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Reduced subcutaneous adipogenesis in human hypertrophic obesity is linked to senescent precursor cells.

ABSTRACT: Inappropriate expansion of the adipose cells in the subcutaneous adipose tissue (SAT) is a characteristic of hypertrophic obesity and of individuals with genetic predisposition for T2D (first-degree relatives; FDR). It is associated with insulin resistance, a dysfunctional, adipose tissue and reduced adipogenesis. We examined the regulation of adipogenesis in human SAT precursor cells and found ZNF521 to be a critical regulator of early adipogenic commitment and precursor cells leaving the cell cycle. However, neither altered upstream signalling nor lack of SAT progenitor cells could explain the reduced adipogenesis in hypertrophic obesity. Instead, we show that progenitor cells undergoing poor differentiation are characterized by senescence, inability to suppress p53/P16INK4 and secretion of factors reducing adipogenesis in non-senescent cells. We found aging, FDR and established T2D to be associated with increased progenitor cell senescence, reduced adipogenesis and hypertrophic expansion of the SAT adipose cells.

SUBMITTER: Gustafson B

PROVIDER: S-EPMC6588633 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Reduced subcutaneous adipogenesis in human hypertrophic obesity is linked to senescent precursor cells.

Gustafson Birgit B Nerstedt Annika A Smith Ulf U

Nature communications 20190621 1

Inappropriate expansion of the adipose cells in the subcutaneous adipose tissue (SAT) is a characteristic of hypertrophic obesity and of individuals with genetic predisposition for T2D (first-degree relatives; FDR). It is associated with insulin resistance, a dysfunctional, adipose tissue and reduced adipogenesis. We examined the regulation of adipogenesis in human SAT precursor cells and found ZNF521 to be a critical regulator of early adipogenic commitment and precursor cells leaving the cell ...[more]

PMID: 31227697

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Project description:BackgroundObesity is closely related to the abnormal differentiation of adipocytes, which are subjected to high plasma levels of free fatty acids (FFAs). As the most abundant FFA in the bloodstream, oleic acid (OA) has the ability to induce adipogenic differentiation in human adipose-derived stromal cells (hADSCs). Recently, p62, an autophagy mediator, has been shown to play a role in obesity and adipose tissue metabolism. Therefore, the aim of this study was to investigate the roles of autophagy and mitochondrial function at different stages of OA (in combination with insulin and dexamethasone)-induced adipogenesis in hADSCs.MethodsThe hADSCs were incubated with OA, insulin, and dexamethasone after pretreatment with autophagy inhibitors or knockdown of p62 with shRNA. The adiposeness level was then analyzed by oil red O staining in the cells. The related proteins or mRNA levels were detected by western blot analysis or quantitative real-time polymerase chain reaction (PCR).ResultsTreatment with 80 μM OA (substituted for isobutylmethylxantine; IBMX) for 10 days successfully induced hADSCs to adipocytes. During OA-induced adipogenesis, autophagy was induced, with an increased LC3II/I ratio on day 3 and a decreased protein level of p62 on and after day 3. Inhibition of autophagy with 3-methyladenine (3MA) at the early stage (day 0 to day 3) of differentiation, but not at the middle or late stage, significantly decreased OA-induced adipogenesis; while knockdown of p62 with shRNA significantly promoted adipogenesis in hADSCs. Moreover, the copy number of mtDNA (the ND1 gene) and the protein level of TOM20, a mitochondrial membrane protein, were increased following OA treatment, which was related to the stability of mitochondria. Interestingly, knockdown of p62 increased the mito-LC3II/I and cyto-LC3II/I ratios by 110.1% and 73.3%, respectively. The increase in the ratio of mito-LC3II/I was higher than that of cyto-LC3II/I. Furthermore, p62 knockdown-enhanced adipogenesis in hADSCs was abolished by inhibiting mitophagy with cyclosporine A.ConclusionsThese results suggested that p62 plays a protective role in adipogenesis of hADSCs through regulating mitophagy.

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Reduced subcutaneous adipogenesis in human hypertrophic obesity is linked to senescent precursor cells.

Publications

Reduced subcutaneous adipogenesis in human hypertrophic obesity is linked to senescent precursor cells.

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