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Adipocyte p53 coordinates the adipose tissue immune cell landscape upon intermittent fasting

ABSTRACT: In obesity, sustained adipose tissue (AT) inflammation constitutes a cellular memory that limits the effectiveness of weight loss interventions. Yet, its fasting regimen-dependent regulation is unknown. Here, we show that cyclic intermittent fasting (IF) exacerbates the lipid-associated macrophage (LAM) inflammatory phenotype of visceral AT in obese mice. Importantly, we provide evidence that this increase in LAM abundance is almost entirely dependent on p53-driven adipocyte apoptosis. Adipocyte-specific deletion of p53 prevents LAM accumulation in AT during IF and increases the catabolic state of adipocytes, ameliorates metabolic flexibility, and insulin sensitivity. Finally, in cohorts of obese/diabetic patients, we describe a p53 polymorphism that links to long-term efficacy of a fasting-mimicking diet and that the expression of LAM markers and p53 in AT negatively correlates with maintaining weight loss after bariatric surgery. Overall, our results demonstrate that p53 signaling in adipocytes dictates LAM accumulation in AT under IF and that adipocyte p53 modulates fasting effectiveness in mice and humans.

ORGANISM(S): Mus musculus

PROVIDER: GSE229690 | GEO | 2024/01/16

REPOSITORIES: GEO

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Adipocyte p53 coordinates the adipose tissue immune cell landscape upon intermittent fasting

Project description:In obesity, sustained adipose tissue (AT) inflammation constitutes a cellular memory that limits the effectiveness of weight loss interventions. Yet, its fasting regimen-dependent regulation is unknown. Here, we show that cyclic intermittent fasting (IF) exacerbates the lipid-associated macrophage (LAM) inflammatory phenotype of visceral AT in obese mice. Importantly, we provide evidence that this increase in LAM abundance is almost entirely dependent on p53-driven adipocyte apoptosis. Adipocyte-specific deletion of p53 prevents LAM accumulation in AT during IF and increases the catabolic state of adipocytes, ameliorates metabolic flexibility, and insulin sensitivity. Finally, in cohorts of obese/diabetic patients, we describe a p53 polymorphism that links to long-term efficacy of a fasting-mimicking diet and that the expression of LAM markers and p53 in AT negatively correlates with maintaining weight loss after bariatric surgery. Overall, our results demonstrate that p53 signaling in adipocytes dictates LAM accumulation in AT under IF and that adipocyte p53 modulates fasting effectiveness in mice and humans.

2024-01-16 | PXD041351 | Pride

Resolution of Type 2 Diabetes Following Bariatric Surgery is Associated with Changes in Whole Blood Gene Expression

Project description:To investigate the effects of bariatric surgery on gene expression profile changes in whole blood in obese subjects with type 2 diabetes in a pilot study setting. Whole blood from eleven obese subjects with type 2 diabetes was collected in PAXgene tubes prior to and 6-12 months after bariatric surgery. Total RNA was isolated, amplified, labeled and hybridized to Illumina gene expression microarrays. Clinical and expression data were analyzed using a paired t-test, and correlations between changes in clinical trait and transcript levels were calculated. Pathways were identified using Ingenuity Pathway Analysis and DAVID gene ontology software. Bariatric surgery resulted in significant reduction of BMI, fasting plasma glucose and normalization of HbA1c levels. The expression levels of 204 transcripts, representing 200 unique genes, were significantly altered after bariatric surgery. Among the significantly regulated genes were GGT1, CAMP, DEFA1, LCN2, TP53, ZNF684, GPR50, PDSS1, OLR1, CNTNAP5, DHCR24, HHAT and SARDH, which have been previously implicated in lipid metabolism, obesity and/or type 2 diabetes. The changes in expression of seven transcripts, WDR35, FLF45244, DHCR24, TIGD7, TOPBP1, TSHZ1, and FAM8A1 were strongly correlated with the changes in body weight, fasting plasma glucose and HbA1c content. These preliminary data suggest that whole blood expression levels of specific transcripts may identify biomarkers associated with susceptibility for type 2 diabetes and/or therapeutic response. Trasncriptome profiling was performed on eleven obese subjects with type 2 diabetes, (5 females and 6 males) to compare expression changes before and 6 to 12 months after the subjects underwent bariatric surgery.

2011-01-06 | E-GEOD-19790 | biostudies-arrayexpress

f99e97b0-359a-40b8-aaef-30c63cc77d85 - samples

Project description:94 human adipocyte samples isolated from whole adipose tissues using collagenase digestion of tissue and flotation of lipid-laden adipocytes, followed by RNA isolation and RNA sequencing (SMARTer Stranded Total RNA-Seq library preparation, HiSeq 4000 100-bp paired-end reads). Adipocyte samples comprise subcutaneous and visceral adipocytes isolated from obese and lean people (N=24 obese-subcutaneous, N=24 obese-visceral, N=22 control-subcutaneous, N=24 control-visceral). Human adipocyte RNA sequencing data are provided as BAM files.

| EGAD00001010195 | EGA

Resolution of Type 2 Diabetes Following Bariatric Surgery is Associated with Changes in Whole Blood Gene Expression

2011-01-06 | GSE19790 | GEO

Changes in CIDEA expression associate with adipocytes size and functionality in adolescent obese girls

Project description:About 20% of youth are obese with higher risk for cardiovascular disease and type 2 diabetes (T2D). We have recently reported that in obese adolescents altered pattern of fat distribution is associated with insulin resistance and T2D. In particular, the high ratio of visceral AT depot (VAT) to abdominal subcutaneous AT depot (SAT) (high VAT/(VAT+SAT)) was associated with a metabolically unhealthy phenotype with high risk for insulin resistance and T2D. CIDEA (Cell death inducing DNA fragmentation factor-alpha-like A) is a member of CIDE family and it is not only involved in the promotion of cell death and DNA fragmentation but it also plays critical roles in the lipid droplets formation and growth. Here we demonstrated in abdominal SAT from adolescent obese girls with high VAT/(VAT+SAT) a significant reduction of CIDEA expression associated with an increase in fasting insulin, serum FFA and consequent insulin resistance. We also demonstrated a direct correlation between CIDEA expression and fraction of large cells and an inverse correlation with small adipocytes number and pre-adipocytes proliferation. After gaining weight, we observed an increase in adipocytes cell diameter but a decrease in CIDEA expression, and the transcriptomic analysis showed a gene profile linked to adipocyte dysfunction. Together, these data suggested that in subjects with high VAT/(VAT+SAT) decreased CIDEA expression is associated with an increase in adipocyte cell sizing and consecutive insulin resistance.

2021-12-01 | GSE159955 | GEO

Microarray of isolated adipocytes from subcutaneous adipose tissue of severely obese patients compared to lean controls

Project description:The aim of the project was to compare global gene expression in adipocytes from obese patients and lean controls. Subcutaneous adipose tissue was collected from severely obese patients undergoing bariatric surgery (average body-mass index (BMI) of 45.5 kg/m2 (n = 12, thereof 4 men) and healthy lean patients undergoing hernia repairs (average BMI of 24.2 kg/m2 (n = 12, thereof 7 men), between 27 and 56 years of age. Adipocytes were isolated by collagenase treatment of adipose tissue, followed by filtering and centrifugation. Floating adipocytes were lysed in Qiazol before RNA purification and microarray analysis.

2018-12-12 | E-MTAB-6728 | biostudies-arrayexpress

Transcriptome analysis of circulating monocytes in obese patients before and three months after bariatric surgery

Project description:Low-grade chronic inflammation plays an important role in the development of obesity and obesity-associated disorders such as insulin resistance, type 2 diabetes, the metabolic syndrome and atherosclerosis. One possible link between obesity and inflammation is the enhanced activation of circulating monocytes making them more prone to infiltration into the adipose and vascular tissues of obese persons. Furthermore, weight loss after bariatric surgery is associated with less inflammation. Transcriptome analysis of circulating monocytes from control and obese patients before and after bariatric surgery will potentially provide insights into the pathophysiology of obesity and associated disorders and supply biomarkers for diagnostic purpose. The cohort comprised 6 lean age-matched controls (BMI: 20.3±0.5 kg/m2, mean±SEM) and 18 obese individuals without clinical symptoms of cardiovascular disease (BMI: 45.1±1.4 kg/m2, P<0.001 compared with lean controls). These 18 morbidly obese subjects were referred to our hospital for bariatric surgery. Before they were included, individuals were evaluated by an endocrinologist, an abdominal surgeon, a psychologist and a dietician. Only after multidisciplinary deliberation, the selected patients received a laparoscopic Roux-en-Y gastric bypass. CD14+ monocytes were collected before and three months after bariatric surgery (BMI: 37.5±1.3 kg/m2, P<0.001 compared with before weight loss), total RNA was extracted and subjected to genome-wide expression analysis. Samples consisted of CD14+ monocytes from 6 lean controls and 18 morbidly obese patients before and three months after bariatric surgery. The 6 lean controls were also used to make 6 control pools.

2012-05-23 | E-GEOD-32575 | biostudies-arrayexpress

Transcriptional profiling of subcutaneous adipose tissue of morbidly obese subjects before and after 2 years of bariatric surgery.

Project description:Transcriptional profiling of subcutaneous adipose tissue before and after 2 years of bariatric surgery. This type of surgery produce a masive weight loss in morbidly obese subjects, and improve the comorbidities associated to obesity. Goal was to determine the effects of bariatric surgery on the gene expression of subcutaneous adipose tissue.

2017-03-16 | GSE66921 | GEO

STAT1 Dissociates Adipose Tissue Inflammation from Insulin Sensitivity in Obesity

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.

2020-11-27 | GSE153337 | GEO

Transcriptome analysis of circulating monocytes in obese patients before and three months after bariatric surgery

2012-05-24 | GSE32575 | GEO

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