Glucagon-receptor signaling regulates weight loss via central KLB receptor complexes

Shelly R. Nason; Jessica P. Antipenko; Natalie Presedo; Stephen E. Cunningham; Tanya H. Pierre; Teayoun Kim; Jodi R. Paul; Cassie L. Holleman; Martin E. Young; Karen L. Gamble; Brian Finan; Richard DiMarchi; Chad S. Hunter; Alexei Kharitonenkov; Kirk M. Habegger

doi:10.1172/jci.insight.141323

Glucagon-receptor signaling regulates weight loss via central KLB receptor complexes

Shelly R. Nason,¹ Jessica P. Antipenko,¹ Natalie Presedo,¹ Stephen E. Cunningham,¹ Tanya H. Pierre,¹ Teayoun Kim,¹ Jodi R. Paul,² Cassie L. Holleman,¹ Martin E. Young,³ Karen L. Gamble,² Brian Finan,⁴ Richard DiMarchi,⁵ Chad S. Hunter,¹ Alexei Kharitonenkov,⁶ and Kirk M. Habegger¹

Published January 7, 2021 - More info

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Abstract

Glucagon regulates glucose and lipid metabolism and also 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 co-receptor (B-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 (Klb^∆CNS) exhibit a partial reduction in body weight with chronic GCGR-agonism (via IUB288) compared to controls (p<0.0001), 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 display partial weight loss (p<0.0001). 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 against obesity and metabolic syndrome.

Glucagon-receptor signaling regulates weight loss via central KLB receptor complexes

Shelly R. Nason,¹ Jessica P. Antipenko,¹ Natalie Presedo,¹ Stephen E. Cunningham,¹ Tanya H. Pierre,¹ Teayoun Kim,¹ Jodi R. Paul,² Cassie L. Holleman,¹ Martin E. Young,³ Karen L. Gamble,² Brian Finan,⁴ Richard DiMarchi,⁵ Chad S. Hunter,¹ Alexei Kharitonenkov,⁶ and Kirk M. Habegger¹

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Glucagon-receptor signaling regulates weight loss via central KLB receptor complexes

Shelly R. Nason,1 Jessica P. Antipenko,1 Natalie Presedo,1 Stephen E. Cunningham,1 Tanya H. Pierre,1 Teayoun Kim,1 Jodi R. Paul,2 Cassie L. Holleman,1 Martin E. Young,3 Karen L. Gamble,2 Brian Finan,4 Richard DiMarchi,5 Chad S. Hunter,1 Alexei Kharitonenkov,6 and Kirk M. Habegger1

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Shelly R. Nason,¹ Jessica P. Antipenko,¹ Natalie Presedo,¹ Stephen E. Cunningham,¹ Tanya H. Pierre,¹ Teayoun Kim,¹ Jodi R. Paul,² Cassie L. Holleman,¹ Martin E. Young,³ Karen L. Gamble,² Brian Finan,⁴ Richard DiMarchi,⁵ Chad S. Hunter,¹ Alexei Kharitonenkov,⁶ and Kirk M. Habegger¹