ArticleMolecular metabolism2015
Hypothalamic CaMKKβ mediates glucagon anorectic effect and its diet-induced resistance.
Article in Molecular metabolism, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 55 citations in OpenAlex.
- Neuropsychological and metabolic interconnectivity in obesity, anorexia and bulimia nervosa - an integrative literature review.Metabolic brain disease · 2026Review
- Postprandial Glucagon Action in the Human Brain.Diabetes, obesity & metabolism · 2026Article
- Hypothalamus-liver talks: whispers in the language of metabolism.Reviews in endocrine & metabolic disorders · 2026Review
- Survodutide acts through circumventricular organs in the brain and activates neuronal regions associated with appetite regulation.Molecular metabolism · 2026Article
- AMPK at the interface of nutrient sensing, metabolic flux and energy homeostasis.Nature metabolism · 2026Review
- Efficacy of Dual Glucagon and GLP-1 Agonists as New Treatments for Type II Diabetes.Mini reviews in medicinal chemistry · 2026Review
- Emerging Insights into Brown Adipose Tissue Crosstalk With Pancreatic β-Cells in Metabolic Regulation.Endocrinology · 2025Review
- The Glucagon Receptor Is Expressed in the Frontal Cortex and Impaired Signaling Associates With Cognitive Decline.Journal of the Endocrine Society · 2025Article
- The role of the glucagon-FGF21 axis in improving beta cell function during glucose intolerance and SGLT2 inhibition.Diabetes, obesity & metabolism · 2025Article
- Class B1 GPCRs: insights into multireceptor pharmacology for the treatment of metabolic disease.American journal of physiology. Endocrinology and metabolism · 2024Review
- New Developments in Pharmacological Treatment of Obesity and Type 2 Diabetes-Beyond and within GLP-1 Receptor Agonists.Biomedicines · 2024Review
- Obesity and the kidney: mechanistic links and therapeutic advances.Nature reviews. Endocrinology · 2024Review
- Mechanisms of action of incretin receptor based dual- and tri-agonists in pancreatic islets.American journal of physiology. Endocrinology and metabolism · 2023Review
- Gut hormone-based pharmacology: novel formulations and future possibilities for metabolic disease therapy.Diabetologia · 2023Review
- 100 years of glucagon and 100 more.Diabetologia · 2023Review
- The human α cell in health and disease.The Journal of endocrinology · 2023Review
- RISING STARS: Targeting G protein-coupled receptors to regulate energy homeostasis.Journal of molecular endocrinology · 2023Review
- Circadian rhythms and pancreas physiology: A review.Frontiers in endocrinology · 2022Review
- Multifaceted actions of melanin-concentrating hormone on mammalian energy homeostasis.Nature reviews. Endocrinology · 2021Review
- Glucagon's Metabolic Action in Health and Disease.Comprehensive Physiology · 2021Article
Corrections and comments
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Authors and funding
7 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
objectiveGlucagon receptor antagonists and humanized glucagon antibodies are currently studied as promising therapies for obesity and type II diabetes. Among its variety of actions, glucagon reduces food intake, but the molecular mechanisms mediating this effect as well as glucagon resistance are totally unknown.
methodsGlucagon and adenoviral vectors were administered in specific hypothalamic nuclei of lean and diet-induced obese rats. The expression of neuropeptides controlling food intake was performed by in situ hybridization. The regulation of factors of the glucagon signaling pathway was assessed by western blot.
resultsThe central injection of glucagon decreased feeding through a hypothalamic pathway involving protein kinase A (PKA)/Ca(2+)-calmodulin-dependent protein kinase kinase β (CaMKKβ)/AMP-activated protein kinase (AMPK)-dependent mechanism. More specifically, the central injection of glucagon increases PKA activity and reduces protein levels of CaMKKβ and its downstream target phosphorylated AMPK in the hypothalamic arcuate nucleus (ARC). Consistently, central glucagon significantly decreased AgRP expression. Inhibition of PKA and genetic activation of AMPK in the ARC blocked glucagon-induced anorexia in lean rats. Genetic down-regulation of glucagon receptors in the ARC stimulates fasting-induced hyperphagia. Although glucagon was unable to decrease food intake in DIO rats, glucagon sensitivity was restored after inactivation of CaMKKβ, specifically in the ARC. Thus, glucagon decreases food intake acutely via PKA/CaMKKβ/AMPK dependent pathways in the ARC, and CaMKKβ mediates its obesity-induced hypothalamic resistance.
conclusionsThis work reveals the molecular underpinnings by which glucagon controls feeding that may lead to a better understanding of disease states linked to anorexia and cachexia.
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