Project description:The aim of this study was to identify new genes controlling insulin sensitivity in adipocytes from obese women with either insulin-resistant (OIR) or -sensitive (OIS) adipocytes. 432 genes were differentially expressed between the OIR and OIS group (FDR <5%). These genes are enriched in pathways related to glucose and amino acid metabolism, cellular respiration, and insulin signaling. Two IR-associated genes, KLF15 and SLC25A10, were selected for functional evaluation.
Project description:The aim of this study was to identify new genes controlling insulin sensitivity in adipocytes from obese women with either insulin-resistant (OIR) or -sensitive (OIS) adipocytes. 432 genes were differentially expressed between the OIR and OIS group (FDR <5%). These genes are enriched in pathways related to glucose and amino acid metabolism, cellular respiration, and insulin signaling, and include SLC2A4, AKT2, as well as enzymes in the mitochondria respiratory chain. Two IR-associated genes, KLF15 and SLC25A10, were selected for functional evaluation.
Project description:Global transcriptome profiling identifies KLF15 and SLC25A10 as regulators of adipocytes insulin sensitivity in obese women [siRNA]
Project description:Purpose: To determine how STAT1 activity in white adipocytes affects insulin sensitivity. Methods: Adipocyte specific (ADIPOQ-Cre) STAT1 fl/fl mice (STAT1 fKO) and littermate controls (STAT1 fl/fl) were placed on 60% HFD for 18 weeks, followed by metabolic phenoptying and tissue harvest for RNA-seq Results: STAT1 expression in WAT inversely correlated with fasting plasma glucose in both obese mice and humans. Metabolomic and gene expression profiling established STAT1 deletion in adipocytes (STAT1 fKO) enhanced mitochondrial function and accelerated TCA cycle flux coupled with subcutaneous WAT hyperplasia. STAT1 fKO reduced WAT inflammation, but insulin resistance persisted in obese mice. Rather, elimination of type I cytokine interferon gamma (IFNg) activity enhanced insulin sensitivity in diet-induced obesity. Conclusions: Our findings reveal a permissive mechanism that bridges WAT inflammation to whole-body insulin sensitivity.
Project description:Obesity is associated with a chronic, low-grade, systemic inflammation that may contribute to the development of insulin resistance and type 2 diabetes. Resveratrol, a natural compound with anti-inflammatory properties, is shown to improve glucose tolerance and insulin sensitivity in obese mice and humans. Here we tested the effect of a 2-year resveratrol administration on the pro-inflammatory profile and insulin resistance caused by a high-fat, high-sugar (HFS) diet in white adipose tissue (WAT) from rhesus monkeys. Eighty mg/day of resveratrol for 12-month followed by 480 mg/day for the second year decreased adipocyte size, increased sirtuin 1 expression, decreased NF-kB activation and improved insulin sensitivity in visceral but not subcutaneous WAT from HFS-fed animals. These effects were reproduced in 3T3-L1 adipocytes cultured in media supplemented with serum from monkeys fed HFS +/- resveratrol diets. In conclusion, chronic administration of resveratrol exerts beneficial metabolic and inflammatory adaptations in visceral WAT from diet-induced obese monkeys.
Project description:In this study, we tested the hypothesis that restoration of miR-30a expression in WAT would improve peripheral insulin sensitivity. Exogenous miR-30a expression in subcutaneous WAT depots of obese mice improved insulin sensitivity, decreased ectopic liver fat deposition, and reduced WAT inflammation compared to matched controls. We identified the target genes and pathways of miR-30a using RNA-Seq technology
Project description:B cell-activating factor (BAFF) is critical for the survival and maturation of B2 cells. However, excess BAFF breaks the peripheral tolerance of B2-cells leading to the production of autoantibodies that cause autoimmune diseases. During obesity, BAFF is predominantly produced by white adipose tissue (WAT), and IgG autoantibodies against adipocytes are identified in the WAT of obese humans. However, it remains to be determined if the autoantibodies formed during obesity affect WAT remodeling and systemic insulin resistance. Here, we show that IgGs from high-fat diet (HFD)-induced obese mice bind to apoptotic adipocytes and promote their clearance by macrophages. Next, using murine models of obesity in which the gonadal WAT undergoes remodeling, unexpectedly we found that BAFF neutralization increased the number of dead adipocytes and exacerbated WAT inflammation and insulin resistance despite depletion of IgG autoantibodies. RNA sequencing of the stromal vascular fraction from the WAT revealed impaired B cell activation and phagocytosis pathways. In-vitro, the clearance of apoptotic adipocytes by macrophages was attenuated in the presence of IgGs from BAFF-neutralized mice compared to the control mice. Altogether, our study suggests a beneficial role of BAFF and IgG autoantibodies in WAT remodeling in obesity and the regulation of systemic insulin resistance.
Project description:White adipose tissue (WAT) plays a critical role in whole-body energy homeostasis. In this study, we established the differential proteomic signatures of WAT in glucose-tolerant lean and obese individuals and patients with type 2 diabetes (T2D) and in response to 8 weeks of high intensity interval training (HIIT). We combined a high-throughput and reproducible mass spectrometry-based proteomics pipeline and identified a total of 3773 proteins. We find that a majority of regulated proteins displayed progression from lean to obese and T2D individuals and were highly associated with clinical measures of glucose homeostasis (e.g., insulin sensitivity, HbA1c) and they could, therefore, serve as potential disease biomarkers. Interestingly, HIIT induced a strong increase in WAT ferritin levels independent of group. WAT ferritin levels strongly correlated with individual insulin sensitivity. Thus, we report novel proteomic signatures of WAT related to obesity and T2D and highlight an unrecognized role of human WAT iron metabolism in exercise training adaptations.
Project description:The gut microbiota is a key environmental determinant of mammalian metabolism. Regulation of white adipose tissue (WAT) by the gut microbiota is a critical process that maintains metabolic fitness, while dysbiosis contributes to the development of obesity and insulin resistance (IR). However, how the gut microbiota controls WAT functions remain largely unknown. Herein, we show that tryptophan-derived metabolites produced by the microbiota control the expression of the miR-181 family in white adipocytes to regulate energy expenditure and insulin sensitivity. Moreover, we show that dysregulation of the microbiota-miR-181 axis is required for the development of obesity, IR, and WAT inflammation. Thus, our results indicate that regulation of miRNA levels in WAT by microbiota-derived cues is a central mechanism by which host metabolism is tuned in response to dietary and environmental changes. As MIR-181 is dysregulated in WAT from obese human individuals, the MIR-181 family may represent a potential therapeutic target to modulate WAT function in the context of obesity.