Downstream Pathways of Glucagon Receptor Agonism in Obesity

Authors

Shelly Nason, University of Alabama at Birmingham

Advisory Committee Chair

Kirk M Habegger

Advisory Committee Members

Karen L Gamble

Shannon M Bailey

Lyse A Norian

Glenn C Rowe

Document Type

Dissertation

Date of Award

2020

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Obesity is highly prevalent and strategies to improve weight loss maintenance are critical for healthcare. Behavioral interventions are effective but require major lifestyle changes that are often difficult to maintain long-term. Therefore, modifying energy balance with pharmacotherapy is a strategy to combine with lifestyle modifications for sustained weight loss. Glucagon, a hormone involved in maintaining glucose homeostasis, also regulates energy expenditure, food intake, and lipid metabolism. As such, glucagon-based therapies have gained attention as an attractive clinical target. Glucagon Receptor (GCGR) mono-agonism induces glucose intolerance; therefore, dissecting the mechanisms by which GCGR signaling mediates energy balance are clinically relevant to treating obesi-ty and metabolic disease. This dissertation examines two downstream pathways of GCGR signaling: 1) the hepatic leptin receptor (LEPR) in GCGR-mediated reduction of liver triglycerides and 2) central Fibroblast Growth Factor 21 (FGF21) signaling in mediat-ing GCGR-stimulated weight loss. To address the first pathway, we used a mouse model deficient for hepatic Lepr (Leprliver). Leprliver mice exhibit increased liver triglycerides on a chow diet, suggesting hepatic LEPR are involved in liver lipid homeostasis. Although liver triglycerides are exac-erbated in Leprliver mice on a high-fat diet (HFD), we found that hepatic LEPR are dispensable in GCGR-mediated reductions in liver triglycerides. For the second pathway, we utilized two mouse models to interrogate central FGF21 signaling via the obligate co-receptor B-klotho (KLB): mice deficient for neuronal Klb (KlbCNS) and central administration of a KLB antagonist. We found that KlbCNS mice are partially resistant to GCGR-stimulated weight loss, suggesting FGF21 signals centrally to mediate weight loss. Congruent with these findings, we observed a similar partial reduction in weight loss with KLB antagonism. Chronic GCGR agonism administered sub-cutaneously increases energy expenditure in control mice, while this effect is abrogated with central KLB antagonism. These data suggest central FGF21 signaling mediates GCGR-stimulated weight loss via increasing energy expenditure. Overall, our work has uncovered that hepatic LEPR is dispensable for GCGR-mediated reductions in liver triglyc-erides and central FGF21 mediates GCGR-stimulated weight loss and energy expenditure.

Recommended Citation

Nason, Shelly, "Downstream Pathways of Glucagon Receptor Agonism in Obesity" (2020). All ETDs from UAB. 871.
https://digitalcommons.library.uab.edu/etd-collection/871