<i>Glp1r-Lepr</i> coexpressing neurons modulate the suppression of food intake and body weight by a GLP-1/leptin dual agonist
Joseph Polex-Wolf, Kristine Deibler, Wouter F. J. Hogendorf, S. Sherona Bau, Tine Glendorf, Carsten E. Stidsen, Christian W. Tornøe, Dong Tiantang, Sofia Lundh, Charles Pyke, Abigail J. Tomlinson, Stace Kernodle, I. Jack Magrisso, Kilian W. Conde‐Frieboes, Martin G. Myers, Lotte Bjerre Knudsen, Randy J. Seeley
Abstract
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 ( Lepr )–containing dorsomedial hypothalamus (DMH) neurons marked by the expression of GLP-1 receptor ( Glp1r ; 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 Lepr- 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 Lepr in Glp1r -expressing neurons (Lepr Glp1r KO mice) abrogated the suppression of food intake by the dual agonist. Furthermore, reactivation of Glp1r expression in Lepr neurons on an otherwise Glp1r -null background (Glp1r Lepr Re 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.