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.

P2Y13 receptor deficiency favors adipose tissue lipolysis and worsens insulin resistance and fatty liver disease.

Excessive lipolysis in white adipose tissue (WAT) leads to insulin resistance (IR) and ectopic fat accumulation in insulin-sensitive tissues. However, the impact of Gi-coupled receptors in restraining adipocyte lipolysis through inhibition of cAMP production remained poorly elucidated. Given that the Gi-coupled P2Y13 receptor (P2Y13-R) is a purinergic receptor expressed in WAT, we investigated its role in adipocyte lipolysis and its effect on IR and metabolic dysfunction-associated steatotic liver disease (MASLD). In humans, mRNA expression of P2Y13-R in WAT was negatively correlated to adipocyte lipolysis. In mice, adipocytes lacking P2Y13-R displayed higher intracellular cAMP levels, indicating impaired Gi signaling. Consistently, the absence of P2Y13-R was linked to increased lipolysis in adipocytes and WAT explants via hormone-sensitive lipase activation. Metabolic studies indicated that mice lacking P2Y13-R showed a greater susceptibility to diet-induced IR, systemic inflammation, and MASLD compared with their wild-type counterparts. Assays conducted on precision-cut liver slices exposed to WAT conditioned medium and on liver-specific P2Y13-R-knockdown mice suggested that P2Y13-R activity in WAT protects from hepatic steatosis, independently of liver P2Y13-R expression. In conclusion, our findings support the idea that targeting adipose P2Y13-R activity may represent a pharmacological strategy to prevent obesity-associated disorders, including type 2 diabetes and MASLD.

Sex differences in adipose insulin resistance are linked to obesity, lipolysis and insulin receptor substrate 1.

BACKGROUND/OBJECTIVE: Insulin resistance is more prominent in men than women. If this involves adipose tissue is unknown and was presently examined. SUBJECTS/METHODS: AdipoIR (in vivo adipose insulin resistance index) was measured in 2344 women and 787 men. In 259 of the women and 54 of the men, insulin induced inhibition of lipolysis (acylglycerol breakdown) and stimulation of lipogenesis (glucose conversion to acylglycerols) were determined in subcutaneous adipocytes; in addition, basal (spontaneous) lipolysis was also determined in the fat cells. In 234 women and 115 men, RNAseq expression of canonical insulin signal genes were measured in subcutaneous adipose tissue. Messenger RNA transcripts of the most discriminant genes were quantified in 175 women and 109 men. RESULTS: Men had higher AdipoIR values than women but only when obesity (body mass index 30 kg/m2 or more) was present (p < 0.0001). The latter sex dimorphism was found among physically active and sedentary people, in those with and without cardiometabolic disease and in people using nicotine or not (p = 0.0003 or less). In obesity, adipocyte insulin sensitivity (half maximum effective hormone concentration) and maximal antilipolytic effect were tenfold and 10% lower, respectively, in men than women (p = 0.005 or less). Basal rate of lipolysis was two times higher in men than women (p > 0.0001). Sensitivity and maximum effect of insulin on lipogenesis were similar in both sexes (p = 0.26 and p = 0.18, respectively). When corrected for multiple comparison only RNAseq expression of insulin receptor substrate 1 (IRS1) was lower in men than women (p < 0.0001). The mRNA transcript for IRS1 was 60% higher in women than men (p < 0.0001). CONCLUSIONS: In obesity, adipose tissue insulin resistance is more pronounced in men than in women. The mechanism involves less efficient insulin-mediated inhibition of adipocyte lipolysis, increased basal rate of lipolysis and decreased adipose expression of a key element of insulin signaling, IRS1.

Common mouse models of chronic kidney disease are not associated with cachexia.

The 5/6 nephrectomy and adenine-induced nephropathy mouse models have been extensively used to study Chronic Kidney Disease (CKD)-related cachexia. One common caveat of these CKD models is the cross-sectional nature of comparisons made versus controls. We here performed a comprehensive longitudinal assessment of body composition and energy metabolism in both models. The most striking finding is that weight loss is largely driven by reduced food intake which promotes rapid loss of lean and fat mass. However, in both models, mice catch up weight and lean mass a few days after the surgery or when they are switched back to standard chow diet. Muscle force and mass are fully recovered and no sign of cachexia is observed. Our data demonstrate that the time-course of kidney failure and weight loss are unrelated in these common CKD models. These data highlight the need to reconsider the relative contribution of direct and indirect mechanisms to muscle wasting observed in CKD.

Gpcpd1-GPC metabolic pathway is dysfunctional in aging and its deficiency severely perturbs glucose metabolism.

Skeletal muscle plays a central role in the regulation of systemic metabolism during lifespan. With aging, this function is perturbed, initiating multiple chronic diseases. Our knowledge of mechanisms responsible for this decline is limited. Glycerophosphocholine phosphodiesterase 1 (Gpcpd1) is a highly abundant muscle enzyme that hydrolyzes glycerophosphocholine (GPC). The physiological functions of Gpcpd1 remain largely unknown. Here we show, in mice, that the Gpcpd1-GPC metabolic pathway is perturbed in aged muscles. Further, muscle-specific, but not liver- or fat-specific, inactivation of Gpcpd1 resulted in severely impaired glucose metabolism. Western-type diets markedly worsened this condition. Mechanistically, Gpcpd1 muscle deficiency resulted in accumulation of GPC, causing an 'aged-like' transcriptomic signature and impaired insulin signaling in young Gpcpd1-deficient muscles. Finally, we report that the muscle GPC levels are markedly altered in both aged humans and patients with type 2 diabetes, displaying a high positive correlation between GPC levels and chronological age. Our findings reveal that the muscle GPCPD1-GPC metabolic pathway has an important role in the regulation of glucose homeostasis and that it is impaired during aging, which may contribute to glucose intolerance in aging.

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.

Plasma level of ATPase inhibitory factor 1 (IF1) is associated with type 2 diabetes risk in humans: A prospective cohort study.

AIM: Mitochondrial dysfunction is associated with the development of type 2 diabetes mellitus (T2DM). It is thus of clinical relevance to identify plasma biomarkers of mitochondrial dysfunction associated with the risk of T2DM. ATPase inhibitory factor 1 (IF1) endogenously inhibits mitochondrial ATP synthase activity. Here, we analyzed association of the plasma IF1 level with markers of glucose homeostasis and with the conversion to new-onset diabetes (NOD) in individuals with prediabetes. METHODS: In the IT-DIAB prospective study, the baseline plasma level of IF1 was measured in 307 participants with prediabetes. The primary outcome was the incidence of NOD within five years of follow-up. Cross-sectional analysis of the IF1 level was also done in two independent interventional studies. Correlations between plasma IF1 and metabolic parameters at baseline were assessed by Spearman's correlation coefficients, and the association with the risk of NOD was determined using Cox proportional-hazards models. RESULTS: In IT-DIAB, the mean IF1 plasma level was lower in participants who developed NOD than in those who did not (537 ± 248 versus 621 ± 313 ng/mL, P   = 0.01). The plasma IF1 level negatively correlated with clinical variables associated with obesity and insulin resistance, including the body mass index (r = -0.20, P  = 0.0005) and homeostasis model assessment of insulin resistance (HOMA-IR). (r = -0.37, P < 0.0001). Conversely, IF1 was positively associated with plasma markers of cardiometabolic health, such as HDL-C (r = 0.63, P  <  0.0001) and apoA-I (r = 0.33, P  <  0.0001). These correlations were confirmed in cross-sectional analyses. In IT-DIAB, the IF1 level was significantly associated with a lower risk of T2DM after adjustment for age, sex, and fasting plasma glucose (HR [95% CI] per 1 SD = 0.76 [0.62; 0.94], P   = 0.012). CONCLUSION: We identified for the first time the mitochondrial-related biomarker IF1 as being associated with the risk of T2DM.

Network Analyses Reveal Negative Link Between Changes in Adipose Tissue GDF15 and BMI During Dietary-induced Weight Loss.

CONTEXT: Adipose tissue (AT) transcriptome studies provide holistic pictures of adaptation to weight and related bioclinical settings changes. OBJECTIVE: To implement AT gene expression profiling and investigate the link between changes in bioclinical parameters and AT gene expression during 3 steps of a 2-phase dietary intervention (DI). METHODS: AT transcriptome profiling was obtained from sequencing 1051 samples, corresponding to 556 distinct individuals enrolled in a weight loss intervention (8-week low-calorie diet (LCD) at 800 kcal/day) followed with a 6-month ad libitum randomized DI. Transcriptome profiles obtained with QuantSeq sequencing were benchmarked against Illumina RNAseq. Reverse transcription quantitative polymerase chain reaction was used to further confirm associations. Cell specificity was assessed using freshly isolated cells and THP-1 cell line. RESULTS: During LCD, 5 modules were found, of which 3 included at least 1 bioclinical variable. Change in body mass index (BMI) connected with changes in mRNA level of genes with inflammatory response signature. In this module, change in BMI was negatively associated with changes in expression of genes encoding secreted protein (GDF15, CCL3, and SPP1). Through all phases of the DI, change in GDF15 was connected to changes in SPP1, CCL3, LIPA and CD68. Further characterization showed that these genes were specific to macrophages (with LIPA, CD68 and GDF15 expressed in anti-inflammatory macrophages) and GDF15 also expressed in preadipocytes. CONCLUSION: Network analyses identified a novel AT feature with GDF15 upregulated with calorie restriction induced weight loss, concomitantly to macrophage markers. In AT, GDF15 was expressed in preadipocytes and macrophages where it was a hallmark of anti-inflammatory cells.

Adipose-Derived Lipid-Binding Proteins: The Good, the Bad and the Metabolic Diseases.

Adipose tissue releases a large range of bioactive factors called adipokines, many of which are involved in inflammation, glucose homeostasis and lipid metabolism. Under pathological conditions such as obesity, most of the adipokines are upregulated and considered as deleterious, due to their pro-inflammatory, pro-atherosclerotic or pro-diabetic properties, while only a few are downregulated and would be designated as beneficial adipokines, thanks to their counteracting properties against the onset of comorbidities. This review focuses on six adipose-derived lipid-binding proteins that have emerged as key factors in the development of obesity and diabetes: Retinol binding protein 4 (RBP4), Fatty acid binding protein 4 (FABP4), Apolipoprotein D (APOD), Lipocalin-2 (LCN2), Lipocalin-14 (LCN14) and Apolipoprotein M (APOM). These proteins share structural homology and capacity to bind small hydrophobic molecules but display opposite effects on glucose and lipid metabolism. RBP4 and FABP4 are positively associated with metabolic syndrome, while APOD and LCN2 are ubiquitously expressed proteins with deleterious or beneficial effects, depending on their anatomical site of expression. LCN14 and APOM have been recently identified as adipokines associated with healthy metabolism. Recent findings on these lipid-binding proteins exhibiting detrimental or protective roles in human and murine metabolism and their involvement in metabolic diseases are also discussed.

Metabolic and cardiovascular adaptations to an 8-wk lifestyle weight loss intervention in younger and older obese men.

The number of older obese adults is increasing worldwide. Whether obese adults show similar health benefits in response to lifestyle interventions at different ages is unknown. The study enrolled 25 obese men (body mass index: 31-39 kg/m2) in two arms according to age (30-40 and 60-70 yr old). Participants underwent an 8-wk intervention with moderate calorie restriction (∼20% below individual energy requirements) and supervised endurance training resulting in ∼5% weight loss. Body composition was measured using dual energy X-ray absorptiometry. Insulin sensitivity was assessed during a hypersinsulinemic-euglycemic clamp. Cardiometabolic profile was derived from blood parameters. Subcutaneous fat and vastus lateralis muscle biopsies were used for ex vivo analyses. Two-way repeated-measure ANOVA and linear mixed models were used to evaluate the response to lifestyle intervention and comparison between the two groups. Fat mass was decreased and bone mass was preserved in the two groups after intervention. Muscle mass decreased significantly in older obese men. Cardiovascular risk (Framingham risk score, plasma triglyceride, and cholesterol) and insulin sensitivity were greatly improved to a similar extent in the two age groups after intervention. Changes in adipose tissue and skeletal muscle transcriptomes were marginal. Analysis of the differential response to the lifestyle intervention showed tenuous differences between age groups. These data suggest that lifestyle intervention combining calorie restriction and exercise shows similar beneficial effects on cardiometabolic risk and insulin sensitivity in younger and older obese men. However, attention must be paid to potential loss of muscle mass in response to weight loss in older obese men.NEW & NOTEWORTHY Rise in obesity and aging worldwide are major trends of critical importance in public health. This study addresses a current challenge in obesity management. Do older obese adults respond differently to a lifestyle intervention composed of moderate calorie restriction and supervised physical activity than younger ones? The main conclusion of the study is that older and younger obese men similarly benefit from the intervention in terms of cardiometabolic risk.

Atrial Natriuretic Peptide Orchestrates a Coordinated Physiological Response to Fuel Non-shivering Thermogenesis.

Atrial natriuretic peptide (ANP) is a cardiac hormone controlling blood volume and pressure in mammals. It is still unclear whether ANP controls cold-induced thermogenesis in vivo. Here, we show that acute cold exposure induces cardiac ANP secretion in mice and humans. Genetic inactivation of ANP promotes cold intolerance and suppresses half of cold-induced brown adipose tissue (BAT) activation in mice. While white adipocytes are resistant to ANP-mediated lipolysis at thermoneutral temperature in mice, cold exposure renders white adipocytes fully responsive to ANP to activate lipolysis and a thermogenic program, a physiological response that is dramatically suppressed in ANP null mice. ANP deficiency also blunts liver triglycerides and glycogen metabolism, thus impairing fuel availability for BAT thermogenesis. ANP directly increases mitochondrial uncoupling and thermogenic gene expression in human white and brown adipocytes. Together, these results indicate that ANP is a major physiological trigger of BAT thermogenesis upon cold exposure in mammals.

Integrative phenotyping of glycemic responders upon clinical weight loss using multi-omics.

Weight loss aims to improve glycemic control in obese but strong variability is observed. Using a multi-omics approach, we investigated differences between 174 responders and 201 non-responders, that had lost >8% body weight following a low-caloric diet (LCD, 800 kcal/d for 8 weeks). The two groups were comparable at baseline for body composition, glycemic control, adipose tissue transcriptomics and plasma ketone bodies. But they differed significantly in their response to LCD, including improvements in visceral fat, overall insulin resistance (IR) and tissue-specific IR. Transcriptomics analyses found down-regulation in key lipogenic genes (e.g. SCD, ELOVL5) in responders relative to non-responders; metabolomics showed increase in ketone bodies; while proteomics revealed differences in lipoproteins. Findings were consistent between genders; with women displaying smaller improvements owing to a better baseline metabolic condition. Integrative analyses identified a plasma omics model that was able to predict non-responders with strong performance (on a testing dataset, the Receiving Operating Curve Area Under the Curve (ROC AUC) was 75% with 95% Confidence Intervals (CI) [67%, 83%]). This model was based on baseline parameters without the need for intrusive measurements and outperformed clinical models (p = 0.00075, with a +14% difference on the ROC AUCs). Our approach document differences between responders and non-responders, with strong contributions from liver and adipose tissues. Differences may be due to de novo lipogenesis, keto-metabolism and lipoprotein metabolism. These findings are useful for clinical practice to better characterize non-responders both prior and during weight loss.

Growth and differentiation factor 15 is secreted by skeletal muscle during exercise and promotes lipolysis in humans.

We hypothesized that skeletal muscle contraction produces a cellular stress signal, triggering adipose tissue lipolysis to sustain fuel availability during exercise. The present study aimed at identifying exercise-regulated myokines, also known as exerkines, able to promote lipolysis. Human primary myotubes from lean healthy volunteers were submitted to electrical pulse stimulation (EPS) to mimic either acute intense or chronic moderate exercise. Conditioned media (CM) experiments with human adipocytes were performed. CM and human plasma samples were analyzed using unbiased proteomic screening and/or ELISA. Real-time qPCR was performed in cultured myotubes and muscle biopsy samples. CM from both acute intense and chronic moderate exercise increased basal lipolysis in human adipocytes. Growth and differentiation factor 15 (GDF15) gene expression and secretion increased rapidly upon skeletal muscle contraction. GDF15 protein was upregulated in CM from both acute and chronic exercise-stimulated myotubes. We further showed that physiological concentrations of recombinant GDF15 protein increased lipolysis in human adipose tissue, while blocking GDF15 with a neutralizing antibody abrogated EPS CM-mediated lipolysis. We herein provide the first evidence to our knowledge that GDF15 is a potentially novel exerkine produced by skeletal muscle contraction and able to target human adipose tissue to promote lipolysis.

Apolipoprotein M: new connections with diet, adipose tissue and metabolic syndrome.

PURPOSE OF REVIEW: To focus on state-of-the-art knowledge on the apolipoprotein M (ApoM) physiology and physiopathology regarding metabolism. RECENT FINDINGS: In humans, the ApoM was recently described as secreted by adipocytes. Obesity, metabolic syndrome and type 2 diabetes are associated with low circulating ApoM and adipose tissue APOM expression. Dieting-induced weight loss enhances adipose tissue expression and secretion, and exercise training increases plasma ApoM. The ApoM is a chaperone for the bioactive sphingolipid, sphingosine-1-phosphate (S1P), which has a specific role in inflammation. Its association with S1P in the inhibition of brown adipose tissue activity and subsequent insulin sensitivity was reported with the model of ApoM-deficient mouse. SUMMARY: The adipose tissue is an endocrine organ responsible for obesity-related comorbidities. Obesity and dieting impact the adipose tissue secretory profile. The recent demonstration of ApoM being secreted by healthy adipocytes questions about the possible role of this adipose production in metabolic diseases. Low-circulating ApoM is associated with unhealthy metabolic phenotype. The lower circulating apoM during metabolic syndrome might be a cause of obesity-related comorbidities. Lifestyle interventions enhance ApoM production. Whether it acts in combination to S1P or other small lipidic molecules deserves further investigations.

Apolipoprotein M: a novel adipokine decreasing with obesity and upregulated by calorie restriction.

BACKGROUND: The adipose tissue (AT) is a secretory organ producing a wide variety of factors that participate in the genesis of metabolic disorders linked to excess fat mass. Weight loss improves obesity-related disorders. OBJECTIVES: Transcriptomic studies on human AT, and a combination of analyses of transcriptome and proteome profiling of conditioned media from adipocytes and stromal cells isolated from human AT, have led to the identification of apolipoprotein M (apoM) as a putative adipokine. We aimed to validate apoM as novel adipokine, investigate the relation of AT APOM expression with metabolic syndrome and insulin sensitivity, and study the regulation of its expression in AT and secretion during calorie restriction-induced weight loss. METHODS: We examined APOM mRNA level and secretion in AT from 485 individuals enrolled in 5 independent clinical trials, and in vitro in human multipotent adipose-derived stem cell adipocytes. APOM expression and secretion were measured during dieting. RESULTS: APOM was expressed in human subcutaneous and visceral AT, mainly by adipocytes. ApoM was released into circulation from AT, and plasma apoM concentrations correlate with AT APOM mRNA levels. In AT, APOM expression inversely correlated with adipocyte size, was lower in obese compared to lean individuals, and reduced in subjects with metabolic syndrome and type 2 diabetes. Regardless of fat depot, there was a positive relation between AT APOM expression and systemic insulin sensitivity, independently of fat mass and plasma HDL cholesterol. In human multipotent adipose-derived stem cell adipocytes, APOM expression was enhanced by insulin-sensitizing peroxisome proliferator-activated receptor agonists and inhibited by tumor necrosis factor α, a cytokine that causes insulin resistance. In obese individuals, calorie restriction increased AT APOM expression and secretion. CONCLUSIONS: ApoM is a novel adipokine, the expression of which is a hallmark of healthy AT and is upregulated by calorie restriction. AT apoM deserves further investigation as a potential biomarker of risk for diabetes and cardiovascular diseases.

Genome-wide gene-based analyses of weight loss interventions identify a potential role for NKX6.3 in metabolism.

Hundreds of genetic variants have been associated with Body Mass Index (BMI) through genome-wide association studies (GWAS) using observational cohorts. However, the genetic contribution to efficient weight loss in response to dietary intervention remains unknown. We perform a GWAS in two large low-caloric diet intervention cohorts of obese participants. Two loci close to NKX6.3/MIR486 and RBSG4 are identified in the Canadian discovery cohort (n = 1166) and replicated in the DiOGenes cohort (n = 789). Modulation of HGTX (NKX6.3 ortholog) levels in Drosophila melanogaster leads to significantly altered triglyceride levels. Additional tissue-specific experiments demonstrate an action through the oenocytes, fly hepatocyte-like cells that regulate lipid metabolism. Our results identify genetic variants associated with the efficacy of weight loss in obese subjects and identify a role for NKX6.3 in lipid metabolism, and thereby possibly weight control.

Interaction between hormone-sensitive lipase and ChREBP in fat cells controls insulin sensitivity.

Impaired adipose tissue insulin signalling is a critical feature of insulin resistance. Here we identify a pathway linking the lipolytic enzyme hormone-sensitive lipase (HSL) to insulin action via the glucose-responsive transcription factor ChREBP and its target, the fatty acid elongase ELOVL6. Genetic inhibition of HSL in human adipocytes and mouse adipose tissue results in enhanced insulin sensitivity and induction of ELOVL6. ELOVL6 promotes an increase in phospholipid oleic acid, which modifies plasma membrane fluidity and enhances insulin signalling. HSL deficiency-mediated effects are suppressed by gene silencing of ChREBP and ELOVL6. Mechanistically, physical interaction between HSL, independent of lipase activity, and the isoform activated by glucose metabolism ChREBPα impairs ChREBPα translocation into the nucleus and induction of ChREBPß, the isoform with high transcriptional activity that is strongly associated with whole-body insulin sensitivity. Targeting the HSL-ChREBP interaction may allow therapeutic strategies for the restoration of insulin sensitivity.

Niacin induces miR-502-3p expression which impairs insulin sensitivity in human adipocytes.

MicroRNAs have been involved in insulin resistance (IR). As the mechanism whereby niacin, an anti-dyslipidemic agent, leads to IR remains elusive, we sought to identify differentially expressed microRNAs in adipose tissue (AT) of individuals receiving niacin and to explore the link between microRNAs, niacin and IR in human adipocytes.In a double-blind controlled study, 22 obese men received extended-release niacin or placebo over 8 weeks. Bioclinical data and subcutaneous AT biopsies were obtained before and after treatment. AT microRNA expression profiles were determined using RTqPCR for 758 human-specific microRNAs. hMADS adipocytes were treated with niacin, or acipimox (a niacin-like drug without effect on IR), or transfected with miR-502-3p. Glucose uptake and Western blotting were performed.In obese men, insulin sensitivity decreased after niacin treatment. In AT, the expression of 6 microRNAs including miR-502-3p was up-regulated. Treatment of hMADS adipocytes with niacin specifically increased miR-502-3p expression. Acipimox had no effect. Overexpression of miR-502-3p in adipocytes led to reduced insulin-induced glucose uptake and lower insulin-stimulated AKT phosphorylation.Long term niacin treatment altered microRNA expression levels in human AT. Increased miR-502-3p expression may play a role in the mediation of IR due to niacin in adipocytes.The study is registered in Clinical Trials NCT01083329 and EudraCT 2009-012124-85.

FADS1 genotype is distinguished by human subcutaneous adipose tissue fatty acids, but not inflammatory gene expression.

BACKGROUND: Single nucleotide polymorphisms (SNPs) in FADS1/FADS2 genes are associated with changes in serum and tissue polyunsaturated fatty acid (PUFA) content. PUFA regulate inflammatory signaling pathways in adipose tissue; however, the effect of SNPs in FADS1/FADS2 on adipose tissue inflammation is equivocal. The present study examined if SNPs in FADS1/FADS2 modify human subcutaneous adipose tissue (SAT) fatty acid profiles and the expression of genes associated with inflammation/immune function, lipid metabolism, and cellular differentiation. METHODS: SAT fatty acids and the expression of 117 genes were measured in 174 men and women from the DiOGenes Study using gas chromatography and qRT-PCR, respectively. Associations between fatty acids, gene expression, and SNPs in FADS1/FADS2 were investigated by linear regression and multivariate analysis. RESULTS: Four SNPs (rs174537, rs174546, rs174556, rs174601) in FADS1/FADS2 were significantly associated with SAT fatty acids. All SNPs were in high linkage disequilibrium with the commonly reported rs174537 SNP in FADS1. Minor allele carriers for rs174537 (GT+TT) had reduced 20:4n-6 (p = 1.74E-5), lower delta-5 desaturase enzyme activity (p = 2.09E-9), and lower FADS1 gene expression (p = 0.03) compared to major GG carriers. Multivariate analysis revealed that 20:4n-6 and 20:3n-6 explained ~19% of the variance between rs174537 genotypes, while gene expression explained <7%. Receiver operating characteristic (ROC) curves indicated that rs174537 genotype can be distinguished with SAT fatty acids (AUC = 0.842), but not gene expression (AUC = 0.627). No differences in SAT inflammatory gene expression were observed between rs174537 genotypes. SAT 20:3n-6 levels were positively correlated with the expression of several inflammatory genes, and inversely correlated with FADS1 expression. CONCLUSION: This study showed that FADS1 genotype is distinguished by SAT fatty acid profiles, but not inflammatory gene expression.

Plasma metabolites and lipids predict insulin sensitivity improvement in obese, nondiabetic individuals after a 2-phase dietary intervention.

Background: Weight loss in obese individuals aims to reduce the risk of type 2 diabetes by improving glycemic control. Yet, significant intersubject variability is observed and the outcomes remain poorly predictable. Objective: The aim of the study was to predict whether an individual will show improvements in insulin sensitivity above or below the median population change at 6 mo after a low-calorie-diet (LCD) intervention. Design: With the use of plasma lipidomics and metabolomics for 433 subjects from the Diet, Obesity, and Genes (DiOGenes) Study, we attempted to predict good or poor Matsuda index improvements 6 mo after an 8-wk LCD intervention (800 kcal/d). Three independent analysis groups were defined: "training" (n = 119) for model construction, "testing" (n = 162) for model comparison, and "validation" (n = 152) to validate the final model. Results: Initial modeling with baseline clinical variables (body mass index, Matsuda index, total lipid concentrations, sex, age) showed limited performance [area under the curve (AUC) on the "testing dataset" = 0.69; 95% CI: 0.61, 0.77]. Significantly better performance was achieved with an omics model based on 27 variables (AUC = 0.77; 95% CI: 0.70, 0.85; P = 0.0297). This model could be greatly simplified while keeping the same performance. The simplified model relied on baseline Matsuda index, proline, and phosphatidylcholine 0-34:1. It successfully replicated on the validation set (AUC = 0.75; 95% CI: 0.67, 0.83) with the following characteristics: specificity = 0.73, sensitivity = 0.68, negative predictive value = 0.60, and positive predictive value = 0.80. Marginally lower performance was obtained when replacing the Matsuda index with homeostasis model assessment of insulin resistance (AUC = 0.72; 95% CI: 0.64, 0.80; P = 0.08). Conclusions: Our study proposes a model to predict insulin sensitivity improvements, 6 mo after LCD completion in a large population of overweight or obese nondiabetic subjects. It relies on baseline information from 3 variables, accessible from blood samples. This model may help clinicians assessing the large variability in dietary interventions and predict outcomes before an intervention. This trial was registered at www.clinicaltrials.gov as NCT00390637.