Mol Cell Biol 2013 September; 33 (18): 3659 -66.

Insulin Inhibits Lipolysis in Adipocytes via the Evolutionarily Conserved mTORC1-Egr1-ATGL-Mediated Pathway.

Partha Chakrabarti*2, Ju Youn Kim1, Maneet Singh1, Yu-Kyong Shin1, Jessica Kim1, Joerg Kumbrink1, Yuanyuan Wu1, Mi-Jeong Lee1, Kathrin H. Kirsch1, Susan K. Fried1, Konstantin V. Kandror*1

1Boston University School of Medicine, Boston, Massachusetts, USA and 2 CSIR-Indian Institute of Chemical Biology, Kolkata, India

 

Abstract

One of the basic functions of insulin in the body is to inhibit lipolysis in adipocytes. Recently, we have found that insulin inhibits lipolysis and promotes triglyceride storage by decreasing transcription of adipose triglyceride lipase via the mTORC1-mediated pathway (P. Chakrabarti et al., Diabetes 59:775–781, 2010), although the mechanism of this effect remained unknown. Here, we used a genetic screen in Saccharomyces cerevisiae in order to identify a transcription factor that mediates the effect of Tor1 on the expression of the ATGL ortholog in yeast. This factor, Msn4p, has homologues in mammalian cells that form a family of early growth response transcription factors. One member of the family, Egr1, is induced by insulin and nutrients and directly inhibits activity of the ATGL promoter in vitro and expression of ATGL in cultured adipocytes. Feeding animals a high-fat diet increases the activity of mTORC1 and the expression of Egr1 while decreasing ATGL levels in epididymal fat. We suggest that the evolutionarily conserved mTORC1-Egr1-ATGL regulatory pathway represents an important component of the antilipolytic effect of insulin in the mammalian organism.

Keywords: Adipocyte, Lipolysis, mTOR, EGR1, ATGL

PMID: 23858058

 

Supplement

Global epidemic of insulin resistance and type 2 diabetes mellitus are often causally linked to obesity, i.e. increased (predominantly visceral) adipose tissue mass. Insulin, the major anabolic hormone is a crucial regulator of adipose function with a wide range of actions. For example, insulin stimulates the differentiation of pre-adipocytes to adipocytes and, in mature adipocytes, enhances glucose transport and triglyceride synthesis, in addition to inhibiting lipolysis. The mechanisms of nutrients and insulin-mediated regulation of lipolysis is currently under intense investigation. ATGL is considered to be the rate-limiting enzyme of the evolutionarily conserved lipolytic pathway. We and others have previously shown that insulin suppresses the expression of ATGL. Mechanistically, insulin action is linked to the molecular energy sensors such as Sirtuins, AMPK, FoxO and mTOR. We have initiated a search for the pathways that regulate expression of ATGL by nutrients and insulin. We and others have implicated a complex yet regulated interaction of these players in the regulation of insulin dependent ATGL expression.

We have recently identified mTORC1-mediated suppression of ATGL expression as one of the important pathways in nutrient/insulin mediated attenuation of lipolysis. However, the mechanism of mTORC1 action on transcription of ATGL remained elusive. Importantly, a similar regulatory link between dTORC1 and the ATGL homologue, Brummer, exists in Drosophila. Conservation of this regulatory pathway in the evolution suggests that it plays an essential role in animal physiology and makes it an attractive target for investigation. Here, we report that mTORC1 suppresses lipolysis in cultured adipocytes via the immediate-early response transcription factor Egr1 that directly inhibits ATGL gene expression. Interestingly, we found that mTORC1-Egr1-ATGL pathway is also conserved in yeast as Tor1-Msn4-Tgl4 pathway (See Fig below).Fig 1Our findings demonstrate a new level of nutrient/insulin dependent regulation of lipolysis that is essential for better understanding and restraining the metabolic disease. For example, the downregulation of ATGL via this pathway may represent an essential compensatory mechanism that may be needed for maintaining physiological concentrations of circulating free fatty acid in obesity.

 

Acknowledgement: This study was supported by research grants DK52057 and AG039612 from the National Institutes of Health, research grant 7-11-BS-76 from the American Diabetes Association, and a research award from the Allen Foundation to K.V.K.

Contact: Address correspondence to Partha Chakrabarti, pc1@csiriicb.in , or Konstantin V. Kandror, kkandror@bu.edu.

Fig 2

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