ArticleJCI insight2021
Glucagon receptor signaling regulates weight loss via central KLB receptor complexes.
Article in JCI insight, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 32 citations in OpenAlex.
- Review
- GCGR agonism requires GABAergic signaling in the medial basal hypothalamus to promote weight loss in obese mice.Molecular metabolism · 2026Article
- Development of a severe rat refeeding syndrome model and mathematical modeling of the associated hypophosphatemia.NPJ systems biology and applications · 2026Article
- Bile Acid Binding Resins Improve Glucagon Receptor Agonist-Mediated Weight Loss in Diet-Induced Obese Mice.Obesity (Silver Spring, Md.) · 2026Article
- IUPHAR review: From foe to friend: Repurposing glucagon to treat obesity and type 2 diabetes.Pharmacological research · 2026Review
- Oxyntomodulin physiology and its therapeutic development in obesity and associated complications.The Journal of physiology · 2025Review
- Avian GCGR-mediated continuous fat utilization offers perspectives for obesity treatment.Nature communications · 2025Article
- GLP-1R/GCGR dual agonism dissipates hepatic steatosis to restore insulin sensitivity and rescue pancreatic β-cell function in obese male mice.Nature communications · 2025Article
- Article
- The role of the glucagon-FGF21 axis in improving beta cell function during glucose intolerance and SGLT2 inhibition.Diabetes, obesity & metabolism · 2025Article
- Variable glucagon metabolic actions in diverse mouse models of obesity and type 2 diabetes.Molecular metabolism · 2024Article
- The dual GLP-1/glucagon receptor agonist G49 mimics bariatric surgery effects by inducing metabolic rewiring and inter-organ crosstalk.Nature communications · 2024Article
- CD9 Counteracts Liver Steatosis and Mediates GCGR Agonist Hepatic Effects.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Impaired Fat Absorption from Intestinal Tract in High-Fat Diet Fed Male Mice Deficient in Proglucagon-Derived Peptides.Nutrients · 2024Article
- Fibroblast growth factor 21: An emerging pleiotropic regulator of lipid metabolism and the metabolic network.Genes & diseases · 2024Review
- From classical dualistic antagonism to hormone synergy: potential of overlapping action of glucagon, insulin and GLP-1 for the treatment of diabesity.Endocrine connections · 2024Review
- Review
- Review
- RISING STARS: Targeting G protein-coupled receptors to regulate energy homeostasis.Journal of molecular endocrinology · 2023Review
- Opposing effects of chronic glucagon receptor agonism and antagonism on amino acids, hepatic gene expression, and alpha cells.iScience · 2022Article
Corrections and comments
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Authors and funding
15 authors at 5 institutions in 2 countries.
Funding
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.