with HIRI or MISI. Interestingly, carriers of the G allele of VDR FokI showed higher Adipo-IR (GG + GA 7.8 ± 0.4 vs. AA 5.6 ± 0.5, P = 0.010) and higher systemic FFA (GG + GA: 637.8 ± 13.4 vs. AA: 547.9 ± 24.7 µmol/L, P = 0.011), even after adjustment with age, sex, center, and FM. However, eQTL analysis showed minor to no effect of these genotypes on the transcriptional level in SAT. Also, VDR polymorphisms were not related to changes in body weight and IR as result of dietary intervention (P > 0.05 for all parameters).The VDR Fokl variant is associated with elevated circulating FFA and Adipo-IR at baseline. Nevertheless, minor to no effect of VDR SNPs on the transcriptional level in SAT, indicating that putative mechanisms of action remain to be determined. Finally, VDR SNPs did not affect dietary intervention outcome in the present cohort.

Cathepsin L1 (CTSL1) and B (CTSB) are lysosomal proteases, of which the expression and activity are impaired in adipose tissue (AT) of obese rodents, indicating AT lysosomal dysfunction. Here we assess the relation between abdominal subcutaneous AT (SCAT) CTSL1 and CTSB gene expression (qRT-PCR), body composition and tissue-specific insulin resistance in 77 overweight/obese (BMI: 225.6–38.6 kg/m2) well phenotyped men and women (61 M/16 F). A two-step hyperinsulinemic-euglycemic clamp was performed to assess AT, hepatic and skeletal muscle insulin sensitivity. Our data show that reduced CTSB expression is associated with markers of insulin resistance (standardized β = −0.561, p < 0.001), independent of adiposity, while CTSL1 expression is only associated with markers of body composition. Our data suggest the presence of lysosomal dysfunction in SCAT of obese humans with an impaired glucose homoeostasis. However, this needs to be investigated in more detail in future mechanistic studies.

Dear Editor, Obesity leads to macrophage infiltration in adipose tissue (AT), causing chronic low-grade inflammation (LGI). This in turn leads to insulin resistance, contributing to the increased risk for type 2 diabetes in obese individuals. Obesity shifts the polarization status of adipose tissue macrophages (ATM) away from an anti-inflammatory or “M2" phenotype toward the inflammatory “M1” state, hallmarked by the surface expression of CD11C and the production of inflammatory cytokines.1 The exact mechanisms that trigger ATM accumulation and activation remain to be elucidated. Animal studies identified that natural killer (NK) cells are able to induce M1 ATM accumulation by producing interferon gamma (IFN-γ), tumor necrosis factor (TNF), or interleukin (IL)-6, culminating in insulin resistance.2-4 NK cells function perform surveillance and elimination of virally infected, tumorigenic or stressed cells, also leading to cytokine production.5 NK cells were found to accumulate in human adipose tissue of obese individuals,6 but whether they contribute to accumulation and polarization of ATMs and insulin resistance in humans remains unknown. We therefore investigated NK cell accumulation in human adipose tissue and their potential contribution to low-grade inflammation and insulin resistance in humans. We collected NK cells from lean and obese individuals and cultured them with primary monocyte-derived macrophages from a healthy donor. Compared to controls, NK cells from obese donors contained elevated levels of TNF. Moreover, they promoted M1 polarization of monocyte-derived macrophages (Figure 1A,B; Figure S1A-D). These results are in line with results showing enhanced TNF production by NK cells in epididymal AT from obese mice.2 Although data in mouse models show that also IFN-γ produced by NK cells causes inflammation and insulin resistance,4 we did not observe increased IFN-γ in NK cells of obese individuals (data not shown). Then, we analyzed blood, visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT) from lean and obese men (baseline characteristics in Table S1).7 NK cells were higher in VAT (Figure 2A) and blood, but not in SAT from obese subjects (Table S1). In VAT, but not in SAT, NK cell abundance was associated with an increased inflammatory macrophage polarization (Figure 2B). These data support the previously found role for NK cells in skewing M1 macrophage polarization specifically in VAT of mice.2-4 Previous studies also show that human VAT contains more inflammatory NK cells than SAT8 and that VAT contains ligands of the NK cell activating receptor NKp46.4 Together with our observations, these data suggest that NK cells can sense stressed VAT adipocytes, accumulate in VAT and TNF production, leading to ATM activation. To obtain biopsies of VAT in large cohort studies is difficult. Therefore, we sought for a marker of the accumulation of NK cells in VAT. Circulating NK cell numbers were not associated with NK cells in VAT (r = 0.058, P = 0.759). However, surface expression of CD11B on blood NK cells (referred to as NK-CD11B) was a suitable marker. Despite that all NK cells express CD11B, NK-CD11B was elevated in obese men (Figure 2C; Figure S1E) and was closely associated with the accumulation of NK cells in VAT (Figure 2D), but not in SAT. In line with our results showing an association between VAT NK cells and macrophage polarization, also M1/M2 ratio was found to associate with NK-CD11B (r = 0.364; P = 0.048). Of note, there was also a close association between surface expression of CD11B on isolated NK cells and intracellular TNF (r = 0.806, P = 0.016; Figure 1C). These important findings support the use of NK-CD11B as an easy-to-measure marker of NK cells in VAT. We next measured NK-CD11B to determine the link between VAT NK cells and insulin resistance, using a study consisting of 53 abdominally obese and 25 lean men9 (Clinical characteristics: Table S2). Also here, NK-CD11B was elevated in obese compared to lean men (Figure 3A), thus reflecting increased NK cells in VAT. NK-CD11B was also associated with VAT volume (Figure 3B) and LGI (Figure 3C). Interestingly, NK-CD11B was inversely associated with whole body glucose disposal (Figure 3D). Since NK-CD11B reflects VAT NK cell accumulation, these results corroborate with previously identified findings showing that NK cells cause insulin resistance in mice,2-4 and that these events are also of importance in humans. Additionally, with multiple mediation analyses we explored if NK-CD11B and consecutive systemic LGI contribute to the existing association between VAT volume and insulin resistance. NK-CD11B explained 53.9% of the contribution of LGI to VAT-associated insulin resistance (Figure 3E). This was mainly mediated by TNF (β –0.048 [–0.170 to –0.006]), but not by IL-6 (β –0.018 [–0.077 to 0.043]). Together with our data showing that NK-CD11B and intracellular TNF levels in circulating NK cells were closely associated (Figure 1C), these analyses suggest that NK cell recruitment is an important event that contributes to the development of inflammation in VAT and systemic LGI in humans. For the validation of our findings in the general population, we used a population-based cohort study enriched in individuals with type 2 diabetes, “The Maastricht Study” (Table S3). VAT volume, assessed by MRI, was found to associate with NK-CD11B (β = 3.2, P = 0.006; Table S4). This result was not affected by further adjustment for SAT volume (not shown). Moreover, NK-CD11B was associated with LGI and circulating levels of TNF and IL-6 (P < 0.05 for each; Table S5). NK-CD11B was also associated with insulin resistance (Table S6). These results support the concept that NK cells play a role in low-grade inflammation and insulin resistance development in the general population. To conclude, we show that NK cells contribute to inflammatory macrophage polarization, LGI, and concomitant insulin resistance in humans, possibly via TNF production. Thus, targeting NK cells may be promising for the inhibition of insulin resistance and possibly for the prevention of progressing toward type 2 diabetes. Moreover, our study identified that CD11B surface expression on blood NK cells closely reflect NK cell accumulation in VAT, making it an easy to use biomarker of VAT NK cells. Maria Vroomen, José van de Gaar, and Jos op ‘t Roodt are greatly acknowledged for their technical assistance. We thank Marleen van Greevenbroek for epidemiological counseling. Part of this study was financed by The Netherlands Organization for Scientific Research (NWO) (Veni 916.12.056), The Netherlands Heart Foundation (2013T143), and a Seventh Framework Program (FP7) Grant (CIG 322070) to KW. The metabolic phenotyping study was supported by research grant CH001 from the Top Institute Food and Nutrition, a public-private partnership on precompetitive research in food and nutrition. The public partners are responsible for the study design, data collection and analysis, decision to publish, and preparation of the manuscript. The validation study was supported by the European Regional Development Fund via OP-Zuid, the Province of Limburg, the Dutch Ministry of Economic Affairs (grant 31O.041), Stichting De Weijerhorst (Maastricht, the Netherlands), the Pearl String Initiative Diabetes (Amsterdam, the Netherlands), CARIM School for Cardiovascular Diseases (Maastricht, the Netherlands), Stichting Annadal (Maastricht, the Netherlands), Health Foundation Limburg (Maastricht, the Netherlands) and by unrestricted grants from Janssen-Cilag B.V. (Tilburg, the Netherlands), Novo Nordisk Farma B.V. (Alphen aan den Rijn, the Netherlands) and Sanofi-Aventis Netherlands B.V. (Gouda, the Netherlands). Part of this work was supported by the Hasselt University and Maastricht University and Research Foundation – Flanders (FWO) (grant number KAN 1507217N). Kristiaan Wouters is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. KW designed, supervised, and performed experiments in all studies, analyzed the data and wrote the manuscript; YHAMK performed experiments in the metabolic phenotyping study and performed the statistical analyses of all studies, analyzed data, and wrote the manuscript; MB and XZ performed experiments and analyzed data; SW performed experiments; PBCL analyzed data of the validation study; KG performed experiments and analyzed data of the first biopsy study; YHAMK, AJHMH, PPJ, JP, RPM, CGS, and CDAS designed the metabolic phenotyping study; EK designed the MRI protocols; CJHvdK and CDAS designed and supervised the validation study (The Maastricht Study); KV collected samples, performed measurements, and recruited individuals undergoing surgery in the first biopsy study; JJ performed experiments in the first biopsy study; DH and EEB supervised experiments in the first biopsy study; FAIE and LW designed and performed the ex-vivo experiments from the second biopsy study; SR and JWG designed and supervised experiments in the second biopsy study; CGS supervised experiments and wrote the manuscript. All authors critically read and commented on the manuscript. None of the authors have a conflict of interest to declare. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

BACKGROUND Vitamin D has been suggested to affect peripheral insulin sensitivity. Evidence regarding the effect of vitamin D supplementation on insulin sensitivity is still conflicting. PURPOSE This meta-analysis aimed to assess the effect of vitamin D supplementation on insulin sensitivity in humans with or at risk for insulin resistance. DATA SOURCES AND STUDY SELECTION PubMed, Web of Science, Embase, CINAHL, and Cochrane Library were systematically searched for randomized controlled trials (RCTs) from 1980 until 31 December 2018 reporting treatment effects of vitamin D supplementation on insulin sensitivity. DATA EXTRACTION The main outcome of interest was the change in insulin sensitivity, derived from the gold standard hyperinsulinemic-euglycemic clamp or the Matsuda index derived from the oral glucose tolerance test and insulin sensitivity index from intravenous glucose tolerance test. We extracted data on the standardized mean difference between the vitamin D treatment and placebo groups in change from baseline insulin sensitivity. DATA SYNTHESIS Eighteen RCTs were included in this meta-analysis comparing vitamin D supplementation (n= 612) with placebo (n= 608). Vitamin D supplementation had no effect on insulin sensitivity (standardized mean difference -0.01, 95% CI -0.12, 0.10;P= 0.87,I-2= 0%). Visual inspection of funnel plot symmetry did not suggest potential publication bias. LIMITATIONS The number of individuals who participated in the included studies was relatively small, possibly due to the invasive character of the measurement (e.g., clamp). CONCLUSIONS This meta-analysis provides no evidence that vitamin D supplementation has a beneficial effect on peripheral insulin sensitivity in people with or at risk for insulin resistance.

BACKGROUND Vitamin D has been suggested to affect peripheral insulin sensitivity. Evidence regarding the effect of vitamin D supplementation on insulin sensitivity is still conflicting. PURPOSE This meta-analysis aimed to assess the effect of vitamin D supplementation on insulin sensitivity in humans with or at risk for insulin resistance. DATA SOURCES AND STUDY SELECTION PubMed, Web of Science, Embase, CINAHL, and Cochrane Library were systematically searched for randomized controlled trials (RCTs) from 1980 until 31 December 2018 reporting treatment effects of vitamin D supplementation on insulin sensitivity. DATA EXTRACTION The main outcome of interest was the change in insulin sensitivity, derived from the gold standard hyperinsulinemic-euglycemic clamp or the Matsuda index derived from the oral glucose tolerance test and insulin sensitivity index from intravenous glucose tolerance test. We extracted data on the standardized mean difference between the vitamin D treatment and placebo groups in change from baseline insulin sensitivity. DATA SYNTHESIS Eighteen RCTs were included in this meta-analysis comparing vitamin D supplementation (n = 612) with placebo (n = 608). Vitamin D supplementation had no effect on insulin sensitivity (standardized mean difference −0.01, 95% CI −0.12, 0.10; P = 0.87, I2 = 0%). Visual inspection of funnel plot symmetry did not suggest potential publication bias. LIMITATIONS The number of individuals who participated in the included studies was relatively small, possibly due to the invasive character of the measurement (e.g., clamp). CONCLUSIONS This meta-analysis provides no evidence that vitamin D supplementation has a beneficial effect on peripheral insulin sensitivity in people with or at risk for insulin resistance.

Acute intake of the wheat bran extract Arabinoxylan-Oligosaccharide (AXOS) modulates the gut microbiota, improves stool characteristics and postprandial glycemia in healthy humans. Yet, little is known on how long-term AXOS intake influences gastrointestinal (GI) functioning, gut microbiota, and metabolic health. In this randomized, placebo-controlled, double-blind study, we evaluated the effects of AXOS intake on GI function and metabolic health in adults with slow GI transit without constipation. Forty-eight normoglycemic adults were included with whole-gut transit time (WGTT) of >35 h receiving either 15 g/day AXOS or placebo (maltodextrin) for 12-wks. The primary outcome was WGTT, and secondary outcomes included stool parameters, gut permeability, short-chain fatty acids (SCFA), microbiota composition, energy expenditure, substrate oxidation, glucose, insulin, lipids, gut hormones, and adipose tissue (AT) function. WGTT was unchanged, but stool consistency softened after AXOS. 12-wks of AXOS intake significantly changed the microbiota by increasing Bifidobacterium and decreasing microbial alpha-diversity. With a good classification accuracy, overall microbiota composition classified responders with decreased WGTT after AXOS. The incretin hormone Glucagon-like protein 1 was reduced after AXOS compared to placebo. Energy expenditure, plasma metabolites, AT parameters, SCFA, and gut permeability were unchanged. In conclusion, intake of wheat bran extract increases fecal Bifidobacterium and softens stool consistency without major effects on energy metabolism in healthy humans with a slow GI transit. We show that overall gut microbiota classified responders with decreased WGTT after AXOS highlighting that GI transit and change thereof were associated with gut microbiota independent of Bifidobacterium. NCT02491125.

Obesity is associated with many adverse health effects, such as an increased cardiometabolic risk. Despite higher adiposity for a given BMI, premenopausal women are at lower risk of cardiometabolic disease than men of the same age. This cardiometabolic advantage in women seems to disappear after the menopause or when type 2 diabetes mellitus develops. Sexual dimorphism in substrate supply and utilization, deposition of excess lipids and mobilization of stored lipids in various key metabolic organs (such as adipose tissue, skeletal muscle and the liver) are associated with differences in tissue-specific insulin sensitivity and cardiometabolic risk profiles between men and women. Moreover, lifestyle-related factors and epigenetic and genetic mechanisms seem to affect metabolic complications and disease risk in a sex-specific manner. This Review provides insight into sexual dimorphism in adipose tissue distribution, adipose tissue, skeletal muscle and liver substrate metabolism and tissue-specific insulin sensitivity in humans, as well as the underlying mechanisms, and addresses the effect of these sex differences on cardiometabolic health. Additionally, this Review highlights the implications of sexual dimorphism in the pathophysiology of obesity-related cardiometabolic risk for the development of sex-specific prevention and treatment strategies.

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 nuclear-magnetic-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.