Neural circuits in semaglutide-induced weight loss

Semaglutide is a long-acting GLP-1 analogue that has revolutionized the treatment of obesity, but its brain-mediated mechanisms are unclear. The overarching goal of my research is to determine the neural mechanisms behind semaglutide-induced weight loss.

Based on my exciting preliminary data, I hypothesize that a specific population in the caudal brainstem orchestrates the beneficial responses to semaglutide via direct projections to a key region of the hypothalamus, involved in energy balance and inhibition of AgRP neurons (“hunger neurons”).

By using transgenic mouse lines and in vivo optogenetics, I aim to determine the role of this brainstem to hypothalamus circuit in mediating semaglutide-induced reduction of food intake, metabolic alterations and weight loss (year 1-2).

Moreover, I aim to use viral vectors to ablate semaglutide-activated brainstem and hypothalamic populations that are part of this specific circuit and study their causal role to the effects of semaglutide, and to the semaglutide-mediated inhibition of AgRP neurons that we have identified (year 3-4).

Last, I will determine the role of these neuronal populations on weight loss in a clinically relevant model of diet-induced obese mice undergoing subchronic treatment with semaglutide (year 5).

The proposed research will identify a neural circuit behind the beneficial effects of semaglutide on body weight loss, which can aid in finding more directed future therapies with fewer side-effects.