Non-canonical mTORC2 Signaling Regulates Brown Adipocyte Lipid Catabolism through SIRT6-FoxO1

Area of Science:

• Metabolic signaling
• Adipocyte biology
• Obesity research

Background:

• The mechanistic target of rapamycin complex 2 (mTORC2) regulates glucose and lipid metabolism, but its precise mechanisms remain incompletely understood.
• Brown adipocytes are crucial for thermogenesis and energy expenditure, playing a key role in metabolic homeostasis.

Purpose of the Study:

• To elucidate the role of the mTORC2 subunit Rictor in brown adipocyte function and its impact on overall metabolism.
• To investigate the molecular pathways by which mTORC2 influences lipid metabolism and thermogenesis in brown adipose tissue.

Main Methods:

• Conditional deletion of the Rictor gene in murine brown adipocytes.
• Analysis of lipid synthesis, catabolism, and thermogenic gene expression (e.g., UCP1).
• Investigation of signaling pathways involving AKT, FoxO1 acetylation, and SIRT6.

Main Results:

• Rictor deletion in brown adipocytes inhibited de novo lipid synthesis and promoted lipid catabolism and thermogenesis.
• This manipulation protected mice against diet-induced obesity and hepatic steatosis.
• Lipid catabolism was mediated by AKT-independent deacetylation of FoxO1, enhancing its nuclear retention, lipid uptake, lipolysis, and UCP1 expression.
• SIRT6 was identified as the FoxO1 deacetylase suppressed by mTORC2, with evidence of an endogenous interaction between SIRT6 and mTORC2.

Conclusions:

• mTORC2, through Rictor in brown adipocytes, plays a critical role in suppressing lipid catabolism and thermogenesis.
• The findings reveal a novel AKT-independent pathway where mTORC2 regulates FoxO1 deacetylation via SIRT6, impacting lipid metabolism and energy balance.
• This study proposes a new paradigm for mTORC2 function, highlighting its significance in metabolic regulation and offering potential therapeutic targets for obesity and related disorders.