Dual regulation of adipose triglyceride lipase by pigment epithelium-derived factor: A novel mechanistic insight into progressive obesity

Zhiyu Dai, Weiwei Qi, Cen Li, Juling Lu, Yuling Mao, Yachao Yao, Lei Li, Ting Zhang, Honghai Hong, Shuai Li, Ti Zhou, Zhonghan Yang, Xia Yang, Guoquan Gao*, Weibin Cai

*Corresponding author for this work

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

Both elevated plasma free fatty acids (FFA) and accumulating triglyceride in adipose tissue are observed in the process of obesity and insulin resistance. This contradictory phenomenon and its underlying mechanisms have not been thoroughly elucidated. Recent studies have demonstrated that pigment epithelium-derived factor (PEDF) contributes to elevated plasma FFA and insulin resistance in obese mice via the activation of adipose triglyceride lipase (ATGL). However, we found that PEDF downregulated adipose ATGL protein expression despite of enhancing lipolysis. Plasma PEDF and FFA were increased in associated with a progressive high-fat-diet, and those outcomes were also accompanied by fat accumulation and a reduction in adipose ATGL. Exogenous PEDF injection downregulated adipose ATGL protein expression and elevated plasma FFA, while endogenous PEDF neutralization significantly rescued the adipose ATGL reduction and also reduced plasma FFA in obese mice. PEDF reduced ATGL protein expression in a time- and dose-dependent manner in differentiated 3T3-L1 cells. Small interfering RNA-mediated PEDF knockdown and antibody-mediated PEDF blockage increased endogenous ATGL expression, and PEDF overexpression downregulated ATGL. PEDF resulted in a decreased half-life of ATGL and regulated ATGL degradation via ubiquitin-dependent proteasomal degradation pathway. PEDF stimulated lipolysis via ATGL using ATGL inhibitor bromoenol lactone, and PEDF also downregulated G0/G1 switch gene 2 (G0S2) expression, which is an endogenous inhibitor of ATGL activation. Overall, PEDF attenuated ATGL protein accumulation via proteasome-mediated degradation in adipocytes, and PEDF also promoted lipolysis by activating ATGL. Elevated PEDF may contribute to progressive obesity and insulin resistance via its dual regulation of ATGL.

Original languageEnglish (US)
Pages (from-to)123-134
Number of pages12
JournalMolecular and Cellular Endocrinology
Volume377
Issue number1-2
DOIs
StatePublished - Sep 5 2013

Keywords

  • ATGL
  • Free fatty acid
  • Lipolysis
  • Obesity
  • PEDF
  • Proteasome degradation pathway

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Endocrinology

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  • Cite this

    Dai, Z., Qi, W., Li, C., Lu, J., Mao, Y., Yao, Y., Li, L., Zhang, T., Hong, H., Li, S., Zhou, T., Yang, Z., Yang, X., Gao, G., & Cai, W. (2013). Dual regulation of adipose triglyceride lipase by pigment epithelium-derived factor: A novel mechanistic insight into progressive obesity. Molecular and Cellular Endocrinology, 377(1-2), 123-134. https://doi.org/10.1016/j.mce.2013.07.001