Fasting and postprandial plasma metabolite responses to a 12-week dietary intervention in tissue-specific insulin resistance: a secondary analysis of the PERSON randomized trial.

BACKGROUND: We previously showed that dietary intervention effects on cardiometabolic health were driven by tissue-specific insulin resistance (IR) phenotype: individuals with predominant muscle IR (MIR) benefitted more from a low-fat, high-protein, high-fiber diet (LFHP), while individuals with predominant liver IR (LIR) benefitted more from a diet rich in mono-unsaturated fat (HMUFA). OBJECTIVE: To further characterize the effects of LFHP and HMUFA diets and their interaction with tissue-specific IR, we investigated dietary intervention effects on fasting and postprandial plasma metabolite profile. METHODS: Adults with MIR or LIR (40-75 years, BMI 25-40 kg/m2) were randomized to a 12-week HMUFA or LFHP diet (n=242). After exclusion of statin use, 214 participants were included in this pre-specified secondary analysis. Plasma samples were collected before (T=0) and after (T=30, 60, 120, 240 min) a high-fat mixed meal for quantification of 247 metabolite measures using nuclear magnetic resonance spectroscopy. RESULTS: A larger reduction in fasting VLDL-TAG and VLDL particle size was observed in individuals with MIR following the LFHP diet and those with LIR following the HMUFA diet, although no longer statistically significant after false discovery rate (FDR) adjustment. No IR phenotype-diet interactions were found for postprandial plasma metabolites assessed as total area under the curve (tAUC). Irrespective of IR phenotype, the LFHP diet induced greater reductions in postprandial plasma tAUC of the larger VLDL particles and small HDL particles, and TAG content in most VLDL subclasses and the smaller LDL and HDL subclasses (e.g. VLDL-TAG tAUC standardized mean change [95% CI] LFHP = -0.29 [-0.43, -0.16] compared to HMUFA = -0.04 [-0.16, 0.09]; FDR-adjusted P for Diet x Time = 0.041). CONCLUSIONS: Diet effects on plasma metabolite profiles were more pronounced than phenotype-diet interactions. A LFHP diet may be more effective than a HMUFA diet for reducing cardiometabolic risk in individuals with tissue-specific IR, irrespective of IR phenotype. GOV REGISTRATION: NCT03708419, https://clinicaltrials.gov/study/NCT03708419?term=NCT03708419&rank=1 CCMO REGISTRATION: NL63768.068.17, https://www.toetsingonline.nl/to/ccmo_search.nsf/fABRpop?readform&unids=3969AABCD9BA27FEC12587F1001BCC65.

Leveraging continuous glucose monitoring for personalized modeling of insulin-regulated glucose metabolism.

Continuous glucose monitoring (CGM) is a promising, minimally invasive alternative to plasma glucose measurements for calibrating physiology-based mathematical models of insulin-regulated glucose metabolism, reducing the reliance on in-clinic measurements. However, the use of CGM glucose, particularly in combination with insulin measurements, to develop personalized models of glucose regulation remains unexplored. Here, we simultaneously measured interstitial glucose concentrations using CGM as well as plasma glucose and insulin concentrations during an oral glucose tolerance test (OGTT) in individuals with overweight or obesity to calibrate personalized models of glucose-insulin dynamics. We compared the use of interstitial glucose with plasma glucose in model calibration, and evaluated the effects on model fit, identifiability, and model parameters' association with clinically relevant metabolic indicators. Models calibrated on both plasma and interstitial glucose resulted in good model fit, and the parameter estimates associated with metabolic indicators such as insulin sensitivity measures in both cases. Moreover, practical identifiability of model parameters was improved in models estimated on CGM glucose compared to plasma glucose. Together these results suggest that CGM glucose may be considered as a minimally invasive alternative to plasma glucose measurements in model calibration to quantify the dynamics of glucose regulation.

Immunometabolic Signatures of Circulating Monocytes in Humans with Obesity and Insulin Resistance.

Obesity is associated with chronic inflammation and metabolic complications, including insulin resistance (IR). Immune cells drive inflammation through the rewiring of intracellular metabolism. However, the impact of obesity-related IR on the metabolism and functionality of circulating immune cells, like monocytes, remains poorly understood. To increase insight into the inter-individual variation of immunometabolic signatures among individuals and their role in the development of IR, we assessed systemic and tissue-specific IR and circulating immune markers, and we characterized metabolic signatures and cytokine secretion of circulating monocytes from 194 individuals with a BMI≥25kg/m2. Monocyte metabolic signatures were defined using extracellular acidification rates (ECAR) to estimate glycolysis and oxygen consumption rates (OCR) for oxidative metabolism. Although monocyte metabolic signatures and function based on cytokine secretion varied greatly among subjects, they were strongly associated with each other. The ECAR/OCR ratio, representing the balance between glycolysis and oxidative metabolism, was negatively associated with fasting insulin, systemic IR, and liver-specific IR. These results indicate that monocytes from individuals with IR were relatively more dependent on oxidative metabolism, while monocytes from more insulinsensitive individuals were more dependent on glycolysis. Additionally, circulating CXCL11 was negatively associated with the degree of systemic IR and positively with the ECAR/OCR ratio in monocytes, suggesting that individuals with high IR and a monocyte metabolic dependence on oxidative metabolism also have lower levels of circulating CXCL11. Our findings suggest that monocyte metabolism is related to obesity-associated IR progression and deepen insights into the interplay between innate immune cell metabolism and IR development in humans.

Body composition and body fat distribution in tissue-specific insulin resistance and in response to a 12-week isocaloric dietary macronutrient intervention.

BACKGROUND: Body composition and body fat distribution are important predictors of cardiometabolic diseases. The etiology of cardiometabolic diseases is heterogenous, and partly driven by inter-individual differences in tissue-specific insulin sensitivity. OBJECTIVES: To investigate (1) the associations between body composition and whole-body, liver and muscle insulin sensitivity, and (2) changes in body composition and insulin sensitivity and their relationship after a 12-week isocaloric diet high in mono-unsaturated fatty acids (HMUFA) or a low-fat, high-protein, high-fiber (LFHP) diet. METHODS: This subcohort analysis of the PERSON study includes 93 individuals (53% women, BMI 25-40 kg/m2, 40-75 years) who participated in this randomized intervention study. At baseline and after 12 weeks of following the LFHP, or HMUFA diet, we performed a 7-point oral glucose tolerance test to assess whole-body, liver, and muscle insulin sensitivity, and whole-body magnetic resonance imaging to determine body composition and body fat distribution. Both diets are within the guidelines of healthy nutrition. RESULTS: At baseline, liver fat content was associated with worse liver insulin sensitivity (ß [95%CI]; 0.12 [0.01; 0.22]). Only in women, thigh muscle fat content was inversely related to muscle insulin sensitivity (-0.27 [-0.48; -0.05]). Visceral adipose tissue (VAT) was inversely associated with whole-body, liver, and muscle insulin sensitivity. Both diets decreased VAT, abdominal subcutaneous adipose tissue (aSAT), and liver fat, but not whole-body and tissue-specific insulin sensitivity with no differences between diets. Waist circumference, however, decreased more following the LFHP diet as compared to the HMUFA diet (-3.0 vs. -0.5 cm, respectively). After the LFHP but not HMUFA diet, improvements in body composition were positively associated with improvements in whole-body and liver insulin sensitivity. CONCLUSIONS: Liver and muscle insulin sensitivity are distinctly associated with liver and muscle fat accumulation. Although both LFHP and HMUFA diets improved in body fat, VAT, aSAT, and liver fat, only LFHP-induced improvements in body composition are associated with improved insulin sensitivity. TRIAL REGISTRATION: NCT03708419 (clinicaltrials.gov).

The individual response to antibiotics and diet - insights into gut microbial resilience and host metabolism.

Antibiotic use disrupts microbial composition and activity in humans, but whether this disruption in turn affects host metabolic health is unclear. Cohort studies show associations between antibiotic use and an increased risk of developing obesity and type 2 diabetes mellitus. Here, we review available clinical trials and show the disruptive effect of antibiotic use on the gut microbiome in humans, as well as its impact on bile acid metabolism and microbial metabolites such as short-chain fatty acids. Placebo-controlled human studies do not show a consistent effect of antibiotic use on body weight and insulin sensitivity at a population level, but rather an individual-specific or subgroup-specific response. This response to antibiotic use is affected by the resistance and resilience of the gut microbiome, factors that determine the extent of disruption and the speed of recovery afterwards. Nutritional strategies to improve the composition and functionality of the gut microbiome, as well as its recovery after antibiotic use (for instance, with prebiotics), require a personalized approach to increase their efficacy. Improved insights into key factors that influence the individual-specific response to antibiotics and dietary intervention may lead to better efficacy in reversing or preventing antibiotic-induced microbial dysbiosis as well as strategies for preventing cardiometabolic diseases.

Identification of circulating apolipoprotein M as a new determinant of insulin sensitivity and relationship with adiponectin.

BACKGROUND: The adiponectin is one of the rare adipokines down-regulated with obesity and protects against obesity-related disorders. Similarly, the apolipoprotein M (apoM) is expressed in adipocytes and its expression in adipose tissue is associated with metabolic health. We compared circulating apoM with adiponectin regarding their relationship with metabolic parameters and insulin sensitivity and examined their gene expression patterns in adipocytes and in the adipose tissue. METHODS: Circulating apoM and adiponectin were examined in 169 men with overweight in a cross-sectional study, and 13 patients with obesity during a surgery-induced slimming program. Correlations with clinical parameters including the insulin resistance index (HOMA-IR) were analyzed. Multiple regression analyses were performed on HOMA-IR. The APOM and ADIPOQ gene expression were measured in the adipose tissue from 267 individuals with obesity and a human adipocyte cell line. RESULTS: Participants with type 2 diabetes had lower circulating adiponectin and apoM, while apoM was higher in individuals with dyslipidemia. Similar to adiponectin, apoM showed negative associations with HOMA-IR and hs-CRP (r < -0.2), and positive correlations with HDL markers (HDL-C and apoA-I, r > 0.3). Unlike adiponectin, apoM was positively associated with LDL markers (LDL-C and apoB100, r < 0.20) and negatively correlated with insulin and age (r < -0.2). The apoM was the sole negative determinant of HOMA-IR in multiple regression models, while adiponectin not contributing significantly. After surgery, the change in HOMA-IR was negatively associated with the change in circulating apoM (r = -0.71), but not with the change in adiponectin. The APOM and ADIPOQ gene expression positively correlated in adipose tissue (r > 0.44) as well as in adipocytes (r > 0.81). In adipocytes, APOM was downregulated by inflammatory factors and upregulated by adiponectin. CONCLUSIONS: The apoM rises as a new partner of adiponectin regarding insulin sensitivity. At the adipose tissue level, the adiponectin may be supported by apoM to promote a healthy adipose tissue. TRIAL REGISTRATION: NCT01277068, registered 13 January 2011; NCT02332434, registered 5 January 2015; and NCT00390637, registered 20 October 2006.

Hepatic insulin resistance and muscle insulin resistance are characterized by distinct postprandial plasma metabolite profiles: a cross-sectional study.

BACKGROUND: Tissue-specific insulin resistance (IR) predominantly in muscle (muscle IR) or liver (liver IR) has previously been linked to distinct fasting metabolite profiles, but postprandial metabolite profiles have not been investigated in tissue-specific IR yet. Given the importance of postprandial metabolic impairments in the pathophysiology of cardiometabolic diseases, we compared postprandial plasma metabolite profiles in response to a high-fat mixed meal between individuals with predominant muscle IR or liver IR. METHODS: This cross-sectional study included data from 214 women and men with BMI 25-40 kg/m2, aged 40-75 years, and with predominant muscle IR or liver IR. Tissue-specific IR was assessed using the muscle insulin sensitivity index (MISI) and hepatic insulin resistance index (HIRI), which were calculated from the glucose and insulin responses during a 7-point oral glucose tolerance test. Plasma samples were collected before (T = 0) and after (T = 30, 60, 120, 240 min) consumption of a high-fat mixed meal and 247 metabolite measures, including lipoproteins, cholesterol, triacylglycerol (TAG), ketone bodies, and amino acids, were quantified using nuclear magnetic resonance spectroscopy. Differences in postprandial plasma metabolite iAUCs between muscle and liver IR were tested using ANCOVA with adjustment for age, sex, center, BMI, and waist-to-hip ratio. P-values were adjusted for a false discovery rate (FDR) of 0.05 using the Benjamini-Hochberg method. RESULTS: Sixty-eight postprandial metabolite iAUCs were significantly different between liver and muscle IR. Liver IR was characterized by greater plasma iAUCs of large VLDL (p = 0.004), very large VLDL (p = 0.002), and medium-sized LDL particles (p = 0.026), and by greater iAUCs of TAG in small VLDL (p = 0.025), large VLDL (p = 0.003), very large VLDL (p = 0.002), all LDL subclasses (all p < 0.05), and small HDL particles (p = 0.011), compared to muscle IR. In liver IR, the postprandial plasma fatty acid (FA) profile consisted of a higher percentage of saturated FA (p = 0.013), and a lower percentage of polyunsaturated FA (p = 0.008), compared to muscle IR. CONCLUSION: People with muscle IR or liver IR have distinct postprandial plasma metabolite profiles, with more unfavorable postprandial metabolite responses in those with liver IR compared to muscle IR.

Impaired mitochondrial respiration in upper compared to lower body differentiated human adipocytes and adipose tissue.

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 OXPHOS protein expression and 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 lower in upper compared to lower body differentiated hMADS and AT, respectively, in postmenopausal women.

Fetuin B in white adipose tissue induces inflammation and is associated with peripheral insulin resistance in mice and humans.

OBJECTIVE: Fetuin B is a steatosis-responsive hepatokine that causes glucose intolerance in mice, but the underlying mechanisms remain incompletely described. This study aimed to elucidate the mechanisms of action of fetuin B by investigating its putative effects on white adipose tissue metabolism. METHODS: First, fetuin B gene and protein expression was measured in multiple organs in mice and in cultured adipocytes. Next, the authors performed a hyperinsulinemic-euglycemic clamp in mice and in humans to examine the link between white adipose tissue fetuin B content and indices of insulin sensitivity. Finally, the effect of fetuin B on inflammation was investigated in cultured adipocytes by quantitative polymerase chain reaction and full RNA sequencing. RESULTS: This study demonstrated in adipocytes and mice that fetuin B was produced and secreted by the liver and taken up by adipocytes and adipose tissue. There was a strong negative correlation between white adipose tissue fetuin B content and peripheral insulin sensitivity in mice and in humans. RNA sequencing and polymerase chain reaction analysis revealed that fetuin B induced an inflammatory response in adipocytes. CONCLUSIONS: Fetuin B content in white adipose tissue strongly associated with peripheral insulin resistance in mice and humans. Furthermore, fetuin B induced a proinflammatory response in adipocytes, which might drive peripheral insulin resistance.

Greater male variability in daily energy expenditure develops through puberty.

There is considerably greater variation in metabolic rates between men than between women, in terms of basal, activity and total (daily) energy expenditure (EE). One possible explanation is that EE is associated with male sexual characteristics (which are known to vary more than other traits) such as musculature and athletic capacity. Such traits might be predicted to be most prominent during periods of adolescence and young adulthood, when sexual behaviour develops and peaks. We tested this hypothesis on a large dataset by comparing the amount of male variation and female variation in total EE, activity EE and basal EE, at different life stages, along with several morphological traits: height, fat free mass and fat mass. Total EE, and to some degree also activity EE, exhibit considerable greater male variation (GMV) in young adults, and then a decreasing GMV in progressively older individuals. Arguably, basal EE, and also morphometrics, do not exhibit this pattern. These findings suggest that single male sexual characteristics may not exhibit peak GMV in young adulthood, however total and perhaps also activity EE, associated with many morphological and physiological traits combined, do exhibit GMV most prominently during the reproductive life stages.

Metabolic phenotyping in people living with obesity: Implications for dietary prevention.

Given the increasing number of people living with obesity and related chronic metabolic disease, precision nutrition approaches are required to increase the effectiveness of prevention strategies. This review addresses these approaches in different metabolic phenotypes (metabotypes) in obesity. Although obesity is typically associated with an increased cardiometabolic disease risk, some people with obesity are relatively protected against the detrimental effects of excess adiposity on cardiometabolic health, also referred to as 'metabolically healthy obesity' (MHO). Underlying mechanisms, the extent to which MHO is a transient state as well as lifestyle strategies to counteract the transition from MHO to metabolically unhealthy obesity (MUO) are discussed. Based on the limited resources that are available for dietary lifestyle interventions, it may be reasonable to prioritize interventions for people with MUO, since targeting high-risk patients for specific nutritional, lifestyle or weight-loss strategies may enhance the cost-effectiveness of these interventions. Additionally, the concept of tissue insulin resistant (IR) metabotypes is discussed, representing distinct etiologies towards type 2 diabetes (T2D) as well as cardiovascular disease (CVD). Recent evidence indicates that these tissue IR metabotypes, already present in individuals with obesity with a normal glucose homeostasis, respond differentially to diet. Modulation of dietary macronutrient composition according to these metabotypes may considerably improve cardiometabolic health benefits. Thus, nutritional or lifestyle intervention may improve cardiometabolic health, even with only minor or no weight loss, which stresses the importance of focusing on a healthy lifestyle and not on weight loss only. Targeting different metabotypes towards T2D and cardiometabolic diseases may lead to more effective lifestyle prevention and treatment strategies. Age and sex-related differences in tissue metabotypes and related microbial composition and functionality (fermentation), as important drivers and/or mediators of dietary intervention response, have to be taken into account. For the implementation of these approaches, more prospective trials are required to provide the knowledge base for precision nutrition in the prevention of chronic metabolic diseases.

2'-fucosyllactose alone or combined with resistant starch increases circulating short-chain fatty acids in lean men and men with prediabetes and obesity.

Background: Infusion of short-chain fatty acids (SCFA) to the distal colon beneficially affects human substrate and energy metabolism. Here, we hypothesized that the combination of 2'-fucosyllactose (2'-FL) with resistant starch (RS) increases distal colonic SCFA production and improves metabolic parameters. Methods: In this randomized, crossover study, 10 lean (BMI 20-24.9 kg/m2) and nine men with prediabetes and overweight/obesity (BMI 25-35 kg/m2) were supplemented with either 2'-FL, 2'-FL+RS, or placebo one day before a clinical investigation day (CID). During the CID, blood samples were collected after a overnight fast and after intake of a liquid high-fat mixed meal to determine plasma SCFA (primary outcomes). Secondary outcomes were fasting and postprandial plasma insulin, glucose, free fatty acid (FFA), glucagon-like peptide-1, and peptide YY concentrations. In addition, fecal SCFA and microbiota composition, energy expenditure and substrate oxidation (indirect calorimetry), and breath hydrogen excretion were determined. Results: In lean men, supplementation with 2'-FL increased postprandial plasma acetate (P = 0.017) and fasting H2 excretion (P = 0.041) compared to placebo. Postprandial plasma butyrate concentration increased after 2'-FL and 2'-FL+RS as compared to placebo (P < 0.05) in lean men and men with prediabetes and overweight/obesity. Additionally, 2'-FL+RS decreased fasting and postprandial plasma FFA concentrations compared to placebo (P < 0.05) in lean men. Conclusion: Supplementation of 2'-FL with/without RS the day before investigation increased systemic butyrate concentrations in lean men as well as in men with prediabetes and obesity, while acetate only increased in lean men. The combination of 2'-FL with RS showed a putatively beneficial metabolic effect by lowering plasma FFA in lean men, indicating a phenotype-specific effect. Clinical trial registration: nr. NCT04795804.

Distinct inflammatory signatures of upper and lower body adipose tissue and adipocytes in women with normal weight or obesity.

Introduction: Upper and lower body fat accumulation poses an opposing obesity-related cardiometabolic disease risk. Depot-differences in subcutaneous adipose tissue (SAT) function may underlie these associations. We aimed to investigate the inflammatory signatures of abdominal (ABD) and femoral (FEM) SAT in postmenopausal women with normal weight or obesity. Methods: We included 23 postmenopausal women with normal weight (n = 13) or obesity (n = 10). In vivo secretion of adipokines from ABD and FEM SAT was measured using the arterio-venous balance technique. Adipokine gene expression and adipocyte morphology were examined in ABD and FEM SAT. Furthermore, adipokine expression and secretion were investigated in vitro using differentiated human primary ABD and FEM subcutaneous adipocytes derived from the study participants. Results: Plasma leptin and plasminogen activator inhibitor (PAI)-1 concentrations were higher, and ABD and FEM adipocytes were larger in women with obesity than normal weight. No differences in adipocyte size and blood flow were apparent between ABD and FEM SAT. We found significant release of leptin and monocyte chemoattractant protein (MCP)-1 from ABD and FEM SAT, with higher fractional release of MCP-1 from ABD than FEM SAT. Gene expression of leptin, PAI-1, and tumor necrosis factor-α was lower in ABD than FEM SAT and higher in women with obesity than normal weight. In ABD adipocytes, interleukin-6, PAI-1, and leptin gene expression were higher, while adiponectin and dipeptidyl-peptidase-4 gene expression were lower than in FEM adipocytes. Finally, ABD adipocytes secreted less MCP-1 compared to FEM adipocytes. Discussion: These findings demonstrate that upper and lower body SAT and adipocytes are characterized by distinct inflammatory signatures in postmenopausal women, which seem independent of adipocyte size.

Quantifying postprandial glucose responses using a hybrid modeling approach: Combining mechanistic and data-driven models in The Maastricht Study.

Computational models of human glucose homeostasis can provide insight into the physiological processes underlying the observed inter-individual variability in glucose regulation. Modelling approaches ranging from "bottom-up" mechanistic models to "top-down" data-driven techniques have been applied to untangle the complex interactions underlying progressive disturbances in glucose homeostasis. While both approaches offer distinct benefits, a combined approach taking the best of both worlds has yet to be explored. Here, we propose a sequential combination of a mechanistic and a data-driven modeling approach to quantify individuals' glucose and insulin responses to an oral glucose tolerance test, using cross sectional data from 2968 individuals from a large observational prospective population-based cohort, the Maastricht Study. The best predictive performance, measured by R2 and mean squared error of prediction, was achieved with personalized mechanistic models alone. The addition of a data-driven model did not improve predictive performance. The personalized mechanistic models consistently outperformed the data-driven and the combined model approaches, demonstrating the strength and suitability of bottom-up mechanistic models in describing the dynamic glucose and insulin response to oral glucose tolerance tests.

The effect of weight loss on whole-body and tissue-specific insulin sensitivity and hepatic lipid content and composition: SWEET substudy.

OBJECTIVE: This study (1) investigated the effect of weight loss on whole-body and tissue-specific insulin sensitivity and on intrahepatic lipid (IHL) content and composition and (2) investigated the association between weight-loss-induced changes in insulin sensitivity and IHL content in individuals with overweight or obesity. METHODS: In this secondary analysis of the European SWEET project, 50 adults (age 18-65 years) with overweight or obesity (BMI ≥ 25 kg/m2 ) followed a low-energy diet (LED) for 2 months. At baseline and after the LED, body composition (dual-energy x-ray absorptiometry), IHL content and composition (proton magnetic resonance spectroscopy), whole-body insulin sensitivity (Matsuda index), muscle insulin sensitivity index (MISI), and hepatic insulin resistance index (HIRI) were determined (7-point oral glucose tolerance test). RESULTS: The LED reduced body weight (p < 0.001). This was accompanied by increased Matsuda index and reduced HIRI (both p < 0.001) but no change in MISI (p = 0.260). Weight loss decreased IHL content (mean [SEM], 3.9% [0.7%] vs. 1.6% [0.5%], p < 0.001) and the hepatic saturated fatty acid fraction (41.0% [1.5%] vs. 36.6% [1.9%], p = 0.039). The reduced IHL content was associated with an improvement in HIRI (r = 0.402, p = 0.025). CONCLUSIONS: Weight loss decreased IHL content and the hepatic saturated fatty acid fraction. The decrease in IHL content was associated with weight-loss-induced improvement in hepatic insulin sensitivity in individuals with overweight or obesity.

Influence of the gut microbiota on satiety signaling.

Recent studies show a link between the gut microbiota and the regulation of satiety and energy intake, processes that contribute to the development and pathophysiology of metabolic diseases. However, this link is predominantly established in animal and in vitro studies, whereas human intervention studies are scarce. In this review we focus on recent evidence linking satiety and the gut microbiome, with specific emphasis on gut microbial short-chain fatty acids (SCFAs). Based on a systematic search we provide an overview of human studies linking the intake of prebiotics with gut microbial alterations and satiety signaling. Our outcomes highlight the importance of in-depth examination of the gut microbiota in relation to satiety and provide insights into recent and future studies in this field.

Baseline gene expression in subcutaneous adipose tissue predicts diet-induced weight loss in individuals with obesity.

Background: Weight loss effectively reduces cardiometabolic health risks among people with overweight and obesity, but inter-individual variability in weight loss maintenance is large. Here we studied whether baseline gene expression in subcutaneous adipose tissue predicts diet-induced weight loss success. Methods: Within the 8-month multicenter dietary intervention study DiOGenes, we classified a low weight-losers (low-WL) group and a high-WL group based on median weight loss percentage (9.9%) from 281 individuals. Using RNA sequencing, we identified the significantly differentially expressed genes between high-WL and low-WL at baseline and their enriched pathways. We used this information together with support vector machines with linear kernel to build classifier models that predict the weight loss classes. Results: Prediction models based on a selection of genes that are associated with the discovered pathways 'lipid metabolism' (max AUC = 0.74, 95% CI [0.62-0.86]) and 'response to virus' (max AUC = 0.72, 95% CI [0.61-0.83]) predicted the weight-loss classes high-WL/low-WL significantly better than models based on randomly selected genes (P < 0.01). The performance of the models based on 'response to virus' genes is highly dependent on those genes that are also associated with lipid metabolism. Incorporation of baseline clinical factors into these models did not noticeably enhance the model performance in most of the runs. This study demonstrates that baseline adipose tissue gene expression data, together with supervised machine learning, facilitates the characterization of the determinants of successful weight loss.

Circulating and adipose tissue immune cells in tissue-specific insulin resistance in humans with overweight and obesity.

OBJECTIVE: 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. METHODS: Individuals with overweight and obesity from the PERSonalized Glucose Optimization Through Nutritional Intervention (PERSON) Study (n = 219) and the Maastricht Study (replication cohort; n = 1256) underwent a seven-point oral glucose tolerance test to assess liver and muscle insulin sensitivity, and circulating inflammatory markers were determined. In subgroups, flow cytometry was performed to identify circulating and aSAT immune cells, and aSAT gene expression was evaluated. RESULTS: The relative abundances of circulating T cells, nonclassical monocytes, and CD56dim CD16+ natural killer cells were inversely associated with liver, but not muscle, insulin sensitivity in the PERSON Study. The inverse association between circulating (classical) monocytes and liver insulin sensitivity was confirmed in the Maastricht Study. In aSAT, immune cell populations were not related to insulin sensitivity. Furthermore, aSAT gene expression of interleukin 6 and CD14 was positively associated with muscle, but not liver, insulin sensitivity. CONCLUSIONS: The present findings demonstrate that circulating immune cell populations and inflammatory gene expression in aSAT show distinct associations with liver and muscle insulin sensitivity.

The impact of mild hypoxia exposure on myokine secretion in human obesity.

BACKGROUND/OBJECTIVE: Compelling evidence indicates that myokines act in an autocrine, paracrine and endocrine manner to alter metabolic homeostasis. The mechanisms underlying exercise-induced changes in myokine secretion remain to be elucidated. Since exercise acutely decreases oxygen partial pressure (pO2) in skeletal muscle (SM), the present study was designed to test the hypothesis that (1) hypoxia exposure impacts myokine secretion in primary human myotubes and (2) exposure to mild hypoxia in vivo alters fasting and postprandial plasma myokine concentrations in humans. METHODS: Differentiated primary human myotubes were exposed to different physiological pO2 levels for 24 h, and cell culture medium was harvested to determine myokine secretion. Furthermore, we performed a randomized single-blind crossover trial to investigate the impact of mild intermittent hypoxia exposure (MIH: 7-day exposure to 15% O2, 3x2h/day vs. normoxia: 21% O2) on in vivo SM pO2 and plasma myokine concentrations in 12 individuals with overweight and obesity (body-mass index ≥ 28 kg/m2). RESULTS: Hypoxia exposure (1% O2) increased secreted protein acidic and rich in cysteine (SPARC, p = 0.043) and follistatin like 1 (FSTL1, p = 0.021), and reduced leukemia inhibitory factor (LIF) secretion (p = 0.009) compared to 3% O2 in primary human myotubes. In addition, 1% O2 exposure increased interleukin-6 (IL-6, p = 0.004) and SPARC secretion (p = 0.021), whilst reducing fatty acid binding protein 3 (FABP3) secretion (p = 0.021) compared to 21% O2. MIH exposure in vivo markedly decreased SM pO2 (≈40%, p = 0.002) but did not alter plasma myokine concentrations. CONCLUSIONS: Hypoxia exposure altered the secretion of several myokines in primary human myotubes, revealing hypoxia as a novel modulator of myokine secretion. However, both acute and 7-day MIH exposure did not induce alterations in plasma myokine concentrations in individuals with overweight and obesity. CLINICAL TRIALS IDENTIFIER: This study is registered at the Netherlands Trial Register (NL7120/NTR7325).

An integrated single cell and spatial transcriptomic map of human white adipose tissue.

To date, single-cell studies of human white adipose tissue (WAT) have been based on small cohort sizes and no cellular consensus nomenclature exists. Herein, we performed a comprehensive meta-analysis of publicly available and newly generated single-cell, single-nucleus, and spatial transcriptomic results from human subcutaneous, omental, and perivascular WAT. Our high-resolution map is built on data from ten studies and allowed us to robustly identify >60 subpopulations of adipocytes, fibroblast and adipogenic progenitors, vascular, and immune cells. Using these results, we deconvolved spatial and bulk transcriptomic data from nine additional cohorts to provide spatial and clinical dimensions to the map. This identified cell-cell interactions as well as relationships between specific cell subtypes and insulin resistance, dyslipidemia, adipocyte volume, and lipolysis upon long-term weight changes. Altogether, our meta-map provides a rich resource defining the cellular and microarchitectural landscape of human WAT and describes the associations between specific cell types and metabolic states.