Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RAs) in the Brain–Adipocyte Axis

• Published in: Drugs (New York, N.Y.) Vol. 77; no. 5; pp. 493 - 503
• Main Authors: Geloneze, Bruno, de Lima-Júnior, José Carlos, Velloso, Lício A.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01-04-2017; Springer Nature B.V
• Subjects: Adipocytes; Adipocytes - drug effects; Adipocytes - metabolism; Amphetamines; Animals; Arcuate nucleus; Body weight loss; Brain; Brain - drug effects; Brain - metabolism; Circuits; Clinical trials; Cocaine; Cocaine- and amphetamine-regulated transcript protein; Diabetes; Diabetes mellitus; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; Diet; Energy balance; Energy expenditure; Food; Food intake; Gliosis; Glucagon; Glucagon-like peptide 1; Glucagon-Like Peptide-1 Receptor - agonists; Glucagon-Like Peptide-1 Receptor - metabolism; Glucose; Hepatology; Homeostasis; Hormones; Humans; Hypoglycemic Agents - administration & dosage; Hypothalamus; Insulin; Internal Medicine; Leading; Leading Article; Leptin; Medical research; Medicine; Medicine & Public Health; Metabolism; Microglia; Neural networks; Neuropeptide Y; Neurotransmitters; Nuclei; Nutrients; Obesity; Parkinson's disease; Peptides; Pharmacology/Toxicology; Pharmacotherapy; Physiology; Rodents; Transcription; Weight control; Weight loss; Brown Adipose Tissue; Brown Adipose Tissue Thermogenesis; Exenatide; Liraglutide; Lixisenatide
• ISSN: 0012-6667; 1179-1950
• DOI: 10.1007/s40265-017-0706-4

The complexity of neural circuits that control food intake and energy balance in the hypothalamic nuclei explains some of the constraints involved in the prevention and treatment of obesity. Two major neuronal populations present in the arcuate nucleus control caloric intake and energy expenditure: one population co-expresses orexigenic agouti-related peptide (AgRP) and neuropeptide Y and the other expresses the anorexigenic anorectic neuropeptides proopiomelanocortin and cocaine- and amphetamine-regulated transcript (POMC/CART). In addition to integrating signals from neurotransmitters and hormones, the hypothalamic systems that regulate energy homeostasis are affected by nutrients. Fat-rich diets, for instance, elicit hypothalamic inflammation (reactive activation and proliferation of microglia, a condition named gliosis). This process generates resistance to the anorexigenic hormones leptin and insulin, contributing to the genesis of obesity. Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) have increasingly been used to treat type 2 diabetes mellitus. One compound (liraglutide) was recently approved for the treatment of obesity. Although most studies suggest that GLP-1RAs promote weight loss mainly due to their inhibitory effect on food intake, other central effects that have been described for native GLP-1 and some GLP-1RAs in rodents and humans encourage future clinical trials to explore additional mechanisms that potentially underlie the beneficial effects observed with this drug class. In this article we review the most relevant data exploring the mechanisms involved in the effects of GLP-1RAs in the brain–adipocyte axis.