Obesity and its comorbid sequelae are major health burdens across European nations. Many citizens would greatly benefit from permanent weight loss, but only a few succeed. They rather suffer from weight regain after dieting, often referred to as Yoyo dieting effect. This effect is largely driven by specific areas in our brain that developed over millions of years when food scarcity was a major threat to life. Today, in our highly obesogenic environment with a sedentary lifestyle and overabundance of high calorie food, these brain areas are programmed to drive obesity and/or weight regain in individuals with a history of obesity, and are thus at the centre of my grant proposal.
In the past, my lab explored the potential for therapeutic anti-obesity strategies built upon leptin action in the brain. Leptin is a satiety hormone produced by our fat tissue. The more fat we accumulate, the more leptin is secreted into circulation. Leptin then enters the brain and activates satiety in specific subpopulations of neurons that decrease our food intake and ultimately fat storage and body weight. In lean individuals, leptin is thereby a major contributor to appetite control and weight maintenance. In overweight and obese individuals, that weight regulatory function of leptin is lost due to a phenomenon called leptin resistance. In the grant proposal, we aim to delineate the molecular basis for that failure of leptin to decrease food intake and body weight. Specifically, we employ mouse models of obesity and weight loss and modern techniques to isolate specific subpopulations of neurons, and characterize how leptin, and small plant-derived molecules such as the leptin sensitizer celastrol, affect signalling pathways and transcriptional programs in these major areas of weight control. In the same brain areas and their respective neuronal subpopulations, we moreover aim to explore whether an epigenetic memory for obesity exists. Specifically, we aim to test whether diet induced obesity in mice can encode an epigenetic program in neurons that ultimately drives weight regain after dieting to reach the weight and fat mass the mouse once had. In sum, delineating the largely unexplored, brain-driven molecular events that impede sustainable weight loss and drive the Yoyo effect is a prerequisite for future therapies, and a major goal of my proposal.
