Background: Glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) agonists promote weight loss by activating central GLP-1R to decrease food intake and body weight. Our lab demonstrated that GLP-1R agonists signal to the brain to increase liver and plasma levels of FGF21, a nutrient sensor produced in response to prolonged fasting and large carbohydrate consumption, in a food intake-independent manner. Given the overlapping roles of GLP-1R agonists and FGF21 in modulating feeding behavior, we hypothesize that FGF21 mediates liraglutide-induced reduction in carbohydrate-rich diet consumption via its action in the brain.

Methods: To examine the contribution of FGF21 to liraglutide-induced feeding and weight reduction in the context of carbohydrate-rich diets, age-matched control (wildtype, WT) and liver Fgf21 knockout mice were placed on high-sucrose (17%) diet with low (10%) or high (45%) fat content for 4 weeks, followed by treatment with either liraglutide (200 µg/kg body weight) or vehicle (1x PBS) for 2 weeks (Experiment 1). To test whether central FGF21 signaling is required for liraglutide induced suppression of carbohydrate intake, control mice and mice lacking β-klotho, an obligate co-receptor of FGF21, in CAMK2a+ neurons (brain β-klotho knockout mice) were treated with liraglutide or vehicle for 2 weeks (Experiment 2). Food intake and body weight were monitored daily while body composition and measurements were collected at the start and end of the treatment period. Results:

In Experiment 1, liraglutide-treated liver Fgf21 knockout mice lost less weight than their control counterparts when mice were fed a high-fat, high-sucrose diet, suggesting that liver FGF21 is partially required to reduce food intake and body weight in the context of fat and carbohydrate-rich diets. In Experiment 2, brain β-klotho knockout mice lost less weight than control mice, implicating a role for central FGF21 signaling in mediating the feeding and weight-lowering effects of liraglutide.

Conclusions:

Results from the present studies demonstrate that liraglutide-induced FGF21 signals through KLB expressed in CAMK2A+neurons to facilitate liraglutide-induced weight loss in mice fed a fat and carbohydrate-rich diet. Better understanding of the GLP1-R-FGF21 axis may lead to more effective and efficient therapeutic options for metabolic modulation in disease settings such as diabetes and obesity.

References

1. Doyle ME, Egan JM. Mechanisms of action of glucagon-like peptide 1 in the pancreas. Pharmacol Ther. 2007;113(3):546-593. doi:10.1016/j.pharmthera.2006.11.007
2. Sisley S, Gutierrez-Aguilar R, Scott M, D’Alessio DA, Sandoval DA, Seeley RJ. Neuronal GLP1R mediates liraglutide’s anorectic but not glucose-lowering effect. J Clin Invest. 2014;124(6):2456-2463. doi:10.1172/JCI72434
3. Søberg S, Sandholt CH, Jespersen NZ, et al. FGF21 Is a Sugar-Induced Hormone Associated with Sweet Intake and Preference in Humans. Cell Metab. 2017;25(5):1045-1053.e6. doi:10.1016/j.cmet.2017.04.009
4. Jensen-Cody SO, Flippo KH, Claflin KE, et al. FGF21 Signals to Glutamatergic Neurons in the Ventromedial Hypothalamus to Suppress Carbohydrate Intake. Cell Metab. 2020;32(2):273-286.e6. doi:10.1016/j.cmet.2020.06.008 5. Knudsen LB, Lau J. The Discovery and Development of Liraglutide and Semaglutide. Front Endocrinol (Lausanne). 2019;10:155. Published 2019 Apr 12. doi:10.3389/fendo.2019.00155
5. Liu D, Pang J, Shao W, et al. Hepatic Fibroblast Growth Factor 21 Is Involved in Mediating Functions of Liraglutide in Mice With Dietary Challenge. Hepatology. 2021;74(4):2154-2169. doi:10.1002/hep.31856

7. Hill CM, Qualls-Creekmore E, Berthoud HR, et al. FGF21 and the Physiological Regulation of Macronutrient Preference. Endocrinology. 2020;161(3):bqaa019. doi:10.1210/endocr/bqaa019