Early growth response protein 1 mediates the effect of insulin on leptin transcription in adipocytes

Abstract

All cells and organisms consume energy for survival. A robust system has evolved in vertebrates to serve as an energy reservoir. In particular, specialized cells, adipocytes, are responsible for the dynamic storage of energy by accumulating and releasing fatty acids. Fluctuating energy demands require adipose tissue to adjust in size, however complications can arise in both extremes giving rise to systemic diseases, such as obesity and diabetes mellitus (T2D). In mammals, leptin production in adipocytes is up-regulated by feeding and insulin to provide long-term post-prandial satiety. Although this regulatory connection is central to all physiological effects of leptin, the molecular mechanism remains unknown for leptin production. Here, we show that the transcription factor Egr1 is rapidly but transiently induced by insulin in adipose cells both in vitro and in vivo in a mTORC1-dependent fashion. Induction of Egr1 was immediately followed by an increase in leptin transcription. Chromatin immunoprecipitation and luciferase assays demonstrate that Egr1 directly binds to and activates the leptin promoter. Interestingly, the lipid droplet protein Fat specific protein 27 (FSP27) may work as a co-factor for Egr1 in regulating leptin expression. By using siRNA-mediated knock out of Egr1 along with its over-expression in adipocytes, we demonstrate that Egr1 is both necessary and sufficient for the stimulatory effect of insulin on leptin transcription. Knockout of the mTORC1-regulated translation repressor 4EBP1/2 increases leptin transcription both in vitro and in vivo. Adipose specific doxycycline-inducible constitutively active Rheb transgenic mouse lines contained higher circulating leptin and transcription of leptin following doxycycline treatment and were able to maintain elevated leptin levels following a 16 hour fast. Thus, insulin and nutrients, such as amino acids and glucose, activate leptin expression via the mTORC1-Egr1 regulatory axis.