Adipocyte-secreted lipids as messengers linking insulin resistance to hyperinsulinemia in obesity

• Grant number: 19/26008-4
• Support Opportunities: Regular Research Grants
• Duration: July 01, 2020 - January 31, 2024
• Field of knowledge: Biological Sciences - Biochemistry - Metabolism and Bioenergetics
• Convênio/Acordo: Max Planck Society for the Advancement of Science
• Principal Investigator: Luiz Osório Silveira Leiria
• Grantee: Luiz Osório Silveira Leiria
• Principal researcher abroad: Stefan Offermanns
• Institution abroad: Max Planck Society, Bad Nauheim, Germany
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Obesity is a worldwide epidemy with increasing prevalence and is a major independent risk factor for type 2 diabetes and many other diseases. In the early stages of obesity-induced type 2 diabetes, the cells of the body become insulin resistant as the downstream signaling pathways following insulin receptor stimulation become less responsive. Therefore, pancreatic beta-cells start to secrete increasing levels of insulin in response to continued high-glucose concentration as an attempt to compensate for the impaired insulin sensitivity in the tissues, thus resulting in hyperinsulinemia. Hyperinsulinemia itself can contribute for many obesity-derived comorbidities, such as hypertension, increased adiposity, higher cancer risk, benign prostatic hyperplasia and hepatic steatosis. Studies applying genetic tools in mice have shown that hyperinsulinemia is an independent and essential factor for the progression of obesity and hepatic steatosis under high-fat diet (HFD). If through one side hyperinsulinemia can increase adiposity, on the other side there are evidences supporting the idea that lipolysis of adipose tissue can increase insulin secretion by releasing free fatty-acids capable of stimulating beta-cells. Importantly, insulin resistance in adipocytes also increases lipolysis, however, the link between the insulin resistance in adipocytes and hyperinsulinemia remains elusive. Our hypothesis is that the lipolysis-induced release of lipids and FFA into the circulation is necessary for the continued hyperinsulinemia in the early stage of type 2 diabetes. In addition we believe this crosstalk takes place through the action of specific bioactive lipids that stimulate specific G-protein coupled receptors (GPCRs). Our main goals are: (i) investigate whether mice with adipocyte specific deletion of the rate limiting enzyme for lipolysis, the adipose triglyceride lipase (Atgl; Adipoq-Atgl KO mice), are protected from the high-fat diet-induced hyperinsulinemia; (ii) identify the main lipids and FFAs that are released in obese wild type mice but not in Adipoq-Atgl KO mice; (iii) screen those lipids and FFAs for their capacity to induce insulin secretion in human beta-cells, in the presence and absence of high-glucose levels; (iv) screen and identify the GPCRs that bind to the identified insulinotropic lipids; (v) evaluate the relevance of those GPCRs for the obesity-induced hyperinsulinemia through loss-of-function experiments in in vitro and in vivo settings. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

SPONTON, CARLOS H.; DE LIMA-JUNIOR, JOSE CARLOS; LEIRIA, LUIZ O.. What puts the heat on thermogenic fat: metabolism of fuel substrates. TRENDS IN ENDOCRINOLOGY AND METABOLISM, v. 33, n. 8, p. 13-pg., 2022-07-12. (20/05040-4, 17/08264-8, 19/26008-4, 19/15025-5)

SUGIMOTO, SATORU; MENA, HEBE AGUSTINA; SANSBURY, BRIAN E.; KOBAYASHI, SHIO; TSUJI, TADATAKA; WANG, CHIH-HAO; YIN, XUANZHI; HUANG, TIAN LIAN; KUSUYAMA, JOJI; KODANI, SEAN D.; et al. Brown adipose tissue-derived MaR2 contributes to cold-induced resolution of inflammation. NATURE METABOLISM, v. 4, n. 6, p. 28-pg., 2022-06-01. (19/26008-4, 19/20554-7)