mTORC1 and Autophagy in Human Brown Adipocytes

Overview

The long term goal is to identify the potential therapeutic targets for the treatment of obesity and its associated disorders by studying the driving factors of activation of brown adipose tissue (BAT) in human adults. Whereas activation of brown adipose tissue (BAT) in human adults has been considered as a potential therapeutic target to battle obesity since it was identified in 2009, the underlying mechanisms of beige adipocytes appearance in human adults is unclear. The objective of this proposal is to investigate the role of autophagy in mediating the inhibitory effect of mammalian target of rapamycin complex 1 (mTORC1) in regulating human brown adipocytes. The central hypothesis is that autophagy plays a critical role in regulating browning of white adipose tissue and mediates the beneficial effect of mTORC1 inhibition on thermogenesis in human brown adipocytes.

Specific Aim 1: To investigate the role of mTORC1 and autophagy in regulating thermogenesis in human brown adipocytes. The working hypothesis is that inhibition of mTORC1 or activation of autophagy improves thermogenesis in human brown adipocytes. It will be first determined if the mTORC1/autophagy signaling modulates thermogenic gene expression and beige markers by collecting human brown fat from lean non-diabetic subjects. The brown fat during the anterior cervical spine surgery or thyroidectomy from lean subjects with a BMI \<25, or obese participants who have a BMI \>30, will be harvested and then be used to determine: 1) whether mTORC1 signaling, autophagy and thermogenic gene expression, and the fraction of various types of immune cells in human brown fat are different from those in rodents;2) whether rapamycin treatment enhances basal or CL-induced thermogenic gene expression and O2 consumption in primary human brown adipocytes; and 3) whether inhibition of autophagy by 3-methyladenine (3-MA) suppresses thermogenic gene expression induced by CL316,243, a β3-adrenoceptor agonist that mimics cold stress in vivo in human brown adipocytes. Overall, this study will lead to the identification of mTORC1 as a key regulator of thermogenesis in human adipose tissue and reveal promising new anti-obesity drug targets. In addition, this study will further investigate the role of rapamycin administration in obesity in human adults near the future. These studies are designed to be a proof-of-principle. If the results are promising, then future drug development could focus on designing new inhibitors of mTORC1.