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Autophagy is involved in adipogenic differentiation by repressesing proteasome-dependent PPAR?2 degradation.

ABSTRACT: Animal studies have shown that autophagy is essential in the process of obesity. Here, we performed daily injection of the autophagy inhibitor chloroquine (CQ) in mice and found that systemic administration of CQ blocks high-fat diet-induced obesity. To investigate the potential underlying molecular mechanism, we employed genetic and pharmacological interventions in cultured preadipocytes to investigate the role of autophagy in the control of the expression of the adipogenic regulator peroxisome proliferatior-activated receptor-? (PPAR?). We show that adipogenic differentiation of 3T3-L1 preadipocytes is associated with activation of autophagy and increased PPAR?2 protein level. Treatment with CQ, shRNA-mediated knockdown, or genetic engineering-induced deletion of autophagy-related gene 5 (Atg5) promoted proteasome-dependent PPAR?2 degradation and attenuated adipogenic differentiation. Therefore, activated autophagy increases PPAR?2 stability and promotes adipogenic differentiation, and inhibition of autophagy may prevent high-fat diet-induced obesity and the consequential type 2 diabetes.

SUBMITTER: Zhang C

PROVIDER: S-EPMC5504416 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Autophagy is involved in adipogenic differentiation by repressesing proteasome-dependent PPARγ2 degradation.

Zhang Chongben C He Yingke Y Okutsu Mitsuhara M Ong Lai Chun LC Jin Yi Y Zheng Lin L Chow Pierce P Yu Sidney S Zhang Mei M Yan Zhen Z

American journal of physiology. Endocrinology and metabolism 20130625 4

Animal studies have shown that autophagy is essential in the process of obesity. Here, we performed daily injection of the autophagy inhibitor chloroquine (CQ) in mice and found that systemic administration of CQ blocks high-fat diet-induced obesity. To investigate the potential underlying molecular mechanism, we employed genetic and pharmacological interventions in cultured preadipocytes to investigate the role of autophagy in the control of the expression of the adipogenic regulator peroxisome ...[more]

PMID: 23800883

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Project description:The umbilical cord (UC) matrix is a source of multipotent mesenchymal stem cells (MSCs) that have adipogenic potential and thus can be a model to study adipogenesis. However, existing variability in adipocytic differentiation outcomes may be due to discrepancies in methods utilized for adipogenic differentiation. Additionally, functional characterization of UCMSCs as adipocytes has not been described. We tested the potential of three well-established adipogenic cocktails containing IBMX, dexamethasone, and insulin (MDI) plus indomethacin (MDI-I) or rosiglitazone (MDI-R) to stimulate adipocyte differentiation in UCMSCs. MDI, MDI-I, and MDI-R treatment significantly increased peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT-enhancer binding protein alpha (C/EBPα) mRNA and induced lipid droplet formation. However, MDI-I had the greatest impact on mRNA expression of PPARγ, C/EBPα, FABP4, GPD1, PLIN1, PLIN2, and ADIPOQ and lipid accumulation, whereas MDI showed the least. Interestingly, there were no treatment group differences in the amount of PPARγ protein. However, MDI-I treated cells had significantly more C/EBPα protein compared to MDI or MDI-R, suggesting that indomethacin-dependent increased C/EBPα may contribute to the adipogenesis-inducing potency of MDI-I. Additionally, bone morphogenetic protein 4 (BMP4) treatment of UCMSCs did not enhance responsiveness to MDI-induced differentiation. Finally to characterize adipocyte function, differentiated UCMSCs were stimulated with insulin and downstream signaling was assessed. Differentiated UCMSCs were responsive to insulin at two weeks but showed decreased sensitivity by five weeks following differentiation, suggesting that long-term differentiation may induce insulin resistance. Together, these data indicate that UCMSCs undergo adipogenesis when differentiated in MDI, MDI-I, and MDI-R, however the presence of indomethacin greatly enhances their adipogenic potential beyond that of rosiglitazone. Furthermore, our results suggest that insulin signaling pathways of differentiated UCMSCs are functionally similar to adipocytes.

Dataset Information

Autophagy is involved in adipogenic differentiation by repressesing proteasome-dependent PPAR?2 degradation.

Publications

Autophagy is involved in adipogenic differentiation by repressesing proteasome-dependent PPARγ2 degradation.

Similar Datasets

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