Characterization of the molecular and functional mechanisms involved in hypothalamic dysfunctions induced by amino acid restriction in vitro and in vivo: possible protective role of the bile acid TUDCA

• Grant number: 23/01509-6
• Support Opportunities: Regular Research Grants
• Start date: November 01, 2023
• End date: October 31, 2025
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Agreement: CNPq
• Principal Investigator: Everardo Magalhães Carneiro
• Grantee: Everardo Magalhães Carneiro
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 18/26080-4 - Characterization of molecular and functional mechanisms involved in endocrine-metabolic, cardiovascular and neural dysfunctions induced by the restriction of amino acids in vitro and in vivo: possible therapeutic role of bile acid TUDCA, AP.TEM
• Associated scholarship(s): 23/10229-7 - Characterization of the molecular and functional mechanisms involved in hypothalamic dysfunctions induced by amino acid restriction in vitro and in vivo: Possible protective role of the bile acid TUDCA, BP.JD

Abstract

Despite global efforts, undernutrition still affects thousands of people around the world. Undernutrition in the early stages of life, or during pregnancy/lactation, compromises the development and function of several organs, including the central nervous system (CNS), thus altering feeding behavior, in part, by increasing the expression of orexigenic genes (NPY and AgRP) in the hypothalamus and consequent hyperphagia. We hypothesize that hypothalamic inflammatory processes are triggered by amino acid deprivation, impairing the signaling of anorexigenic hormones, and making these hypothalamic control centers dysfunctional. This condition would contribute to increased food consumption, which could subsequently predispose undernourished individuals to develop metabolic diseases. Currently, several strategies have been proposed to treat metabolic disorders related to undernutrition, such as the use of bile acids. In this context, tauroursodeoxycholic acid (TUDCA) stands out, since it has low toxicity and proven anti-inflammatory activity in several tissues, including the CNS. Thus, using in vitro and in vivo undernutrition models we will i) investigate the impacts of amino acid deprivation on inflammation development; ii) investigate whether the possible hypothalamic inflammation induced by amino acid deprivation alters feeding behavior and the signaling of anorexigenic hormones in the hypothalamus; iii) investigate whether the bile acid TUDCA has a protective effect in the aforementioned conditions and the signaling pathways involved in the actions of TUDCA in the CNS. (AU)