Protein kinase D1 deletion in adipocytes enhances energy dissipation and protects against adiposity
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ABSTRACT:
PROVIDER: PRJNA413844 | ENA |
REPOSITORIES: ENA
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Project description:DAG-activated Pkd1 promotes triglyceride accumulation in adipocytes; Pkd1 promotes lipogenesis and suppresses mitochondrial function in adipocytes in an AMPK-dependent manner; Pkd1 suppresses expression of genes characteristic for beige adipocytes; Deletion of Pkd1 in adipocytes protects mice from diet-induced obesity, T2D and liver steatosis.
2018-09-20 | GSE104797 | GEO
Project description:Ablation of TET proteins in adipocytes protects against adiposity and metabolic dysfunction by potentiating energy expenditure
| PRJNA740303 | ENA
Project description:Ten-eleven translocation (TET) proteins oxidize 5-methylcytosine in DNA to 5- hydroxymethylcytosine and further oxidized derivatives. Here we show that TET proteins are key epigenetic suppressors of adipocyte thermogenesis and energy expenditure in both white and brown adipose tissues in vivo. Tet expression in adipocytes decreases upon cold or adrenergic stimulation but increases following high-fat diet (HFD) consumption. Mice with triple deletion of all three Tet genes in adipocytes have higher energy expenditure due to enhanced fat browning and thermogenesis. They also show significantly enhanced lipolysis because of elevated expression of Adrb3 and key lipases including Atgl and Hsl. Consequently, the knockout mice display improved cold tolerance and are substantially resistant to obesity, inflammation, and associated metabolic complications including insulin resistance. Mechanistically, TET deficiency substantially prevents the HFD-induced transcriptional alterations in adipose tissues. TET proteins recruit histone deacetylases (HDACs) to the key thermogenic gene loci including Adrb3, Ppargc1a, and Ucp1, leading to transcriptional repression through histone deacetylation. Thus, the TET-HDAC axis may be therapeutically targeted to treat obesity and related metabolic diseases.
2021-11-01 | GSE178762 | GEO
Project description: Not available
| S-EPMC6236335 | biostudies-literature
Project description:Parkin, an E3 ubiquitin ligase, plays an essential role in mitochondrial quality control. However, the mechanisms by which Parkin connects mitochondrial homeostasis to cellular metabolism in adipose tissue remain unclear. Here, we demonstrate that Park2 gene (encodes Parkin) deletion specifically from adipose tissue protects mice against high-fat diet and aging-induced obesity. Despite a mild reduction in mitophagy, mitochondrial DNA (mtDNA) content and mitochondrial function are significantly increased in Park2 deficient white adipocytes. Moreover, Park2 gene deletion robustly elevates mitochondrial biogenesis by increasing Pgc1α protein stability through mitochondrial superoxide-activated Nqo1. Both in vitro and in vivo studies show that Nqo1 overexpression elevates Pgc1α protein level and mtDNA content and enhances mitochondrial activity in mouse and human adipocytes. Taken together, our findings indicate that Parkin regulates mitochondrial homeostasis by balancing mitophagy and Pgc1α-mediated mitochondrial biogenesis in white adipocytes, suggesting a potential therapeutic target in adipocytes to combat obesity and obesity-associated disorders.
2022-09-29 | GSE207496 | GEO
Project description:Obesity is linked to the development of metabolic disorders. Expansion of white adipose tissue (WAT) from hypertrophy of pre-existing adipocytes and/or differentiation of precursors into new mature adipocytes contributes to obesity. We found that Nck2 expression is largely restricted to WAT, raising the hypothesis that it may play a unique function in that tissue. Using mice lacking Nck2, we found that Nck2 regulates adipocyte hypertrophy thus contributing to increased adiposity and progressive glucose intolerance, insulin resistance and hepatic steatosis. These findings were recapitulated in humans such that Nck2 expression in omental WAT was inversely correlated with the degree of obesity. Mechanistically, Nck2 deficiency promoted the induction of an adipocyte differentiation program and signaling by the PERK-eIF2α-ATF4 pathway in agreement with a role for the unfolded protein response in adipogenesis. These findings uncover Nck2 as a novel regulator of adipogenesis and that perturbation in its functionality contributes to adiposity-related metabolic disorders. Differential gene expression profile between epididymal white adipose tissue of Nck2-/- and Nck2+/+ mice by RNA sequencing (Illumina HiSEq 2000)
2016-07-01 | E-GEOD-63510 | biostudies-arrayexpress
Project description:White adipose tissue (WAT) is a key regulator of systemic energy metabolism, and impaired WAT plasticity characterized by enlargement of preexisting adipocytes associates with WAT dysfunction, obesity and metabolic complications. However, the mechanisms that retain proper adipose tissue plasticity required for metabolic fitness are unclear. Here, we comprehensively showed that adipocyte-specific DNA methylation, manifested in enhancers and CTCF sites, directs distal enhancer-mediated transcriptomic features required to conserve metabolic functions of white adipocytes. Particularly, genetic ablation of adipocyte Dnmt1, the major methylation writer, led to increased adiposity characterized by increased adipocyte hypertrophy along with reduced expansion of adipocyte precursors (APs). These effects of Dnmt1 deficiency provoked systemic hyperlipidemia and impaired energy metabolism both in lean and obese mice. Mechanistically, Dnmt1 deficiency abrogated mitochondrial bioenergetics by inhibiting mitochondrial fission and promoted aberrant lipid metabolism in adipocytes, rendering adipocyte hypertrophy and WAT dysfunction. Dnmt1-dependent DNA methylation prevented aberrant CTCF binding and, in turn, sustained the proper chromosome architecture to permit interactions between enhancer and dynamin-related protein gene Drp1 in adipocytes. Also, adipose DNMT1 expression inversely correlated with adiposity and markers of metabolic health, but positively correlated with AP-specific markers in obese human subjects. Thus, these findings support strategies utilizing Dnmt1 action on mitochondrial bioenergetics in adipocytes to combat obesity and related metabolic pathology.
2021-03-24 | GSE158944 | GEO
Project description:Brown adipose tissue (BAT) dissipates energy and promotes cardio-metabolic health4. However, loss of BAT during obesity and aging is a principal hurdle for BAT-centered obesity therapies. So far not much is known about BAT apoptosis and signals released by apoptotic brown adipocytes. Here, untargeted metabolomics demonstrated that apoptotic brown adipocytes release a specific pattern of metabolites with purine metabolites being highly enriched. Interestingly, this apoptotic secretome enhances expression of the thermogenic program in healthy adipocytes to maintain tissue functionality. This effect is mediated by the purine inosine which stimulates energy expenditure (EE) in brown adipocytes. Phosphoproteomic analysis demonstrated activation of the cAMP/protein kinase A signaling pathway and of pro-thermogenic transcription factors by inosine.
2022-05-31 | PXD032153 | Pride
Project description:Obesity is a pandemic health problem with poor solutions, especially for targeted treatment. Here we develop a polycation-based nanomedicine to selectively target visceral adiposity, the more metabolically detrimental and manipulation-resistant fat. We demonstrated that the polycationic polymer polyamidoamine (PAMAM) generation 3 (P-G3) was specifically enriched in the visceral fat due to its high charge density when delivered intraperitoneally. Moreover, P-G3 treatment of obese mice inhibited visceral adiposity, increased energy expenditure, prevented obesity, and alleviated the associated metabolic dysfunctions. In vitro adipogenesis models and single-cell RNA sequencing (scRNA-seq) revealed that P-G3 paradoxically uncouples the defining function of adipocyte - lipid synthesis and storage - from adipocyte development to create unique “dwarf” adipocytes that possess normal adipocyte functions but are deficient in hypertrophic growth at least through synergistically modulating NAD and mTOR pathways. The visceral fat distribution of P-G3 was further enhanced by modifying P-G3 with cholesterol to form lipophilic nanoparticles, which were also effective in treating obesity. Our study highlights an unexpected strategy to tackle visceral adiposity and champions a new direction of exploring cationic nanomaterials for treating metabolic diseases.
2022-09-19 | GSE209819 | GEO
Project description:Obesity is linked to the development of metabolic disorders. Expansion of white adipose tissue (WAT) from hypertrophy of pre-existing adipocytes and/or differentiation of precursors into new mature adipocytes contributes to obesity. We found that Nck2 expression is largely restricted to WAT, raising the hypothesis that it may play a unique function in that tissue. Using mice lacking Nck2, we found that Nck2 regulates adipocyte hypertrophy thus contributing to increased adiposity and progressive glucose intolerance, insulin resistance and hepatic steatosis. These findings were recapitulated in humans such that Nck2 expression in omental WAT was inversely correlated with the degree of obesity. Mechanistically, Nck2 deficiency promoted the induction of an adipocyte differentiation program and signaling by the PERK-eIF2α-ATF4 pathway in agreement with a role for the unfolded protein response in adipogenesis. These findings uncover Nck2 as a novel regulator of adipogenesis and that perturbation in its functionality contributes to adiposity-related metabolic disorders.
2016-07-01 | GSE63510 | GEO