Adipose Tissue Insulin Resistance Research Articles

Adipocyte FGF21 Signaling Defect Aggravated Adipose Tissue Inflammation in Gestational Diabetes Mellitus

Gestational diabetes mellitus (GDM) is associated with increased inflammation in adipose tissues. Fibroblast growth factor 21 (FGF21) is an endocrine hormone which signals to multiple tissues to regulate metabolism. However, its role in GDM remains largely unknown. In this study, we found that impaired FGF21 signaling in GDM correlates with worsened inflammation and insulin resistance in white adipose tissues in mice. Mechanistically, the pregnancy-related upregulation of FGF21 signaling in adipocytes promotes the differentiation of regulatory T cells (Tregs), which are critical for reducing pregnancy-induced adipose tissue inflammation. The anti-inflammatory effects of FGF21 may involve linolenic acid-mediated PGE2 synthesis in adipocytes. These findings underscore FGF21’s role in mediating crosstalk between mature adipocytes and immune cells in white adipose tissue and suggest that targeting FGF21 signaling and its downstream metabolites could offer a potential therapeutic approach for GDM in humans.

Ethnic differences in the relationship between ectopic fat deposition and insulin sensitivity in Black African and White European men across a spectrum of glucose tolerance.

To examine the hypothesis that there would be ethnic differences in the relationship between ectopic fat and tissue-specific insulin resistance (IR) across a spectrum of glucose tolerance in Black African (BA) and White European (WE) men. Fifty-three WE men (23/10/20 normal glucose tolerance [NGT]/impaired glucose tolerance [IGT]/type 2 diabetes [T2D]) and 48 BA men (20/10/18, respectively) underwent a two-step hyperinsulinaemic-euglycaemic clamp with infusion of D-[6,6-2H2]-glucose and [2H5]-glycerol to assess hepatic, peripheral and adipose tissue IR. Magnetic resonance imaging was used to measure subcutaneous adipose tissue, visceral adipose tissue (VAT) and intrahepatic lipid (IHL). Associations between ectopic fat and IR were assessed using linear regression models. There were no differences in tissue-specific IR between ethnic groups at any stage of glucose tolerance. VAT level was consistently lower in the BA population; NGT (p = 0.013), IGT (p = 0.006) and T2D (p = 0.015). IHL was also lower in the BA compared with the WE men (p = 0.013). VAT and IHL levels were significantly associated with hepatic IR in the BA population (p = 0.001) and with peripheral IR in the WE population (p = 0.027). The present study suggests that BA and WE men exhibit the same degree of IR across a glucose tolerance continuum, but with lower VAT and IHL levels in the BA population, suggesting that IR may be driven by a mechanism other than increased ectopic fat accumulation in BA men.

Circulating extracellular vesicle-carried PTP1B and PP2A phosphatases as regulators of insulin resistance.

Metabolic disorders associated with abdominal obesity, dyslipidaemia, arterial hypertension and hyperglycaemia are risk factors for the development of insulin resistance. Extracellular vesicles (EVs) may play an important role in the regulation of metabolic signalling pathways in insulin resistance and associated complications. Circulating large EVs (lEVs) and small EVs (sEVs) from individuals with (IR group) and without insulin resistance (n-IR group) were isolated and characterised. lEVs and sEVs were administered by i.v. injection to mice and systemic, adipose tissue and liver insulin signalling were analysed. The role of phosphatases was analysed in target tissues and cells. Injection of lEVs and sEVs from IR participants impaired systemic, adipose tissue and liver insulin signalling in mice, while EVs from n-IR participants had no effect. Moreover, lEVs and sEVs from IR participants brought about a twofold increase in adipocyte size and adipogenic gene expression. EVs from IR participants expressed two types of phosphatases, phosphotyrosine 1 phosphatase (PTP1B) and protein phosphatase 2 (PP2A), IR lEVs being enriched with the active form of PTP1B while IR sEVs mainly carried active PP2A. Blockade of PTP1B activity in IR lEVs fully restored IRS1 and Akt phosphorylation in adipocytes and blunted insulin-induced Akt phosphorylation by inhibition of the macrophage secretome in hepatocytes. Conversely, blockade of PP2A activity in IR sEVs completely prevented insulin resistance in adipocytes and hepatocytes. These data demonstrate that inhibition of phosphatases carried by EVs from IR participants rescues insulin signalling in adipocytes and hepatocytes and point towards PTP1B and PP2A carried by IR EVs as being novel potential therapeutic targets against insulin resistance in adipose tissue and liver and the development of obesity.

Aerobic Exercise Prevents High-Fat-Diet-Induced Adipose Tissue Dysfunction in Male Mice

Background/Objectives: This study aimed to assess the effect of aerobic exercise on capillary density and vascular smooth muscle cell (VSMC) phenotype in the visceral and subcutaneous adipose tissue of high-fat-diet (HFD) mice in order to understand the mechanisms underlying improvements in insulin resistance (IR) and chronic inflammation in adipose tissue (AT). Methods: Male C57BL/6J mice were divided into HFD and normal diet groups for 12 weeks and then further split into sedentary and aerobic exercise subgroups for an additional 8 weeks. Various parameters including body weight, fat weight, blood glucose, lipid profile, insulin levels, glucose tolerance, and inflammatory cytokines were evaluated. Results: Aerobic exercise reduced HFD-induced weight gain, IR, and improved lipid profiles. HFD had a minimal effect on inflammatory cytokines except in visceral adipose tissue (VAT). IR was associated with capillary density in subcutaneous adipose tissue (SAT) and VSMC phenotype in VAT. Aerobic exercise promoted anti-inflammatory responses in VAT, correlating with VSMC phenotype in this tissue. Conclusions: Aerobic exercise can alleviate HFD-induced IR and inflammation through the modulation of VSMC phenotype in AT.

Effect of Clozapine and Olanzapine on the Expression of Selected Genes and Epigenetic Regulators of Insulin Resistance Pathway in Human Preadipocytes – a Preliminary Study

Clozapine and olanzapine, popular second-generation antipsychotics used for various psychiatric disorders, cause significant side effects such as metabolic syndrome, but the exact mechanism remains unclear. The present study aimed to assess clozapine and olanzapine effects on the expression of mRNA insulin pathway genes (IRS-1, PTEN, PIK3CG and PIK3R1), microRNAs (miR-152-3p, miR-214-3p, miR-15b-5p, miR-16-5p, miR-126-3p) and long non-coding RNAs (lncRNAs: XIST, H19, SNHG16, PVT1), in human visceral preadipocytes (HPAd). Expression was examined by real - time PCR. Cell viability was determined by MTT assay. The findings revealed that in HAPd, both clozapine and olanzapine (at doses of 5 µM and 25 µM) decreased IRS-1 gene expression after 24 hours. After 48 hours, IRS-1 expression was reduced by clozapine at both concentrations and olanzapine at 5 µM. In addition, olanzapine (at 25 µM) decreased the expression of PIK3CG, miR-152-3p, miR-214-3p, miR-15b-5p and miR-16-5p after 24 hours, while increasing the expression of miR-126-3p at 5 µM. Clozapine at 25 µM decreased miR-16-5p expression and increased SNHG16 lncRNA expression at 5 µM after 24 hours. After 48 hours, olanzapine (at 25 µM) increased PIK3R1 expression and decreased PIK3CG expression at 5 µM. Both drugs at 5 µM increased the expression of miR-152-3p, miR-214-3p, miR-15b-5p and miR-16-5p after 48 hours, with clozapine further increasing the expression of miR-126-3p at this concentration. The results suggest that clozapine and olanzapine may affect the expression of key genes and epigenetic molecules in the insulin pathway, which is one potential cause leading to insulin resistance in adipose tissue.

Dynamic Roles and Expanding Diversity of Adipose Tissue Macrophages in Obesity.

Adipose tissue macrophages (ATMs) are key regulators of adipose tissue (AT) inflammation and insulin resistance in obesity, and the traditional M1/M2 characterization of ATMs is inadequate for capturing their diversity in obese conditions. Single-cell transcriptomic profiling has revealed heterogeneity among ATMs that goes beyond the old paradigm and identified new subsets with unique functions. Furthermore, explorations of their developmental origins suggest that multiple differentiation pathways contribute to ATM variety. These advances raise concerns about how to define ATM functions, how they are regulated, and how they orchestrate changes in AT. This review provides an overview of the current understanding of ATMs and their updated categorization in both mice and humans during obesity. Additionally, diverse ATM functions and contributions in the context of obesity are discussed. Finally, potential strategies for targeting ATM functions as therapeutic interventions for obesity-induced metabolic diseases are addressed.

Adipose tissue insulin resistance in young Japanese women is associated with metabolic abnormalities and dehydroepiandrosterone-sulfate.

The proportion of young Japanese women who are underweight is exceptionally high. We previously showed that the prevalence of impaired glucose tolerance (IGT) was high in underweight young Japanese women, and that IGT was characterized by high free fatty acid levels and adipose tissue insulin resistance (ATIR). As the next step, this study aimed to explore factors associated with elevated ATIR in this population. Ninety-eight young, healthy, underweight women participated in this study. To investigate the relationship between ATIR and metabolic parameters, participants were divided into three groups (Low, Medium, and High) according to ATIR level. Body composition examination, oral glucose tolerance testing, and blood biochemical analysis were performed; Adipo-IR and the Matsuda index were used as indices of ATIR and systemic insulin sensitivity, respectively. Participants in the High ATIR group had the highest prevalence of IGT (25%), and significantly higher body fat percentage, whole-body insulin resistance, and levels of insulin-like growth factor-1 and dehydroepiandrosterone sulfate (DHEA-S) than the other two groups. They were also significantly younger and had higher systolic blood pressure than the Low ATIR group. Multiple regression analysis showed that DHEA-S, which is known to enhance lipolysis in adipose tissue, was an independent correlate of ATIR. Underweight Japanese women with high ATIR had impaired metabolism, a higher prevalence of IGT, higher systemic insulin resistance, and higher systolic blood pressure. DHEA-S was a determinant of high ATIR levels.

HDL proteome associates with hepatic and adipose tissue insulin resistance and cholesterol efflux capacity in metabolic syndrome patients

HDL proteome associates with hepatic and adipose tissue insulin resistance and cholesterol efflux capacity in metabolic syndrome patients

Associations of adipose insulin resistance index with pancreatic β cell function (inverse) and glucose excursion (positive) in young Japanese women

The relationship of adipose tissue insulin resistance (AT-IR, a product of fasting insulin and free fatty acids) and homeostasis-model assessment-insulin resistance (HOMA-IR) to β-cell function was studied cross-sectionally in the setting of subtle glucose dysregulation. Associations of AT-IR and HOMA-IR with fasting and post-glucose glycemia and β-cell function inferred from serum insulin kinetics during a 75 g oral glucose tolerance test were studied in 168 young female Japanese students. β-cell function was evaluated by disposition index calculated as a product of the insulinogenic index (IGI) and Matsuda index. AT-IR, not HOMA-IR, showed positive associations with post-glucose glycemia and area under the glucose response curve although both indices were associated with fasting glycemia. HOMA-IR, not AT-IR, was associated positively with log IGI whereas both indices were inversely associated with Matsuda index. AT-IR, not HOMA-IR, showed inverse associations with log disposition index. Associations of adipose tissue insulin resistance with β-cell function (inverse) and glucose excursion in young Japanese women may suggest that lipotoxicity to pancreatic β-cells for decades may be associated with β cell dysfunction found in Japanese patients with type 2 diabetes. Positive association of HOMA-IR with insulinogenic index may be associated with compensatory increased insulin secretion.

Adipose tissue insulin resistance index was inversely associated with gluteofemoral fat and skeletal muscle mass in Japanese women

Associations of adipose tissue insulin resistance index (AT-IR, a product of fasting insulin and free fatty acids) with body fat mass and distribution and appendicular skeletal muscle mass (ASM) were compared with results of homeostasis-model assessment-insulin resistance (HOMA-IR) in 284 Japanese female university students and 148 their biological mothers whose BMI averaged < 23 kg/m2. Although mothers compared with daughters had higher BMI, body fat percentage, trunk fat to body fat (TF/BF) ratio and lower leg fat to body fat (LF/BF), AT-IR and HOMA-IR did not differ. We had multivariable linear regression analyses which included TF/BF ratio, LF/BF ratio, weight-adjusted ASM (%ASM), height-adjusted ASM index (ASMI), fat mass index (FMI), and body fat percentage. In young women, AT-IR was independently associated with LF/BF ratio (Standardized β [Sβ]: − 0.139, p = 0.019) and ASMI (Sβ: − 0.167, p = 0.005). In middle-aged women, LF/BF ratio (Sβ: − 0.177, p = 0.049) and %ASM (Sβ: − 0.205, p = 0.02) emerged as independent determinants of AT-IR. HOMA-IR was associated with TF/BF ratio and FMI, a proxy of abdominal and general adiposity, respectively, in both young and middle-aged women. The inverse association of AT-IR with leg fat may support the notion that limited peripheral adipose storage capacity and small skeletal muscle size are important etiological components in insulin-resistant cardiometabolic disease in Japanese women.

Adherence to the Dietary Approaches to Stop Hypertension (DASH) diet is associated with lower visceral and hepatic lipid content in recent-onset type 1 diabetes and type 2 diabetes.

To investigate the associations of the Dietary Approaches to Stop Hypertension (DASH) score with subcutaneous (SAT) and visceral (VAT) adipose tissue volume and hepatic lipid content (HLC) in people with diabetes and to examine whether changes in the DASH diet were associated with changes in these outcomes. In total, 335 participants with recent-onset type 1 diabetes (T1D) and type 2 diabetes (T2D) from the German Diabetes Study were included in the cross-sectional analysis, and 111 participants in the analysis of changes during the 5-year follow-up. Associations between the DASH score and VAT, SAT and HLC and their changes were investigated using multivariable linear regression models by diabetes type. The proportion mediated by changes in potential mediators was determined using mediation analysis. A higher baseline DASH score was associated with lower HLC, especially in people with T2D (per 5 points: -1.5% [-2.7%; -0.3%]). Over 5 years, a 5-point increase in the DASH score was associated with decreased VAT in people with T2D (-514 [-800; -228] cm3). Similar, but imprecise, associations were observed for VAT changes in people with T1D (-403 [-861; 55] cm3) and for HLC in people with T2D (-1.3% [-2.8%; 0.3%]). Body mass index and waist circumference changes explained 8%-48% of the associations between DASH and VAT changes in both groups. In people with T2D, adipose tissue insulin resistance index (Adipo-IR) changes explained 47% of the association between DASH and HLC changes. A shift to a DASH-like diet was associated with favourable VAT and HLC changes, which were partly explained by changes in anthropometric measures and Adipo-IR.

An Increasing Triglyceride-Glucose Index Is Associated with a Pro-Inflammatory and Pro-Oxidant Phenotype.

Background/Objectives: Insulin resistance is crucial in the pathogenesis of Metabolic Syndrome (MetS), type 2 diabetes mellitus (T2DM) and premature atherosclerotic cardiovascular disease (ASCVD). The triglyceride-glucose index (TyG index), a validated measure of insulin resistance, also predicts MetS, T2DM, the severity of albuminuria and ASCVD. There are scant data providing mechanistic insights into these sequalae. Accordingly, we investigated the relationship between the TyG index and biomarkers of inflammation, oxidative stress, free fatty acid (FFA) levels and adipokine dysregulation in a cohort comprising both controls and patients with nascent MetS. Methods: Participants (n = 102) included 59 patients with MetS and 43 controls. People with diabetes, ASCVD, smoking and macro-inflammation were excluded. Fasting blood was obtained for both plasma and monocyte isolation. Results: Receiver Operating Characteristic (ROC) curve analysis revealed that the TyG index was an excellent predictor of MetS with an area under the curve of 0.87, and it correlated with both hepatic and adipose tissue insulin resistance. Both serum RBP-4 levels and non-HDL cholesterol increased significantly over tertiles of the TyG index. Based on the TyG index tertiles and/or correlations, oxidized LDL, nitrotyrosine, C-reactive protein, endotoxin, chemerin, interleukin-6 levels and monocyte toll-like receptor (TLR)-4 and TLR-2 and their cellular signaling were significantly associated with the TyG index. Conclusions: Increased non-HDL-C and, most importantly, a pro-inflammatory and pro-oxidant state could be advanced as potential mechanisms explaining the increased risk for T2DM and ASCVD with an increasing TyG index.

The subcutaneous adipose transcriptome identifies a molecular signature of insulin resistance shared with visceral adipose.

The objective of this study was to identify the transcriptional landscape of insulin resistance (IR) in subcutaneous adipose tissue (SAT) in humans across the spectrum of obesity. We used SAT RNA sequencing in 220 individuals with metabolic phenotyping. We identified a 35-gene signature with high predictive accuracy for homeostatic model of IR that was expressed across a variety of non-immune cell populations. We observed primarily "protective" IR associations for adipocyte transcripts and "deleterious" associations for macrophage transcripts, as well as a high concordance between SAT and visceral adipose tissue (VAT). Multiple SAT genes exhibited dynamic expression 5 years after weight loss surgery and with insulin stimulation. Using available expression quantitative trait loci in SAT and/or VAT, we demonstrated similar genetic effect sizes of SAT and VAT on type 2 diabetes and BMI. SAT is conventionally viewed as a metabolic buffer for lipid deposition during positive energy balance, whereas VAT is viewed as a dominant contributor to and prime mediator of IR and cardiometabolic disease risk. Our results implicate a dynamic transcriptional architecture of IR that resides in both immune and non-immune populations in SAT and is shared with VAT, nuancing the current VAT-centric concept of IR in humans.

Excessive palmitic acid disturbs macrophage α-ketoglutarate/succinate metabolism and causes adipose tissue insulin resistance associated with gestational diabetes mellitus

Abnormal polarization of adipose tissue macrophages (ATMs) results in low-grade systemic inflammation and insulin resistance (IR), potentially contributing to the development of diabetes. However, the underlying mechanisms that regulate the polarization of ATMs associated with gestational diabetes mellitus (GDM) remain unclear. Thus, we aimed to determine the effects of abnormal fatty acids on macrophage polarization and development of insulin resistance in GDM. Levels of fatty acids and inflammation were assessed in the serum samples and adipose tissues of patients with GDM. An in vitro cell model treated with palmitic acid was established, and the mechanisms of palmitic acid in regulating macrophage polarization was clarified. The effects of excessive palmitic acid on the regulation of histone methylations and IR were also explored in the high-fat diet induced GDM mice model. We found that pregnancies with GDM were associated with increased levels of serum fatty acids, and inflammation and IR in adipose tissues. Increased palmitic acid could induce mitochondrial dysfunction and excessive ROS levels in macrophages, leading to abnormal cytoplasmic and nuclear metabolism of succinate and α-ketoglutarate (αKG). Specifically, a decreased nuclear αKG/succinate ratio could attenuate the enrichment of H3K27me3 at the promoters of pro-inflammatory cytokines, such as IL-1β, IL-6, and TNF-α, leading to cytokine secretion. Importantly, GDM mice treated with GSK-J4, an inhibitor of histone lysine demethylase, were protected from abnormal pro-inflammatory macrophage polarization and excessive production of pro-inflammatory cytokines. Our findings highlight the importance of the metabolism of αKG and succinate as transcriptional modulators in regulating the polarization of ATMs and the insulin sensitivity of adipose tissue, ensuring a normal pregnancy. This novel insight sheds new light on gestational fatty acid metabolism and epigenetic alterations associated with GDM.

The association between the size of adipocyte-derived extracellular vesicles and fasting serum triglyceride-glucose index as proxy measures of adipose tissue insulin resistance in a rat model of early-stage obesity.

Obesity is a complex disease that predisposes individuals to cardiometabolic alterations. It leads to adipose tissue (AT) dysfunction, which triggers insulin resistance (IR). This suggests that people with obesity develop local IR first and systemic IR later. AT secretes extracellular vesicles, which may be physiopathologically associated with the development of IR. Our aim was to evaluate the effect of a high-fat diet on different parameters of adiposity in a rat model of early-stage obesity and to determine if these parameters are associated with markers of systemic IR. In addition, we sought to explore the relationship between fasting blood measures of IR (Triglycerides/High Density Lipoprotein-cholesterol [TAG/HDL-c] and Triglycerides-Glucose Index [TyG Index]) with the size of adipocyte-derived extracellular vesicles (adEV). We used a model of diet-induced obesity for ten weeks in Wistar rats exposed to a high-fat diet. Final weight gain was analyzed by Dual X-ray absorptiometry. Visceral obesity was measured as epididymal AT weight. IR was evaluated with fasting TyG Index & TAG/HDL-c, and adEV were isolated from mature adipocytes on ceiling culture. In the high-fat diet group, glucose and triglyceride blood concentrations were higher in comparison to the control group (Log2FC, 0.5 and 1.5 times higher, respectively). The values for TyG Index and adEV size were different between the control animals and the high-fat diet group. Multiple linear regression analyses showed that adEV size can be significantly associated with the TyG Index value, when controlling for epididymal AT weight. Our results show that lipid and glucose metabolism, as well as the size and zeta potential of adEV are already altered in early-stage obesity and that adEV size can be significantly associated with liver and systemic IR, estimated by TyG Index.

Adipose Tissue Insulin Resistance Correlates with Disease Severity in Pediatric Metabolic Dysfunction-Associated Steatotic Liver Disease: A Prospective Cohort Study

ObjectivesTo assess the role of adipose tissue insulin resistance (Adipo-IR) in the pathogenesis of pediatric metabolic dysfunction-associated steatotic liver disease (MASLD) and to determine Adipo-IR evolution during a lifestyle intervention program. Study designIn this prospective, cohort study, children and adolescents with severe obesity were recruited between July 2020 and December 2022 at an inpatient pediatric rehabilitation center. Treatment consisted of dietary intervention and physical activity. Liver steatosis and fibrosis were evaluated using ultrasound and transient elastography with controlled attenuation parameter and liver stiffness measurement. Every 4 to 6 months, anthropometric measurements, serum biochemical analysis, ultrasound and elastography were repeated. Adipo-IR was estimated by the product of the fasting serum insulin times the fasting free fatty acid concentration and hepatic IR by the homeostatic model assessment for insulin resistance (HOMA-IR), respectively. Results56% of 200 patients with obesity had evidence of steatosis on ultrasound and 26% were diagnosed with fibrosis (≥F2). Adipo-IR increased progressively from lean controls to patients with obesity to patients with MASLD and MASLD with fibrosis. Adipo-IR was already elevated in patients with only mild steatosis (p = 0.0403). Patients with more insulin-sensitive adipose tissue exhibited lower liver fat content (p < 0.05) and serum alanine transaminase levels (p = 0.001). Adipo-IR correlated positively with visceral adipose tissue weight, waist circumference, and the visceral adipose tissue/gynoid adipose tissue ratio (p < 0.001), but not with total body fat percentage (p = 0.263). After 4 to 6 months of lifestyle management, both MASLD and Adipo-IR improved. ConclusionsOur data suggest that Adipo-IR is associated with the presence of pediatric MASLD, particularly steatosis.

Myeloid-derived miR-6236 potentiates adipocyte insulin signaling and prevents hyperglycemia during obesity

Adipose tissue macrophages (ATMs) influence obesity-associated metabolic dysfunction, but the mechanisms by which they do so are not well understood. We show that miR-6236 is a bona fide miRNA that is secreted by ATMs during obesity. Global or myeloid cell-specific deletion of miR-6236 aggravates obesity-associated adipose tissue insulin resistance, hyperglycemia, hyperinsulinemia, and hyperlipidemia. miR-6236 augments adipocyte insulin sensitivity by inhibiting translation of negative regulators of insulin signaling, including PTEN. The human genome harbors a miR-6236 homolog that is highly expressed in the serum and adipose tissue of obese people. hsa-MIR-6236 expression negatively correlates with hyperglycemia and glucose intolerance, and positively correlates with insulin sensitivity. Together, our findings establish miR-6236 as an ATM-secreted miRNA that potentiates adipocyte insulin signaling and protects against metabolic dysfunction during obesity.

Growth hormone improves insulin resistance in visceral adipose tissue after duodenal-jejunal bypass by regulating adiponectin secretion

BACKGROUND The mechanism of improvement of type 2 diabetes after duodenal-jejunal bypass (DJB) surgery is not clear. AIM To study the morphological and functional changes in adipose tissue after DJB and explore the potential mechanisms contributing to postoperative insulin sensitivity improvement of adipose tissue in a diabetic male rat model. METHODS DJB and sham surgery was performed in a-high-fat-diet/streptozotocin-induced diabetic rat model. All adipose tissue was weighed and observed under microscope. Use inguinal fat to represent subcutaneous adipose tissue (SAT) and mesangial fat to represent visceral adipose tissue. RNA-sequencing was utilized to evaluate gene expression alterations adipocytes. The hematoxylin and eosin staining, reverse transcription-quantitative polymerase chain reaction, western blot, and enzyme-linked immunosorbent assay were used to study the changes. Insulin resistance was evaluated by immunofluorescence. RESULTS After DJB, whole body blood glucose metabolism and insulin sensitivity in adipose tissue improved. Fat cell volume in both visceral adipose tissue (VAT) and SAT increased. Compared to SAT, VAT showed more significantly functional alterations after DJB and KEGG analysis indicated growth hormone (GH) pathway and downstream adiponectin secretion were involved in metabolic regulation. The circulating GH and adiponectin levels and GH receptor and adiponectin levels in VAT increased. Cytological experiment showed that GH stimulated adiponectin secretion and improve insulin sensitivity. CONCLUSION GH improves insulin resistance in VAT in male diabetic rats after receiving DJB, possibly by increasing adiponectin secretion.

2054-LB: Mitigating Adipose Tissue Dysfunction and Insulin Resistance in Obesity via SVEP1 Peptide-Mediated Suppression of Adipose Tissue Macrophage-Induced Inflammation

2054-LB: Mitigating Adipose Tissue Dysfunction and Insulin Resistance in Obesity via SVEP1 Peptide-Mediated Suppression of Adipose Tissue Macrophage-Induced Inflammation

Role of RIPK3 in lipid metabolism and postnatal overfeeding-induced metabolic disorders in mice

Postnatal overfeeding can increase the long-term risk of metabolic disorders, such as obesity, but the underlying mechanisms remain unclear and treatment approaches are limited. Receptor-interacting protein kinase 3 (RIPK3) is associated with several metabolic diseases. We investigated the effects of RIPK3 on neonatal overfeeding-related metabolic disorders. On postnatal day 3, litter sizes were adjusted to 9-10 (normal litters, NL) or 2-3 (small litters, SL) mice per dam to mimic postnatal overfeeding. After weaning, NL and SL mouse were fed normal diet. We generated an adeno-associated virus (AAV) carrying short hairpin RNA (shRNA) against Ripk3 and an empty vector as a control. The NL and SL groups were treated intravenously with 1×1012 vector genome of AAV vectors at week 6. The SL group showed a higher body weight than the NL group from week 3 of age through adulthood. At weeks 6 and 13, the SL group exhibited impaired glucose and insulin tolerance, RIPK3 up-regulation, and lipid accumulation in liver and adipose tissues. In the SL group, the genes involved in lipid synthesis and lipolysis were increased, whereas fatty acid β-oxidation-related genes were weakened in adipose tissue and liver. At week 13, AAV-shRNA-Ripk3 ameliorated adipose tissue hypertrophy, hepatic steatosis, insulin resistance, and dysregulated lipid metabolism in the adipose tissue and liver of SL mice. These findings support a novel mechanism underlying the pathogenesis of postnatal overfeeding-related metabolic disorders and suggest potential therapeutic targets.