Grant: Project Grant

Obesity is projected to affect more than half of the global population by 2035 and increases the risk of type 2 diabetes, heart disease, and fatty liver disease. Current obesity treatments work by suppressing appetite. However, the body fights back: as weight drops, hunger increases, energy expenditure falls, and muscle mass is often reduced. These biological responses make sustained, healthy weight loss difficult. Our research explores a different strategy. Instead of targeting appetite alone, we focus on fat tissue. Fat is not just a storage depot, it can burn calories and communicate with other organs, including muscle and the brain. We have developed a unique mouse model that allows us to precisely activate two signaling pathways specifically in fat cells. When these pathways are activated together, obese mice burn a substantial amount of energy, they lose all excess fat, and preserve muscle mass. Importantly, they do not develop the strong rebound hunger that usually follows weight loss. This effect does not cause illness or stress-related behavior. This project will determine how this coordinated fat-cell signaling produces what we call "quality weight loss" (preferential fat loss with preserved muscle). We will identify which tissues (fat and/or muscle) are responsible for the increased calorie burning, uncover how the two signaling pathways work together inside fat cells, and determine how fat communicates with the brain to regulate hunger. By understanding how fat tissue can simultaneously increase energy expenditure, protect muscle, and prevent rebound hunger, this research aims to uncover biological principles that could guide the development of more durable and metabolically healthy treatments for obesity, moving beyond appetite suppression alone toward coordinated control of energy balance.