Cited by 34Fibroblast Growth Factor ResearchRegulation of Appetite and ObesityAdipokines, Inflammation, and Metabolic Diseases

Glucagon receptor signaling regulates weight loss via central KLB receptor complexes

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Nason, Shelly R., Antipenko, Jessica, Presedo, Natalie, Cunningham, Stephen E., Pierre, Tanya H., Kim, Teayoun, Paul, Jodi R., Holleman, Cassie +7 more·2021·JCI Insight

Abstract

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.

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  • Previous studies in preclinical models demonstrate the potential for GcgR agonism to induce weight loss either alone or in combination with GLP-1R and/or GIPR agonism.

    “Previous studies in preclinical models demonstrate the potential for GcgR agonism to induce weight loss either alone [54,55] or in combination with GLP-1R and/or GIPR agonism [43].”

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Authors
Nason, S. R., Antipenko, J., Presedo, N., Cunningham, S. E., Pierre, T. H., Kim, T., Paul, J. R., Holleman, C., Young, M. E., Gamble, K. L., Finan, B., DiMarchi, R., Hunter, C. S., Kharitonenkov, A., & Habegger, K. M.
Affiliations
  • Comprehensive Diabetes Center and Division of Endocrinology, Diabetes and Metabolism, Department of Medicine,
  • Department of Psychiatry and Behavioral Neurobiology, and
  • University of Alabama at Birmingham (US)
  • Novo Nordisk Research Center Indianapolis, Inc., Indianapolis, Indiana, USA.
  • Indiana University Bloomington (US)
  • AK Biotechnologies LLC, Zionsville, Indiana, USA.
Corresponding author
Habegger, Kirk M.
Venue
JCI Insight
Published
2021-02-22
Volume
6
Issue
4
ISSN
2379-3708 (ISSN-L)
OpenAlex
W3118898040
Cited by
34
References
81
Citations by year
2026: 4 · 2025: 4 · 2024: 10 · 2023: 5 · 2022: 9 · 2021: 2
FWCI
2.04
Type
journal article
Language
en
Open access
Locations
  • JCI Insight (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Institutes of Health (1R01DK112934,P30DK079626,T32HL105349)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
Keywords
glucagon receptor agonist, weight loss, KLB, β-Klotho, FGF21, central nervous system, obesity treatment, metabolic syndrome, serum cholesterol, hepatic triglycerides
MeSH terms
Klotho Proteins, Animals, Body Weight, Eating, Fibroblast Growth Factors, Glucagon, Glucose, Homeostasis, Liver, Male, Mice, Inbred C57BL, Obesity, Peptides, Signal Transduction, Weight Loss, Gene Expression, Receptors, Glucagon, Mice, Knockout, Lipid Metabolism, Mice

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