Contribution of FGF21 and macronutrient composition towards Glp1r agonist-induced weight loss

About This Grant

Project Summary/ Abstract Glucagon-like peptide-1 (Glp1) receptor (Glp1r) agonists are a promising new class of weight loss drugs for treating obesity, yet weight loss outcomes to Glp1r agonists range from 0% to over 20% of starting body weight which raises the critical question of why some individuals are more responsive than others. Previous findings in my lab suggest that dietary carbohydrate composition influences the weight loss effects induced by Glp1r agonists. Specifically, we observe greater Glp1r agonist-induced weight loss in mice fed a high carbohydrate diet compared to mice fed a calorically matched low carbohydrate diet. Investigating the factors contributing to this effect, multiple groups have observed that Glp1r agonists increase plasma levels of the liver-derived hormone fibroblast growth factor 21 (FGF21). FGF21 levels are increased by the intake of high carbohydrate diets and feed back to suppress subsequent carbohydrate intake. We show that Glp1r agonists increase FGF21 levels by engaging neuronal Glp1r. Furthermore, we show that deleting either liver FGF21 or the obligate FGF21 co-receptor b-klotho (Klb) in neurons impairs Glp1r agonist-induced weight loss only in mice fed a high carbohydrate diet. This suggests that dietary carbohydrate composition plays a crucial role in mediating the effectiveness of Glp1r agonists in promoting weight loss, and FGF21 is a key molecule behind this interaction via crosstalk between the brain and the liver. These data prompt my investigation to determine whether proopiomelanocortin (POMC) neurons mediate the ability of liraglutide to increase FGF21 levels and whether Klb in the ventral medial hypothalamus (VMH) is required for liraglutide-induced FGF21 to reduce body weight in mice fed high carbohydrate diets (Aim 1), and b) how the Glp1r agonist-FGF21 relationship interacts with dietary carbohydrate composition to influence the weight loss effects of Glp1r agonists (Aim 2). In Aim 1, I will test the hypothesis that Glp1r agonists engage Glp1r in POMC neurons to induce liver FGF21, and in turn, I will test the hypothesis that the ventral medial hypothalamus Klb is the target of Glp1r agonist-induced FGF21 to regulate body weight. In Aim 2, I will test the hypothesis that liver FGF21 contributes to enhanced Glp1r agonist-induced weight loss in a manner that not only involves dietary carbohydrate content (low vs. high carbohydrate) but also carbohydrate source (starch vs. sucrose). I will also test whether these effects on weight loss are due to changes in absolute carbohydrate/sucrose intake and/or preference. Findings from these studies will not only provide novel insight into the mechanism of action of Glp1r agonists but will also identify key factors that contribute to the variability in the response to these therapeutics. Upon completion of the experiments proposed in this application will provide me with extensive training in experimental design, data analysis, and interpretation as well as in mastering concepts and methods relevant to neuroendocrinological regulation of metabolic phenotypes and clinical applications. My Sponsor and co- Sponsor are committed to my training and to helping me develop into an academic researcher.