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Depletion of WWP1 increases Adrb3 expression and lipolysis in white adipose tissue of obese mice

ABSTRACT: Obesity is defined as abnormal or excessive fat accumulation of body fat and contributes to several metabolic disorders. White adipose tissue (WAT) stores energy in the form of triglycerides and releases energy as free fatty acids and glycerol through a process called lipolysis. People with obesity have impaired catecholamine-stimulated lipolysis, but comprehensive understanding of this lipolysis is still unclear. WW domain-containing E3 ubiquitin ligase 1 (WWP1) is a member of the HECT-type E3 family of ubiquitin ligases and is associated with several diseases. We previously showed that WWP1 expression was increased in WAT of obese mice. In this study, we investigated the function of WWP1 in WAT of obese mice by analyzing the phenotype of Wwp1 knockout (KO) mice fed a high-fat diet. The mRNA levels of beta-3 adrenergic receptor (Adrb3), which were decreased with a high-fat diet, were increased by Wwp1 KO in WAT. Moreover, Wwp1 KO mice showed increased phosphorylated hormone-sensitive lipase levels in WAT and plasma non-esterified fatty acid concentrations. In contrast, noradrenaline and its metabolism were not altered in WAT of obese Wwp1 KO mice. These findings indicate that WWP1, which is increased in adipocytes because of obesity, is a candidate for suppressing the Adrb3 signaling pathway and lipolysis independently of noradrenaline metabolism.

ORGANISM(S): Mus musculus

PROVIDER: GSE286128 | GEO | 2025/05/29

REPOSITORIES: GEO

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Project description:Background Obesity is associated with changes in fat cell gene expression and metabolism. What drives these changes is not well understood. We aimed to explore fat cell epigenetics, i.e., DNA methylation, as one mediator of gene regulation, in obese women. The global DNA methylome for abdominal subcutaneous fat cells was compared between 15 obese case (BMI 41.4 ± 4.4 kg/m 2 , mean ± SD) and 14 never-obese control women (BMI 25.2 ± 2.5 kg/m 2 ). Global array-based transcriptome analysis was analyzed for subcutaneous white adipose tissue (WAT) from 11 obese and 9 never-obese women. Limma was used for statistical analysis. Results We identified 5529 differentially methylated DNA sites (DMS) for 2223 differentially expressed genes between obese cases and never-obese controls (false discovery rate <5 %). The 5529 DMS displayed a median difference in beta value of 0.09 (range 0.01 to 0.40) between groups. DMS were under-represented in CpG islands and in promoter regions, and over-represented in open sea-regions and gene bodies. The 2223 differentially expressed genes with DMS were over-represented in key fat cell pathways: 31 of 130 (25 %) genes linked to “adipogenesis” (adjusted P = 1.66 × 10 −11 ), 31 of 163 (19 %) genes linked to “insulin signaling” (adjusted P = 1.91 × 10 −9 ), and 18 of 67 (27 %) of genes linked to “lipolysis” (P = 6.1 × 10 −5 ). In most cases, gene expression and DMS displayed reciprocal changes in obese women. Furthermore, among 99 candidate genes in genetic loci associated with body fat distribution in genome-wide association studies (GWAS); 22 genes displayed differential expression accompanied by DMS in obese versus never-obese women (P = 0.0002), supporting the notion that a significant proportion of gene loci linked to fat distribution are epigenetically regulated. Conclusions Subcutaneous WAT from obese women is characterized by congruent changes in DNA methylation and expression of genes linked to generation, distribution, and metabolic function of fat cells. These alterations may contribute to obesity-associated metabolic disturbances such as insulin resistance in women. The global DNA methylome in abdominal subcutaneous fat cells was compared between 15 obese cases (BMI 41.4±4.4 kg/m2, mean ± SD) and 14 never-obese control women (BMI 25.2±2.5 kg/m2).

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Depletion of WWP1 increases Adrb3 expression and lipolysis in white adipose tissue of obese mice

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