Effects of FGF19 on thermogenic capacity and lipids secretion profile in human adipocytes

• Grant number: 22/15148-2
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Effective date (Start): June 01, 2023
• Effective date (End): May 31, 2024
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Helena Cristina de Lima Barbosa
• Grantee: Lucas Zangerolamo
• Supervisor: Yu-Hua Tseng
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Research place: Harvard University, Boston, United States
• Associated to the scholarship: 20/14020-7 - Molecular and functional mechanisms involved in the central effects of FGF19 on hypothalamic dysregulation, BP.DR

Abstract

Activation of brown adipose tissue (BAT) increases energy expenditure (EE), and its activity is inversely correlated with body mass index and fat mass. BAT generates heat in response to cold exposure due to its unique expression of uncoupling protein 1 (UCP1) that dissipates energy by uncoupling the proton motive force from ATP production. Although UCP1 expression is restricted to BAT under basal conditions, prolonged cold exposure or beta-adrenergic stimulation can not only increase UCP1-mediated thermogenic capacity in BAT but can also activate the recruitment of brown-like beige adipocytes in white adipose tissue (WAT) that express UCP1 to produce heat in a process called browning. Moreover, there has recently been growing interest in the secretory role of BAT in regulating whole-body metabolism. Several signaling lipids have been shown to be secreted by brown adipocytes and have demonstrated roles in regulating energy metabolism. In this context, the fibroblast growth factor-19 (FGF19) has shown promise. FGF19 is a gut-derived molecule, and its central and peripheral administration increases EE and reduces body weight in diet-induced obese mice, through a mechanism not fully understood. Moreover, FGF19 levels are directly associated with UCP1 gene expression in subcutaneous WAT in humans and negatively correlated with body mass index, body fat, and plasma insulin concentration. In this present project, we will test the hypothesis that direct signaling of FGF19 can increase thermogenic mechanisms in white and brown human adipocytes, in the face of thermogenic stimuli. To achieve this goal, we will evaluate the effects of direct FGF19 signaling on the expression of thermogenic gene markers, bioenergetic profile, and glucose uptake in white and brown human adipocytes, as well as in human brown-like (HUMBLE) cells, which were created by engineering human white preadipocytes using CRISPR-Cas9-SAM-gRNA to activate endogenous UCP1 expression. In parallel, we also aim to investigate whether FGF19 affects the profile of lipids released by human brown adipocytes, which will be achieved through a signaling lipidome, aiming to identify new molecules with metabolic potential that can be modulated by this FGF. Identifying the mechanism by with FGF19 acts may offer new opportunities for therapeutic approaches to alleviate obesity and significantly improve the quality of life of obese individuals, as well as provide insight into metabolism itself. (AU)