Metabolic Impact of the Succinate/SUCNR1 Axis in Adipocytes: Insights into Circadian and Leptin Regulation

Identifier:  TDX:4507

Handle: https://hdl.handle.net/20.500.11797/TDX4507

Authors:  Villanueva Carmona, Teresa

Abstract:
Adipose tissue (AT) plays a key role in maintaining energy balance through leptin secretion, a hormone that regulates energy homeostasis and body adiposity. Although the mechanisms of leptin action are well-established, the factors influencing its production are less clear. This doctoral thesis investigates the succinate/succinate receptor 1 (SUCNR1) axis in adipocytes, demonstrating that succinate as a hormone-like metabolite that activates SUCNR1, a G proteincoupled receptor (GPCR). The research reveals that SUCNR1, in addition to responding to stress and having antilipolytic effects in AT, regulates leptin expression and energy balance. Using an adipocyte-specific Sucnr1 KO mouse model, in vitro experiments and human studies, this thesis demonstrates that Sucnr1 deficiency in adipocytes improves metabolic health by reducing adipose mass, increasing white AT (WAT) browning, and improving glucose tolerance. However, this deficiency also affects bone mass and impairs the leptin response after feeding. The identified mechanisms are less effective under obesity conditions, as mice on a high-fat diet with adipocyte-specific Sucnr1 deletion show greater hepatic steatosis and glucose intolerance. SUCNR1 also regulates the circadian clock in AT, influencing leptin expression. Finally, obesity-related hyperleptinemia in humans has been observed to correlate with SUCNR1 overexpression, suggesting its potential as a pharmacological target in metabolic disorders.