<i>Glp1r-Lepr</i> coexpressing neurons modulate the suppression of food intake and body weight by a GLP-1/leptin dual agonist

Glucagon-like peptide-1 (GLP-1) and leptin signal recent feeding and long-term energy stores, respectively, and play complementary roles in the modulation of energy balance. Previous work using single-cell techniques in mice revealed the existence of a population of leptin receptor (<i>Lepr</i>)-containing dorsomedial hypothalamus (DMH) neurons marked by the expression of GLP-1 receptor (<i>Glp1r</i>; LepR^Glp1r neurons) that play important roles in the control of feeding and body weight by leptin. Here, we demonstrate the existence of a population of LepR^Glp1r neurons in the DMHs of nonhuman primates (NHPs), suggesting the potential translational relevance of these neurons. Consequently, we developed a GLP-1R/LepR dual agonist and demonstrated the physiological activity of both components in vivo using leptin-deficient and <i>Lepr-</i>deficient murine models. We further found roles for LepR^Glp1r neurons in mediating the dual agonist's efficacy on food intake and body weight loss. Ablating <i>Lepr</i> in <i>Glp1r</i>-expressing neurons (Lepr^Glp1rKO mice) abrogated the suppression of food intake by the dual agonist. Furthermore, reactivation of <i>Glp1r</i> expression in <i>Lepr</i> neurons on an otherwise <i>Glp1r</i>-null background (Glp1r^LeprRe mice) was sufficient to permit the suppression of food intake and body weight by the dual agonist. Hence, LepR^Glp1r neurons represent targets for a GLP-1R/LepR dual agonist that potently reduces food intake and body weight.