Control of breathing and upper airway patency during sleep and wakefulness in obese mice

• Grant number: 24/13971-9
• Support Opportunities: Research Grants - Young Investigators Grants
• Start date: July 01, 2025
• End date: June 30, 2030
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Mateus Ramos Amorim
• Grantee: Mateus Ramos Amorim
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated researchers: Benedito Honorio Machado ; Luiz Guilherme de Siqueira Branco ; Vsevolod Y Polotsky

Abstract

Obesity is a chronic and highly prevalent disease worldwide. Most obese individuals develop sleep-disordered breathing (SDB) manifested by recurrent upper airway obstruction during sleep (OSA) and obesity hypoventilation, defined as daytime hypercapnia in obese individuals in the absence of other underlying causes. There is no effective pharmacotherapy for SDB. Leptin, an adipose-produced hormone, stimulates breathing and improves SDB. However, both obese individuals and rodents are resistant to the metabolic and respiratory effects of the hormone. The melanocortin axis is a downstream target of leptin, but the effects of this axis on the control of breathing and upper airway patency during sleep and wakefulness are poorly studied. We hypothesized that the selective activation of melanocortin neceptor 4 positive neurons found in several regions of the central nervous system augments the control of breathing, improves the upper airway patency during sleep, and treats SDB in diet-induced obese mice without affecting metabolism. To test this hypothesis, we will use C57BL/6J mice with diet-induced obesity, which hypoventilate during sleep and exhibit SDB. We will employ integrative approaches, including genetically modified mice, Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), fiber photometry in freely moving animals, polysomnographic recordings, and immunofluorescence. Our aim is to extend our understanding regarding the neural mechanisms that stimulate control of breathing and improve upper airway patency during wakefulness and sleep in experimental models of obesity. The importance of this study lies in the potential discovery of new therapeutic approaches that could revolutionize the treatment of SDB in obesity, and help millions of people suffering from this complex condition. (AU)