Antiretroviral therapy potentiates high-fat diet induced obesity and glucose intolerance
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ABSTRACT:
PROVIDER: PRJNA432595 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6664300_1.fastq.gz | Fastqsanger.gz | |||
| SRR6664300_2.fastq.gz | Fastqsanger.gz | |||
| SRR6664310_1.fastq.gz | Fastqsanger.gz | |||
| SRR6664310_2.fastq.gz | Fastqsanger.gz | |||
| SRR6664301_1.fastq.gz | Fastqsanger.gz |
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Project description:Background Breakthroughs in HIV treatment, especially antiretroviral therapy (ART), have massively reduced mortality. However, ART-treated individuals display elevated rates of obesity, diabetes, and cardiovascular disease, collectively known as metabolic syndrome. These co-morbidities represent a considerable threat to long-term survival and quality of life. Previous studies have shown that high-fat feeding induces persistent low-grade systemic and adipose tissue inflammation contributing to insulin resistance and metabolic dysregulation via adipose-infiltrating macrophages. Methods and Results Studies herein test the hypothesis that ART potentiates the inflammatory effects of a high-fat diet (HFD). C57Bl/6J mice on a HFD or standard chow containing ART or vehicle, were subjected to functional metabolic testing, RNA-sequencing of epididymal white adipose tissue (eWAT), and array-based kinomic analysis of eWAT-infiltrating macrophages. ART-treated mice on a HFD displayed fat mass accumulation, impaired glucose tolerance, and potentiated insulin resistance. Gene set enrichment and kinomic array analyses revealed a pro-inflammatory transcriptional signature depicting granulocyte migration and activation. Conclusions The current study reveals a HFD-ART interaction that increases inflammatory transcriptional pathways in eWAT consistent with macrophage infiltration, resulting in impaired glucose metabolism, energy balance, and metabolic dysfunction.
2018-09-14 | GSE110035 | GEO
Project description:ObjectiveBreakthroughs in HIV treatment, especially combination antiretroviral therapy (ART), have massively reduced AIDS-associated mortality. However, ART administration amplifies the risk of non-AIDS defining illnesses including obesity, diabetes, and cardiovascular disease, collectively known as metabolic syndrome. Initial reports suggest that ART-associated risk of metabolic syndrome correlates with socioeconomic status, a multifaceted finding that encompasses income, race, education, and diet. Therefore, determination of causal relationships is extremely challenging due to the complex interplay between viral infection, ART, and the many environmental factors.MethodsIn the current study, we employed a mouse model to specifically examine interactions between ART and diet that impacts energy balance and glucose metabolism. Previous studies have shown that high-fat feeding induces persistent low-grade systemic and adipose tissue inflammation contributing to insulin resistance and metabolic dysregulation via adipose-infiltrating macrophages. Studies herein test the hypothesis that ART potentiates the inflammatory effects of a high-fat diet (HFD). C57Bl/6J mice on a HFD or standard chow containing ART or vehicle, were subjected to functional metabolic testing, RNA-sequencing of epididymal white adipose tissue (eWAT), and array-based kinomic analysis of eWAT-infiltrating macrophages.ResultsART-treated mice on a HFD displayed increased fat mass accumulation, impaired glucose tolerance, and potentiated insulin resistance. Gene set enrichment and kinomic array analyses revealed a pro-inflammatory transcriptional signature depicting granulocyte migration and activation.ConclusionThe current study reveals a HFD-ART interaction that increases inflammatory transcriptional pathways and impairs glucose metabolism, energy balance, and metabolic dysfunction.
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Project description:Irisin is secreted by muscle, increased with exercise, and conveys certain physiological benefits. Earlier studies showed that short-term irisin treatment caused browning of subcutaneous adipose tissue (SAT) in mice, with improved glucose tolerance; the effects of more chronic irisin treatment and mechanisms at play have not been explored. We demonstrate here that chronic irisin application improves obesity and dramatically reduces glucose intolerance. This treatment increases an IL-33+ mesenchymal stromal cell (mSC) population in visceral fat tissue while genetic ablation of irisin reduces plasma IL-33 levels and decreases thermogenic gene expression in SAT. Importantly, irisin directly induces IL-33 expression in mSCs and preserves ST2+ regulatory T (Treg) cells. Inhibition of IL-33 blunts these irisin-mediated effects on energy expenditure and glucose homeostasis, largely through IL33-mediated regulation of ST2+ Treg cells. These data indicate that irisin improves obesity and glucose intolerance, with no muscle loss, through a key immunomodulatory pathway in obese mice.
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Project description:Irisin is secreted by muscle, increased with exercise, and conveys certain physiological benefits. Earlier studies showed that short-term irisin treatment caused browning of subcutaneous white fat in mice, with improved glucose tolerance; the effects of more chronic irisin treatment and mechanisms at play have not been explored. We demonstrate here that chronic irisin application improves obesity and dramatically reduces glucose intolerance. This treatment increases an IL-33+ mesenchymal stromal cell (mSC) population, while genetic ablation of irisin reduces plasma IL-33 levels and decreases thermogenic gene expression in subcutaneous adipose tissue. Importantly, irisin directly induces IL-33 expression in mSCs and stimulates ST2+regulatory T (Treg) cells, inducing their tissue accumulation. Inhibition of IL-33 blunts these irisin-mediated effects on energy expenditure and glucose homeostasis, largely through IL33-mediated regulation of ST2+ Treg cells. These data indicate that irisin improves obesity and glucose intolerance, with no muscle loss, through a key immunomodulatory pathway in obese mice .
2026-01-15 | GSE282942 | GEO
Project description:Decreased mitochondrial mass and function in muscle of diabetic patients is associated with low PGC-1alpha, a transcriptional coactivator of the mitochondrial gene program. To investigate whether reduced PGC-1alpha and oxidative capacity in muscle directly contributes to age-related glucose intolerance, we compared the genetic signatures and metabolic profiles of aging mice lacking muscle PGC-1alpha. Microarray analysis revealed that a significant proportion of PGC-1alpha-dependent changes in gene expression overlapped with age-associated effects, and aging muscle and muscle lacking PGC-1alpha shared gene signatures of impaired electron transport chain activity and TGFbeta signalling. Gastrocnemius muscle mRNA from young (10 week old) and old (24 month old) wild-type and knock-out (muscle-specific PGC-1alpha, myogenin-cre) C57Bl/6N/6J/129 mice
2013-12-05 | E-GEOD-52550 | biostudies-arrayexpress
Project description:Decreased mitochondrial mass and function in muscle of diabetic patients is associated with low PGC-1alpha, a transcriptional coactivator of the mitochondrial gene program. To investigate whether reduced PGC-1alpha and oxidative capacity in muscle directly contributes to age-related glucose intolerance, we compared the genetic signatures and metabolic profiles of aging mice lacking muscle PGC-1alpha. Microarray analysis revealed that a significant proportion of PGC-1alpha-dependent changes in gene expression overlapped with age-associated effects, and aging muscle and muscle lacking PGC-1alpha shared gene signatures of impaired electron transport chain activity and TGFbeta signalling.
2013-12-05 | GSE52550 | GEO
Project description:Irisin improves obesity and glucose intolerance through an IL-33-ST2 pathway
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Project description:Irisin improves obesity and glucose intolerance through an IL-33-ST2 pathway
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Project description:Subcutaneous adipose tissue (SAT) is a critical regulator of systemic metabolic homeostasis. Persons with HIV (PWH) have an increased risk of metabolic diseases and have significant alterations in SAT immune cells compared with the general population. We generated a comprehensive SAT atlas from 59 PWH with a spectrum of metabolic diseases to characterize cellular compositional and transcriptional changes associated with glucose intolerance and demographic characteristics. In PWH, glucose intolerance was associated with increased lipid-associated macrophages, CD4+ and CD8+ T effector memory cells, and decreased perivascular macrophages. We observed a coordinated intercellular regulatory program enriched for genes related to inflammation and lipid-processing with glucose intolerance that was also present in diabetic HIV-negative persons. Finally, CD4+ tissue resident cells were most strongly associated with altered whole tissue expression of genes related to lipid and glucose metabolism. These data provide a comprehensive assessment of SAT immune cells that may contribute to glucose intolerance.
2023-08-30 | GSE198809 | GEO
Project description:To determine whether endothelial TFEB is critical for glucose metabolism in vivo, we utilized EC-selective TFEB knockout mice and EC selective TFEB transgenic mice fed a high fat diet (HFD). EC-TFEB knockout mice exhibited significantly impaired glucose tolerance compared with control mice. Consistently, EC-TFEB transgenic mice showed improved glucose intolerance. In primary human ECs, small interfering RNA-mediated TFEB knockdown blunts the Akt signaling. adenovirus-mediated overexpression of TFEB consistently activates Akt signaling and significantly increases glucose uptake in ECs. Mechanically, TFEB upregulates insulin receptor substrate 1 and 2 (IRS1 and IRS2). TFEB increases IRS2 transcription measured by reporter gene and chromatin immunoprecipitation assays. Furthermore, we found that TFEB increases IRS1 protein via downregulation of microRNAs (miR-335, miR-495 and miR548o). In vivo, Akt signaling in the skeletal muscle and adipose tissue was significantly impaired in EC-TFEB knockout mice and consistently improved in EC-TFEB transgenic mice on HFD
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