A LEAP2 reduce overeating

The overconsumption of highly palatable food is the primary determining factor in today’s global obesity crisis. An important role for the brain comes from genetic studies suggesting obesity is largely a heritable disease associated with the neural control of feeding. Taken together, these observations highlight that any attempt to treat or prevent obesity requires a fundamental understanding of how the brain drives the overconsumption of highly palatable food. The overconsumption of food is regulated by pathways reinforcing the motivational properties of highly palatable food5, which is closely tied to dopamine release in the brain. Although, elevated food reward plays an important role in the development and maintenance of obesity in humans, we still lack an understanding of the neurobiological systems driving the overconsumption of palatable food. One reason has been the focus of research studies solely on homeostatic feeding circuits in the brain, however an indepth knowlegde of how the brain reinforces motivation for food, and how this is modulated by homeostatic circuits, may open new avenues for the development of novel pharmacotherapies to treat overeating and obesity. In this proposal we test the novel neuroendocrine actions of Liver-Enriched Antimicrobial Peptide 2 (LEAP2) to regulate the consumption of palatable foods through homeostatic and motivation dopamine brain circuits. But what is LEAP2? Although first identified in 2003 and named for is homology to endogenous antoimicrobial peptides, LEAP2 was serendipitously discovered as an endogenous ghrelin receptor (Growth Hormone Secretagouge Receptor; GHSR) antogonist in 2018. Ghrelin is a well-known stomach hormone, often referred to as “the hunger homone”. It acts on hunger-sensing homeostatic Agouti-related peptide (AgRP) neurons in the brain to stimulate food intake and body weight by binding to its endogenous receptor, the GHSR. Ghrelin can act via its receptor to increase food motivation, food reward and food preference by activating either AgRP or mesolimbic dopamine neurons. Moreover, stress-induced palatable food consumption and body weight gain is prevented by blocking GHSR action on dopamine neurons. Importantly, ghrelin activates reward systems in humans in response to images of food, which positively correlated to plasma ghrelin levels. Thus, exploiting the actions of endogenous LEAP2 to regulate GHSR function in the hypothalamus or mesolimbic dopamine neurons may provide a novel approach to suppress the overconsumption of palatable food. LEAP2 supresses ghrelin-induced food intake by blunting AgRP neuronal activity and impairs metabolic adaptations to calorie restriction. In addition, plasma LEAP2 is higher in the fed vs fasted state and in response to glucose administration, consistent with a postprandial physiological role for LEAP2 to suppress GHSR function to maintain energy homeostasis. Whether LEAP2 regulates AgRP neurons or mesolimbic dopamine neurons to influence food motivation and restrict or prevent the overconsumption of palatable food remains unknown. Hypothesis: LEAP2 antagonises the GHSR to suppress food motivation by acting on hunger-sensing AgRP neurons and motivation-driving mesolimbic dopamine neurons.