mTORC1 and 2 regulation of thermogenic capacity and metabolism in brown adipose tissue

• Grant number: 25/04262-7
• Support Opportunities: Regular Research Grants
• Start date: September 01, 2025
• End date: August 31, 2028
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: William Tadeu Lara Festuccia
• Grantee: William Tadeu Lara Festuccia
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Brown adipose tissue (BAT) thermogenesis results from the uncoupling of mitochondrial inner membrane proton gradient mediated by the uncoupling protein 1 (UCP-1), which is activated by lipolysis-derived fatty acids. Norepinephrine (NE) secreted by sympathetic innervation not only activates BAT lipolysis and UCP-1, but uniquely in brown adipocytes, promotes "futile" metabolic cycles and enhances BAT thermogenic capacity by increasing UCP-1 content, mitochondrial biogenesis and brown adipocyte hyperplasia. NE exerts these actions by triggering signaling in the canonical G protein-coupled beta adrenergic receptors, cAMP and protein kinase A (PKA) pathway which, in brown adipocyte, is under a complex and intricated crosstalk with important growth-promoting signaling pathways such as those of mechanistic target of rapamycin (mTOR) complexes 1 (mTORC1) and 2 (mTORC2). In this proposal, we will investigate how mTOR complexes are modulated by and mediate the thermogenic, metabolic, and growth-promoting effects elicited by NE in BAT. For this, we will evaluate in 4 Research Programs BAT thermogenesis, metabolism, intracellular signaling and mitochondrial respiration in mice bearing either unilateral BAT sympathetic denervation or adipocyte or brown adipocyte deletion of either Rictor (mTORC2 deficiency) or Raptor (mTORC1 deficiency), or Rheb (impaired mTORC1 activation by Tsc1/tsc2) or Pten (mTORC2 gain of function) or Tsc1 (mTORC1 gain of function) maintained at thermoneutrality (30ºC) or exposed to acute or chronic cold (10ºC), or treated with NE or beta3 adrenergic receptor agonist CL-316,243. These parameters will be also evaluated in vitro in primary brown adipocytes harvested from these mice treated with NE or CL-316,243 for different periods. (AU)