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Glucagon receptor signaling regulates weight loss via central KLB receptor complexes

Shelly R Nason1, Jessica Antipenko1, Natalie Presedo1

  • 1Comprehensive Diabetes Center and Division of Endocrinology, Diabetes and Metabolism, Department of Medicine.

JCI Insight
|January 7, 2021
PubMed

Insights

Glucagon receptor (GCGR) agonists promote weight loss partly via central fibroblast growth factor 21 (FGF21) signaling. This involves the coreceptor β-Klotho (KLB) in the brain, offering new obesity treatment strategies.

Area of Science:

  • Metabolic Regulation
  • Neuroendocrinology
  • Obesity Research

Background:

  • Glucagon receptor (GCGR) signaling influences glucose and lipid metabolism, with potential for obesity therapeutics.
  • Fibroblast growth factor 21 (FGF21) is a key regulator of energy balance, and its production is increased by hepatic GCGR signaling.
  • FGF21 exerts its effects through a coreceptor, β-Klotho (KLB), which is expressed in key metabolic tissues and the brain.

Purpose of the Study:

  • To investigate the role of central nervous system (CNS) fibroblast growth factor 21 (FGF21) signaling in mediating weight loss induced by glucagon receptor (GCGR) agonism.
  • To determine if the coreceptor β-Klotho (KLB) in the brain is essential for GCGR-mediated weight loss and metabolic improvements.

Main Methods:

  • Utilized mouse models with genetic deletion of neuronal β-Klotho (KLB) and pharmacological inhibition of central KLB.
  • Administered a glucagon receptor (GCGR) agonist (IUB288) to assess weight loss and metabolic parameters.
  • Evaluated changes in body weight, plasma cholesterol, and liver triglycerides.

Main Results:

  • Mice lacking neuronal KLB showed partially reduced weight loss in response to GCGR agonism, indicating a role for central FGF21 signaling.
  • Pharmacological inhibition of central KLB also resulted in partial weight loss, supporting the involvement of the brain.
  • Central KLB was not required for GCGR-mediated improvements in plasma cholesterol and liver triglycerides.

Conclusions:

  • Glucagon receptor (GCGR) agonism mediates a portion of its weight loss effects through central β-Klotho (KLB)-dependent pathways, likely involving fibroblast growth factor 21 (FGF21).
  • These findings highlight the brain's role in mediating the metabolic benefits of GCGR agonists and suggest potential therapeutic strategies for obesity and metabolic syndrome.
Keywords:
MetabolismObesity

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