Insulin Resistance In Obese Subjects Research Articles

OR07-03 UCP1 Expression In Human Brown Adipose Tissue Is Inversely Associated With Cardiometabolic Risk Factors

Abstract Disclosure: T. Kwok: None. L.E. Ramage: None. K.J. Suchacki: None. C. Gray: None. K. Alexandra: None. L.D. Boyle: None. R.K. Semple: None. S.I. Semple: None. T. MacGillivray: None. E.J. van Beek: None. S. Wakelin: None. R.H. Stimson: None. Brown adipose tissue (BAT) is a promising therapeutic target for obesity. 18F-Fluorodeoxyglucose positron emission tomography (18F-FDG PET) is the most commonly used imaging modality to quantify human BAT activity. 18F-FDG uptake may be reduced in obesity but insulin resistance has been suggested as a potential confounding factor. Uncoupling protein 1 (UCP1) is the key thermogenic protein in BAT and thus serves as a surrogate measure of BAT thermogenic capacity. We quantified UCP1 expression in paired BAT and white adipose tissue (WAT) samples from 141 patients undergoing elective neck surgery. UCP1 mRNA was quantified in whole tissue (n=53) and differentiated pre-adipocytes (n=88). Data are presented as mean ± SEM. Individuals with high UCP1 expression in whole BAT (>2 arbitrary units) were younger (44.2 ± 3.5 vs 55.7 ± 2.0 years) with lower BMI (26.5 ± 1.2 vs 30.1 ± 1.0kg/m2), waist circumference (87.9 ± 2.9 vs 101.1 ± 2.6cm), waist-hip ratio (0.86 ± 0.01 vs 0.92 ± 0.01), fat percentage (29.1 ± 2.6 vs 35.3 ± 1.7%), insulin resistance (HOMA-IR 1.44 ± 0.18 vs 2.69 ± 0.35), systolic (131 ± 6 vs 143 ± 4mmHg) and diastolic blood pressure (79 ± 3 vs 86 ± 2mmHg) (all P<0.05). BAT UCP1 expression was lower in subjects on beta-blockers or with existing hypertension. BAT (but not WAT) UCP1 expression correlated negatively with age (r=−0.305), weight (r=−0.374), waist circumference (r=−0.296), fat mass (r=−0.388) and BMI (r=−0.282) (all P<0.05). However, UCP1 levels in differentiated brown adipocytes were not associated with any of the above measurements. In multiple regression, age was the only independent predictor of high BAT UCP1 expression. Interestingly, BAT UCP1 levels were not reduced in obese subjects aged <40 years. To determine whether BAT activity was preserved in young obese subjects in vivo, we performed 18F-FDG-PET/MR scanning during mild cold exposure (16-17°C) in 6 normal weight (BMI 22 ± 1kg/m2) and 6 obese (BMI 32 ± 1kg/m2) age-matched (22 ± 1 years) subjects. BAT 18F-FDG uptake (standard uptake value 5.1 ± 0.5 vs 4.2 ± 0.6 g/mL) and volume (69 ± 14 vs 72 ± 32 cm3) were similar between weight groups, despite greater insulin resistance in obese subjects (fasting glucose 5.5 ± 0.2 vs 4.3 ± 0.1mmol/L, insulin 11.9 ± 1.3 vs 5.8 ± 0.9mU/L, HOMA-IR 2.9 ± 0.3 vs 1.1 ± 0.2, free fatty acids 465 ± 78 vs 240 ± 34µM, all P<0.05), suggesting that 18F-FDG uptake by BAT is not significantly affected by insulin resistance. In conclusion, BAT UCP1 expression is reduced in individuals with adverse cardiometabolic risk factors, but these subjects retain brown pre-adipocytes with the capacity to form new thermogenic adipocytes after appropriate stimulation. UCP1 expression and cold-induced 18F-FDG uptake by BAT is preserved in young obese subjects. These data highlight the therapeutic potential of BAT mass expansion and activation as a therapeutic strategy to ameliorate the cardiometabolic consequences of obesity. Presentation: Thursday, June 15, 2023

D-Allulose Ameliorates Dysregulated Macrophage Function and Mitochondrial NADH Homeostasis, Mitigating Obesity-Induced Insulin Resistance.

D-allulose, a rare sugar, has been proposed to have potential benefits in addressing metabolic disorders such as obesity and type 2 diabetes (T2D). However, the precise mechanisms underlying these effects remain poorly understood. We aimed to elucidate the mechanisms by which D-allulose influences obesity-induced insulin resistance. We conducted gene set enrichment analysis on the liver and white adipose tissue of mice exposed to a high-fat diet (HFD) along with the white adipose tissue of individuals with obesity. Our study revealed that D-allulose effectively suppressed IFN-γ, restored chemokine signaling, and enhanced macrophage function in the livers of HFD-fed mice. This implies that D-allulose curtails liver inflammation, alleviating insulin resistance and subsequently impacting adipose tissue. Furthermore, D-allulose supplementation improved mitochondrial NADH homeostasis and translation in both the liver and white adipose tissue of HFD-fed mice. Notably, we observed decreased NADH homeostasis and mitochondrial translation in the omental tissue of insulin-resistant obese subjects compared to their insulin-sensitive counterparts. Taken together, these results suggest that supplementation with allulose improves obesity-induced insulin resistance by mitigating the disruptions in macrophage and mitochondrial function. Furthermore, our data reinforce the crucial role that mitochondrial energy expenditure plays in the development of insulin resistance triggered by obesity.

TXLNG improves insulin resistance in obese subjects in vitro and in vivo by inhibiting ATF4 transcriptional activity

Lipotoxicity contributes to insulin resistance and dysfunction of pancreatic β-cells. Insulin promotes 3T3-L1 preadipocyte differentiation and facilitates glucose entry into muscle, adipose, and other tissues. In this study, differential gene expression was analyzed using four datasets, and taxilin gamma (TXLNG) was the only shared downregulated gene in all four datasets. TXLNG expression was significantly reduced in obese subjects according to online datasets and in high-fat diet (HFD)-induced insulin-resistant (IR) mice according to experimental investigations. TXLNG overexpression significantly improved IR induced by HFD in mouse models by reducing body weight and epididymal adipose weight, decreasing mRNA expression of pro-inflammatory factors interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α), and reducing adipocyte size. High-glucose/high-insulin-stimulated adipocytes exhibited decreased TXLNG and increased signal transducer and activator of transcription 3 (STAT3) and activating transcription factor 4 (ATF4). IR significantly decreased glucose uptake, cell surface glucose transporter type 4 (GLUT4) levels, and Akt phosphorylation, while increasing the mRNA expression levels of IL-6 and TNF-α in adipocytes. However, these changes were significantly reversed by TXLNG overexpression, while they were exacerbated by TXLNG knockdown. TXLNG overexpression had no effect on ATF4 protein levels, while ATF4 overexpression increased ATF4 protein levels. Furthermore, ATF4 overexpression notably abolished the improvements in IR adipocyte dysfunction caused by TXLNG overexpression. In conclusion, TXLNG improves IR in obese subjects in vitro and in vivo by inhibiting ATF4 transcriptional activity.

Impaired Insulin Clearance as the Initial Regulator of Obesity-Associated Hyperinsulinemia: Novel Insight Into the Underlying Mechanism Based on Serum Bile Acid Profiles.

To investigate the roles of insulin clearance and insulin secretion in the development of hyperinsulinemia in obese subjects and to reveal the association between insulin clearance and bile acids (BAs). In cohort 1, insulin secretion, sensitivity, and endogenous insulin clearance were evaluated with an oral glucose tolerance test in 460 recruited participants. In cohort 2, 81 participants underwent an intravenous glucose tolerance test and a hyperinsulinemic-euglycemic clamp to assess insulin secretion, endogenous and exogenous insulin clearance, and insulin sensitivity. Based on insulin resistance levels ranging from mild to severe, obese participants without diabetes were further divided into 10 quantiles in cohort 1 and into tertiles in cohort 2. Forty serum BAs were measured in cohort 2 to examine the association between BAs and insulin clearance. All obese participants had impaired insulin clearance, and it worsened with additional insulin resistance in obese subjects without diabetes. However, insulin secretion was unchanged from quantile 1 to 3 in cohort 1, and no difference was found in cohort 2. After adjustments for all confounding factors, serum-conjugated BAs, especially glycodeoxycholic acid (GDCA; β = -0.335, P = 0.004) and taurodeoxycholic acid (TDCA; β = -0.333, P = 0.003), were negatively correlated with insulin clearance. The ratio of unconjugated to conjugated BAs (β = 0.335, P = 0.002) was positively correlated with insulin clearance. Hyperinsulinemia in obese subjects might be primarily induced by decreased insulin clearance rather than increased insulin secretion. Changes in circulating conjugated BAs, especially GDCA and TDCA, might play an important role in regulating insulin clearance.

Weight loss after Roux-En-Y gastric bypass surgery reveals skeletal muscle DNA methylation changes

BackgroundThe mechanisms of weight loss and metabolic improvements following bariatric surgery in skeletal muscle are not well known; however, epigenetic modifications are likely to contribute. The aim of our study was to investigate skeletal muscle DNA methylation after weight loss induced by Roux-en-Y gastric bypass (RYGB) surgery. Muscle biopsies were obtained basally from seven insulin-resistant obese (BMI > 40 kg/m2) female subjects (45.1 ± 3.6 years) pre- and 3-month post-surgery with euglycemic hyperinsulinemic clamps to assess insulin sensitivity. Four lean (BMI < 25 kg/m2) females (38.5 ± 5.8 years) served as controls. We performed reduced representation bisulfite sequencing next generation methylation on DNA isolated from the vastus lateralis muscle biopsies.ResultsGlobal methylation was significantly higher in the pre- (32.97 ± 0.02%) and post-surgery (33.31 ± 0.02%) compared to the lean (30.46 ± 0.02%), P < 0.05. MethylSig analysis identified 117 differentially methylated cytosines (DMCs) that were significantly altered in the post- versus pre-surgery (Benjamini–Hochberg q < 0.05). In addition, 2978 DMCs were significantly altered in the pre-surgery obese versus the lean controls (Benjamini–Hochberg q < 0.05). For the post-surgery obese versus the lean controls, 2885 DMCs were altered (Benjamini–Hochberg q < 0.05). Seven post-surgery obese DMCs were normalized to levels similar to those observed in lean controls. Of these, 5 were within intergenic regions (chr11.68,968,018, chr16.73,100,688, chr5.174,115,531, chr5.1,831,958 and chr9.98,547,011) and the remaining two DMCs chr17.45,330,989 and chr14.105,353,824 were within in the integrin beta 3 (ITGB3) promoter and KIAA0284 exon, respectively. ITGB3 methylation was significantly decreased in the post-surgery (0.5 ± 0.5%) and lean controls (0 ± 0%) versus pre-surgery (13.6 ± 2.7%, P < 0.05). This decreased methylation post-surgery was associated with an increase in ITGB3 gene expression (fold change + 1.52, P = 0.0087). In addition, we showed that ITGB3 promoter methylation in vitro significantly suppressed transcriptional activity (P < 0.05). Transcription factor binding analysis for ITGB3 chr17.45,330,989 identified three putative transcription factor binding motifs; PAX-5, p53 and AP-2alphaA.ConclusionsThese results demonstrate that weight loss after RYGB alters the epigenome through DNA methylation. In particular, this study highlights ITGB3 as a novel gene that may contribute to the metabolic improvements observed post-surgery. Future additional studies are warranted to address the exact mechanism of ITGB3 in skeletal muscle.

Triglycerides to High-Density Lipoprotein Cholesterol Ratio Is the Best Surrogate Marker for Insulin Resistance in Nonobese Middle-Aged and Elderly Population: A Cross-Sectional Study

Objective Insulin resistance (IR) is closely associated with metabolic profiles, including obesity and dyslipidemia. The aim of the present study was to examine how lipid profiles were associated with IR in nonobese middle-aged and elderly Chinese population. Methods This cross-sectional study included 1608 subjects. IR was defined by homeostasis model assessment of insulin resistance (HOMA-IR) of at least 2.5. Results In nonobese subjects (body mass index (BMI) < 25 kg/m2, n = 996), triglyceride (TG) to high-density lipoprotein cholesterol (HDL-C) ratio (odds ratio (OR) = 1.43, 95% confidence interval (CI) 1.13–1.81, P=0.003) was an independent risk factor for IR. The best marker for predicting IR in nonobese subjects was TG/HDL-C ratio with the areas under the receiver operating characteristic curves (AUC) of 0.73 (P < 0.001). The optimal cut-off point to identifying IR for TG/HDL-C ratio was ≥1.50 in the nonobese population. Other markers like BMI, TG, and total cholesterol (TC)/HDL-C also had acceptable discriminatory power for predicting IR in nonobese population (AUC ≥ 0.7 and P < 0.001). BMI had the highest AUC of 0.647 (P < 0.001) after being adjusted, but it was not effective enough to predict IR in obese subjects (BMI ≥ 25.0, n = 612). Conclusions The TG/HDL-C ratio may be the best reliable marker for predicting IR in the nonobese middle-aged and elderly Chinese population.

Pioglitazone does not synergize with mirabegron to increase beige fat or further improve glucose metabolism.

BACKGROUNDBeige and brown adipose tissue (BAT) are associated with improved metabolic homeostasis. We recently reported that the β3-adrenergic receptor agonist mirabegron induced beige adipose tissue in obese insulin-resistant subjects, and this was accompanied by improved glucose metabolism. Here we evaluated pioglitazone treatment with a combination pioglitazone and mirabegron treatment and compared these with previously published data evaluating mirabegron treatment alone. Both drugs were used at FDA-approved dosages.METHODSWe measured BAT by PET CT scans, measured beige adipose tissue by immunohistochemistry, and comprehensively characterized glucose and lipid homeostasis and insulin sensitivity by euglycemic clamp and oral glucose tolerance tests. Subcutaneous white adipose tissue, muscle fiber type composition and capillary density, lipotoxicity, and systemic inflammation were evaluated by immunohistochemistry, gene expression profiling, mass spectroscopy, and ELISAs.RESULTSTreatment with pioglitazone or the combination of pioglitazone and mirabegron increased beige adipose tissue protein marker expression and improved insulin sensitivity and glucose homeostasis, but neither treatment induced BAT in these obese subjects. When the magnitude of the responses to the treatments was evaluated, mirabegron was found to be the most effective at inducing beige adipose tissue. Although monotherapy with either mirabegron or pioglitazone induced adipose beiging, combination treatment resulted in less beiging than either alone. The 3 treatments also had different effects on muscle fiber type switching and capillary density.CONCLUSIONThe addition of pioglitazone to mirabegron treatment does not enhance beiging or increase BAT in obese insulin-resistant research participants.TRIAL REGISTRATIONClinicalTrials.gov NCT02919176.FUNDINGNIH DK112282 and P20GM103527 and Clinical and Translational Science Awards grant UL1TR001998.

Circulating IL-6, clusterin and irisin in obese subjects with different grades of obesity: association with insulin resistance and sexual dimorphism.

There are discrepancies about the relationship of IL-6, clusterin and irisin with obesity and obesity associated insulin resistance and also about their sexual dimorphism. This study aimed at evaluating the circulating levels of IL-6, clusterin and irisin in obese subjects of both sexes who had different grades of obesity and examining their sexual dimorphism and their association with insulin resistance. This study included 176 non-diabetic subjects of both sexes who were classified according to their sex into two groups; the male and the female groups. The male group (88 men) was classified according to BMI into; group 1 (22 lean men), group 2 (22 class I obese men), group 3 (22 class II obese men) and group 4 (22 class III obese men). The female group (88 women) was classified according to BMI exactly as the male group. Metabolic parameters, IL-6, clusterin, and irisin levels were measured. Data were analyzed by ANOVA test, post hoc Tukey's test and independent t-test. Pearson correlation was used to assess the association between variables. In obese subjects of both sexes, circulating IL-6, clusterin and irisin levels were significantly elevated and positively correlated with HOMA-IR. Obese males showed significantly higher HOMA-IR, IL-6, clusterin and irisin levels than obese females. Obesity in both sexes, especially in males was associated with high levels of IL-6, clusterin and irisin and worsened the metabolic pattern. Circulating IL-6, clusterin and irisin may represent possible therapeutic targets for insulin resistance in obese subjects.

Branched-Chain Amino Acids in relation to food preferences and insulin resistance in obese subjects consuming walnuts: A cross-over, randomized, double-blind, placebo-controlled inpatient physiology study

To assess whether the concentrations of circulating Branched-Chain Amino Acids (BCAAs) change after walnut consumption and, whether these changes are associated with alterations in markers of insulin resistance and food preferences. In a crossover, randomized, double-blind, placebo-controlled study, ten subjects participated in two 5-day inpatient study admissions, during which they had a smoothie containing 48g walnuts or a macronutrient-matched placebo smoothie without nuts every morning. Between the two phases there was a 1-month washout period. Fasting valine and isoleucine levels were reduced (p=.047 and p<.001) and beta-hydroxybutyrate levels were increased after 5-days of walnut consumption compared to placebo (p=.023). Fasting valine and isoleucine correlated with HOMA-IR while on walnut (r=0.709, p=.032 and r=0.679, p=.044). The postprandial area under the curve (AUC) of leucine in response to the smoothie consumption on day 5 was higher after walnut vs placebo (p=.023) and correlated negatively with the percentage of Kcal from carbohydrate and protein consumed during an ad libitum buffet meal consumed the same day for lunch (r=-0.661, p=.037; r=-0.628, p=.05, respectively). The fasting and postabsorptive profiles of BCAAs are differentially affected by walnut consumption. The reduction in fasting valine and isoleucine may contribute to the longer-term benefits of walnuts on insulin resistance, cardiovascular risk and mortality, whereas the increase in postabsorptive profiles with walnuts may influence food preference. TRIAL REGISTRATION CLINICALTRIALS.GOV: Number: NCT02673281, Website: https://clinicaltrials.gov/ct2/show/NCT02673281.

Adaptation of Insulin Clearance to Metabolic Demand Is a Key Determinant of Glucose Tolerance.

With the development of insulin resistance (IR), there is a compensatory increase in the plasma insulin response to offset the defect in insulin action to maintain normal glucose tolerance. The insulin response is the result of two factors: insulin secretion and metabolic clearance rate of insulin (MCRI). Subjects (104 with normal glucose tolerance [NGT], 57 with impaired glucose tolerance [IGT], and 207 with type 2 diabetes mellitus [T2DM]), divided in nonobese and obese groups, received a euglycemic insulin-clamp (40 mU/m2 ⋅ min) and an oral glucose tolerance test (OGTT) (75 g) on separate days. MCRI was calculated during the insulin-clamp performed with [3-3H]glucose and the OGTT and related to IR: peripheral (glucose uptake during the insulin clamp), hepatic (basal endogenous glucose production × fasting plasma insulin [FPI]), and adipocyte (fasting free fatty acid × FPI). MCRI during the insulin clamp was reduced in obese versus nonobese NGT (0.60 ± 0.03 vs. 0.73 ± 0.02 L/min ⋅ m2, P < 0.001), in nonobese IGT (0.62 ± 0.02, P < 0.004), and in nonobese T2DM (0.68 ± 0.02, P < 0.03). The MCRI during the insulin clamp was strongly and inversely correlated with IR (r = -0.52, P < 0.0001). During the OGTT, the MCRI was suppressed within 15-30 min in NGT and IGT subjects and remained suppressed. In contrast, suppression was minimal in T2DM. In conclusion, the development of IR in obese subjects is associated with a decline in MCRI that represents a compensatory response to maintain normal glucose tolerance but is impaired in individuals with T2DM.

Serum glypican4 and glycosylphosphatidylinositol-specific phospholipase D levels are associated with adipose tissue insulin resistance in obese subjects with different glucose metabolism status.

Glypican4 (GPC4) is a novel adipokine associated with obesity and insulin resistance. GPC4 was cleaved by the glycosylphosphatidylinositol-specific phospholipase D (GPLD1) in an anchored site of the glycosylphosphatidylinositol, and then was released into the extracellular environment. Herein, we investigated the changes of serum GPC4 and GPLD1 levels in obese subjects with different glucose metabolism status and their relationship with adipose tissue insulin resistance index (Adipo-IR) in Chinese north populations. A total of 221 obese subjects and 37 normal controls (NC) were recruited in this study. Obese subjects were divided into normal insulin (NI) group, hyperinsulinemia (HI) group, impaired glucose tolerance (IGT) group, and type 2 diabetes mellitus (DM) group. Serum GPC4, GPLD1, and adiponectin were determined by commercially available ELISA kits. Serum GPC4 levels in the HI, IGT, and DM groups were significantly higher than those in the NC and NI groups (2.27 ± 0.58ng/mL, 2.21 ± 0.60ng/mL, 2.49 ± 0.67ng/mL vs. 1.70 ± 0.33ng/mL, 1.93 ± 0.34ng/mL, P < 0.05). GPC4 was positively correlated with GPLD1, which was the most important influencing factor of GPC4. Adipo-IR was independently and positively associated with serum GPC4 and GPLD1. For GPC4, afteradjustmentforconfounders, the risk of adipose tissue insulin resistance in subjects with the highest tertile was 2.974-fold that of those with the lowest tertile (OR = 2.974, P = 0.013). For GPLD1, before adjustment for lipids, the increased probability still existed (Model 2, OR = 3.568, P = 0.003). GPC4 is an adipokine associated with adipose tissue insulin resistance, and its activitymay beregulatedby GPLD1. GPC4 may be a marker for adipose tissue insulin resistance in Chinese north obese populations.

1730-P: Thromboxane Signaling and Obesity-Related Insulin Resistance

Background: Thromboxane A2 (TxA2), a lipid mediator plays a critical role in cardiovascular disease and chronic inflammatory disorders. TxA2 signaling is regulated by TxA2 synthase (Tbxas1), an enzyme that produces TxA2, and TxA2 receptor (Tbxa2r). Objective: To determine if Tbxa2r gene expression in adipose tissue (AT) is higher in obese insulin resistant (IR) subjects compared to overweight non-IR subjects. Methods: Insulin resistance was measured via a homeostatic model assessment of insulin resistance (HOMA-IR). Subcutaneous AT biopsies were obtained from overweight (BMI between ≥25 to &amp;lt;30) no IR and obese (BMI ≥30) IR (HOMA-IR&amp;gt;2.5) subjects. Gene expression of Tbxa2r and Tbxas1 were analyzed in tissue samples and compared between groups. Results: The mRNA levels of Tbxa2r and Tbxas1 were significantly higher in obese IR subjects compared to overweight subjects (P&amp;lt;0.05). A positive correlation was observed between AT expression of Tbxa2r and Tbxas1 (Spearman’s r=0.49, n=35, P&amp;lt;0.01). We noted a weak positive correlation between AT Tbxa2r and HOMA-IR (Spearman’s r=0.31, n=35, P&amp;lt;0.07). A positive correlation was also noted between AT Tbxas1 and HOMA-IR (Spearman’s r=0.42, n=37, P&amp;lt;0.05). Conclusion: Our data suggest that TxA2 signaling is activated in AT in obesity and is associated with the development of insulin resistance in obesity. Tbxas1 and/or Tbxa2r may be a potential therapeutic target for obesity-linked metabolic diseases. Disclosure D. Alcaraz Alvarez: None. S. Viswanathan: None. T. Thangavelu: None. N. Kumar: None. K. Kelley: None. C. Desouza: Consultant; Self; AstraZeneca, Bayer AG, Novo Nordisk A/S.

Different Patterns of Left Ventricular Hypertrophy in Metabolically Healthy and Insulin-Resistant Obese Subjects.

Obese subjects showed different cardiovascular risk depending by different insulin sensitivity status. We investigated the difference in left ventricular mass and geometry between metabolically healthy (MHO) and unhealthy (MUHO) obese subjects. From a cohort of 876 obese subjects (48.3 ± 14.1 years) without cardio-metabolic disease and stratified according to increasing values of Matsuda index after 75 g oral glucose tolerance test, we defined MHO (n = 292) those in the upper tertile and MUHO (n = 292) those in the lower tertile. All participants underwent echocardiographic measurements. Left ventricular mass was calculated by Devereux equation and normalized by height2,7 and left ventricular hypertrophy (LVH) was defined by values >44 g/m2.7 for females and >48 g/m2.7 for males. Left ventricular geometric pattern was defined as concentric or eccentric if relative wall thickness was higher or lower than 0.42, respectively. MHO developed more commonly a concentric remodeling (19.9 vs. 9.9%; p = 0.001) and had a reduced risk for LVH (OR 0.46; p < 0.0001) than MUHO, in which the eccentric type was more prevalent (40.4 vs. 5.1%; p < 0.0001). We demonstrated that obese subjects—matched for age, gender and BMI—have different left ventricular mass and geometry due to different insulin sensitivity status, suggesting that diverse metabolic phenotypes lead to alternative myocardial adaptation.

Aging induced by D-galactose aggravates cardiac dysfunction via exacerbating mitochondrial dysfunction in obese insulin-resistant rats.

The prevalence of obesity and an aging population are increasing worldwide. Both obesity and aging are independently known to be associated with cardiac dysfunction. However, in obese insulin-resistant subjects, the effects of aging on metabolic status and cardiac and mitochondrial functions are not completely understood. We hypothesized that in the obese insulin-resistant condition, aging induced by D-galactose increases cardiac senescence markers and aggravates the impairment of metabolic parameters, cardiac and mitochondrial function, and increases oxidative stress, inflammation, apoptosis, and autophagy. Sixty-four male Wistar rats were fed with either normal diet (ND) or high-fat diet (HFD) for 12 weeks. Then, rats were divided into vehicle groups (0.9% NSS, subcutaneous injection (SC)) or D-galactose groups (150 mg/kg/day, SC). After 0.9%NSS or D-galactose treatment for 4 weeks and 8 weeks, metabolic and cardiac functions were determined. The heart was then removed to determine mitochondrial functions and enable biochemical studies. After 4 weeks of D-galactose injection, ND rats treated with D-galactose (NDD4), HFD rats treated with vehicle (HFV4), and HFD rats treated with D-galactose (HFD4) had reduced cardiac function, impaired cardiac mitochondrial function and autophagy, and increased oxidative stress, inflammation, and apoptosis. Interestingly, after 8 weeks, HFD rats treated with D-galactose (HFD8) had the worst impairment of cardiac and mitochondrial function, autophagy, and apoptosis in comparison to the other groups. Aging induced by D-galactose aggravated cardiac dysfunction in obese insulin-resistant rats through the worsening of cardiac mitochondrial function, autophagy, and increased apoptosis in a time-dependent manner.

Suppression of enteroendocrine cell glucagon-like peptide (GLP)-1 release by fat-induced small intestinal ketogenesis: a mechanism targeted by Roux-en-Y gastric bypass surgery but not by preoperative very-low-calorie diet

ObjectiveFood intake normally stimulates release of satiety and insulin-stimulating intestinal hormones, such as glucagon-like peptide (GLP)-1. This response is blunted in obese insulin resistant subjects, but is rapidly restored following...

Selenoprotein W deficiency does not affect oxidative stress and insulin sensitivity in the skeletal muscle of high-fat diet-fed obese mice.

Selenoprotein W (SelW) is a selenium-containing protein with a redox motif found abundantly in the skeletal muscle of rodents. Previous in vitro studies suggest that SelW plays an antioxidant role; however, relatively few in vivo studies have addressed the antioxidant role of SelW. Since oxidative stress is a causative factor for the development of insulin resistance in obese subjects, we hypothesized that if SelW plays a role as an antioxidant, SelW deficiency could aggravate the oxidative stress and insulin resistance caused by a high-fat diet. SelW deficiency did not affect insulin sensitivity and H2O2 levels in the skeletal muscle of control diet-fed mice. SelW levels in the skeletal muscle were decreased by high-fat diet feeding for 12 wk. High-fat diet induced obesity and insulin resistance and increased the levels of H2O2 and oxidative stress makers, which were not affected by SelW deficiency. High-fat diet feeding increased the expression of antioxidant enzymes; however, SelW deficiency did not affect the expression levels of antioxidants. These results suggest that SelW does not play a protective role against oxidative stress and insulin resistance in the skeletal muscle of high-fat diet-fed obese mice.

Serum CTRP3 Levels In Obese Children: A Potential Protective Adipokine Of Obesity, Insulin Sensitivity And Pancreatic β Cell Function.

PurposeCTRP3 is a novel peptide that has recently emerged as an important regulatory adipokine of obesity and related metabolic disease. Little is known about its role in children. The current study aimed to investigate the potential role of CTRP3 in obese children and explore its relationships with insulin sensitivity, pancreatic β cell function, and obesity-related markers.Patients and methodsWe studied the levels of serum CTRP3 in 48 obese and 36 normal weight pre-puberty children. The levels of blood pressure, lipids, glucose, and insulin were measured, and the values of HOMA-IR, HOMA-β and insulinogenic index were calculated. The correlations of these measurements with CTRP3 levels were analyzed.ResultsIn this study, we found that CTRP3 serum levels significantly decreased in obese children compared to controls, and insulin resistant obese subjects have lower CTRP3 levels in contrast with the non-insulin resistant obese subjects. Moreover, serum CTRP3 concentrations significantly decreased, while glucose and insulin concentrations significantly increased after a 3 hrs oral glucose tolerance test in obese children. Furthermore, Serum CTRP3 levels correlated negatively and significantly with BMI, triglycerides, systolic blood pressure, fasting insulin, glucose, HOMA-IR, HOMA-β and insulinogenic index in obese children.ConclusionIn summary, serum CTRP3 levels significantly decreased in obese children, and negatively correlated with insulin resistance and pancreatic β cell function indicators. Therefore, CTRP3 may play a protective role in the glucose homeostasis and tightly related to β cell function as well as obesity-related markers in obese children.

Two-Hour Postprandial Lipoprotein Particle Concentration Differs Between Lean and Obese Individuals.

The concentrations of lipoprotein particles [high-density lipoproteins (HDLs), low-density lipoproteins (LDLs), very-low-density lipoproteins (VLDLs), and chylomicrons] are associated with the risk of cardiovascular diseases. Most studies have examined these associations in the fasting state. Previous studies have shown lipoprotein particle concentration change following meal, and these changes are different in individuals with obesity. In this study, we aimed to assess whether various meal compositions lead to adverse short-term (2-h) postprandial lipoproteinemia in obese insulin resistant (obese-IR) subjects as compared to lean insulin sensitive (lean-IS) subjects. In a randomized crossover trial, nine lean-IS and nine obese-IR Chinese men aged 22–35 years were challenged with isoenergetic and isovolumic meals rich in protein (HP), fat (HF), or carbohydrate (HC). Plasma samples were collected after a 10-h fast, as well as 1-h and 2-h post-meal and analyzed using nuclear magnetic resonance. Plasma concentration of large VLDLs and chylomicron particles was higher and increased more after all meals in obese-IR compared to lean-IS subjects. The HP meal decreased small LDL particle concentration in obese-IR subjects, and increased small HDL particle concentration in all subjects. The HF meal led to a decrease in small HDL concentration in all subjects. In conclusion, obese-IR subjects revealed a detrimental response to meal challenges even as early as 2-h after meal intake.

1941-P: The Relationship among Intramyocellular Lipid, Peak Oxygen Consumption, and Insulin Resistance in Nonobese Japanese Men

Accumulation of intramyocellular lipid (IMCL) is observed not only in insulin resistant obese subjects with low peak oxygen consumption (VO2peak), but also in insulin sensitive endurance athletes with high VO2peak (athlete’s paradox). While the relationship among intramyocellular lipid, peak oxygen consumption and insulin resistance is variable among the different subjects, its relation within non-obese non-athlete subject has not been elucidated yet. To investigate this relation, we studied 61 non-obese (BMI&amp;lt;25kg/m2) non-athlete Japanese men. We evaluated muscle insulin sensitivity (M-IS) by a 2-step hyperinsulinemic euglycemic clamp. We divided the subjects into 4 groups based on the median value of VO2 peak (31.4 ml/kg per min) and the IMCL in soleus muscles (14.3 s-fat/Cre), then we compared M-IS. Compared with Low-VO2peak/High-IMCL group, M-IS was significantly higher in High-VO2peak/Low-IMCL group and High-VO2peak/High-IMCL group (Fig). On the other hand, M-IS was comparable between High-VO2peak/Low-IMCL group and High-VO2peak/High-IMCL group. These results suggest that in non-obese non-athlete Japanese men, VO2peaklevel is an important determinant of muscle insulin sensitivity in IMCL accumulated subjects. In addition, IMCL accumulation is not an important determinant of muscle insulin sensitivity in subjects with high VO2peak. Disclosure N. Yamasaki: None. Y. Tamura: None. K. Takeno: None. S. Kakehi: None. Y. Someya: None. T. Funayama: None. Y. Furukawa: None. H. Kaga: None. R. Suzuki: None. D. Sugimoto: None. S. Kadowaki: None. M. Sato: None. R. Kawamori: None. H. Watada: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Kissei Pharmaceutical Co., Ltd., Merck Sharp &amp; Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Pfizer Inc., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited. Speaker's Bureau; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sanofi, Takeda Pharmaceutical Company Limited, Terumo Medical Corporation. Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Kowa Pharmaceutical Europe Co. Ltd., Merck Sharp &amp; Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Sanwa Chemical Industry Co. Ltd., Takeda Pharmaceutical Company Limited.

High-intensity interval training reduces monocyte activation in obese adults

Alterations in the distribution and activation of monocyte subsets are frequently observed in individuals with obesity and their participation in the pathological complications of obesity is proposed. High-intensity interval training (HIIT) can be a time-efficient alternative to counteract the inflammatory outcomes of obesity, but so far, its effects on monocytes in obesity has not been fully explored. In this study, we investigated whether 8 weeks of HIIT can modify the distribution and activation of the three monocyte subsets (classical, intermediate and non-classical monocytes) in individuals with obesity. Our data show that individuals with obesity have a higher percentage of non-classical monocytes compared to control, lean individuals, and consequently an imbalance among the CD16+ monocyte subsets. Also, the expression of HLA-DR by intermediate monocytes is higher in insulin-resistant obese individuals, which indicates monocyte activation in obesity. After 8 weeks of HIIT, the percentage of non-classical monocytes was reduced in individuals with obesity, restoring the balance among the CD16+ monocytes. Also, the expression of HLA-DR by intermediate monocytes in insulin-resistant obese subjects was lower after HIIT. Both findings indicate that monocyte activation in individuals with obesity was reduced by HIIT. These modifications were observed in the absence of changes in weight and body composition, although they were accompanied by the improvement in the metabolic status (reduced insulin levels). Our findings indicate that HIIT can be considered a time-efficient strategy to manage obesity-related monocyte alterations and strengthen the immunomodulatory potential of HIIT.