mTORC2 in adipocytes is essential to increase cold-induced thermogenic capacity and improve insulin sensitivity induced by cold and high-fat diet rich in omega 3 fatty acids.

Author(s)

Érique de Castro

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI)
• Defense date: 2021-07-16

Examining board members

William Tadeu Lara Festuccia; Luiz Osório Silveira Leiria; Vanessa de Souza Mello; Alice Cristina Rodrigues

• Advisor: William Tadeu Lara Festuccia

Abstract

Rictor is an essential component of mTOR complex 2 (mTORC2) that regulates cell growth, proliferation and metabolism. Upon activation by insulin, Rictor/mTORC2 promotes mainly through the phosphorylation and activation of Akt, glucose uptake and de novo lipogenesis in adipocytes. We investigated herein the involvement of adipocyte mTORC2 as a possible mediator of the increases in thermogenic capacity, glucose uptake in adipose tissue and improvement in glucose homeostasis induced by cold acclimation for 14 days (Chapter 2), treatment with the PPAR γ ligand pioglitazone (Chapter 3) and intake of high-fat diet enriched with omega 3 fatty acids (Chapter 4). For this, mice with Rictor deletion exclusively in adipocytes (ARicKO, Rictor flox/flox adiponectina Cre+) and littermate controls (ARicWT, Rictor flox/flox) were maintained at 30°C or acclimated to cold (10°C) for 14 days (Chapter 2); or fed with a high-fat diet supplemented or not with pioglitazone (Pio, 30 mg/ kg body weight/ day) during 8 weeks at 23°C (Chapter 3); or fed with high-fat diets produced using either lard (HFD) or fish oil (HFn3) as fat source for 8 weeks at 23°C (Chapter 4). Mice were evaluated for body mass, energy expenditure, serum metabolites, tissue oxygen consumption, glucose homeostasis and lipid and glucose metabolism. Our main findings indicate that ARicKO mice acclimated to cold (10°C) are insulin intolerant, and display impairments in brown adipose tissue mass (BAT) and inguinal white adipose tissue (iWAT) browning and total UCP-1 content and therefore thermogenic capacity stimulated by agonist β3-adrenergic. Adipocyte Rictor deficiency, however, did not affect the increase in BAT and iWAT glucose uptake induced by cold acclimation. Furthermore, ARicKO fed with a high-fat diet displayed insulin resistance and hepatic steatosis, despite the lower body weight gain and reduced adiposity. Treatment with Pio did not affect body weight, but improved insulin sensitivity in ARicKO, despite exacerbating hepatic steatosis. ARicKO fed with HFn3 are insulin resistant, display higher body weight gain, and reduced iWAT browning and oxygen consumption than ARicWT and reduced hepatic steatosis when compared to HFD-fed ARicKO. In conclusion, our findings indicate that adipocyte Rictor/mTORC2 is an important mediator of BAT expansion and iWAT browning induced by cold acclimation, which results in an impaired total UCP-1 content and mediated thermogenic capacity. Rictor/mTORC2 is also an important mediator of iWAT expansion induced by intake of HFD, and mediate the improvement in insulin sensitivity induced by HFn3, but not by Pio. Our findings also indicate that adipocyte Rictor/mTORC2 is involved in AT-liver communication axis, through unknown molecular mechanisms. (AU)

• FAPESP's process: 16/23169-9 - Involvement of mTORC1 and 2 and PPARgamma in the regulation of leukocyte profile, recruitment and activation of brown adipose tissue and beige adipocytes induced by cold exposure
• Grantee: Érique de Castro
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)