Glucagon regulates
glucose and lipid metabolism and promotes
weight loss. Thus,
therapeutics stimulating
glucagon receptor (GCGR) signaling are promising for
obesity treatment; however, the underlying mechanism(s) have yet to be fully elucidated. We previously identified that hepatic GCGR signaling increases circulating
fibroblast growth factor 21 (
FGF21), a potent regulator of energy balance. We reported that mice deficient for liver
Fgf21 are partially resistant to GCGR-mediated
weight loss, implicating
FGF21 as a regulator of
glucagon's
weight loss effects.
FGF21 signaling requires an obligate coreceptor (β-Klotho, KLB), with expression limited to adipose tissue, liver, pancreas, and brain. We hypothesized that the GCGR-FGF21 system mediates
weight loss through a central mechanism. Mice deficient for neuronal Klb exhibited a partial reduction in
body weight with chronic GCGR agonism (via
IUB288) compared with controls, supporting a role for central
FGF21 signaling in GCGR-mediated
weight loss. Substantiating these results, mice with central KLB inhibition via a pharmacological KLB antagonist, 1153, also displayed partial
weight loss. Central KLB, however, is dispensable for GCGR-mediated improvements in plasma
cholesterol and liver
triglycerides. Together, these data suggest GCGR agonism mediates part of its
weight loss properties through central KLB and has implications for future treatments of
obesity and
metabolic syndrome.