Author: Bau, Sarah ; Pyke, Charles ; Lundh, Sofia ; Tomlinson, Abigail J. ; Tornøe, Christian Wenzel ; Tiantang, Dong ; Kernodle, Stace ; Stidsen, Carsten Enggaard ; Magrisso, Irwin Jack ; Myers, Martin G. ; Conde-Frieboes, Kilian W. ; Hogendorf, Wouter Frederik Johan ; Seeley, Randy J. ; Polex-Wolf, Joseph ; Glendorf, Tine ; Deibler, Kristine ; Knudsen, Lotte Bjerre

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.

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Indication	Highest Phase	Country/Location	Organization	Date
Obesity	Preclinical	Denmark	Novo Nordisk A/S	04 Dec 2024

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GLP-1R/LepR dual agonist(Novo Nordisk)

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