title: The Role of Circulating Amino Acids in the Hypothalamic Regulation of Liver Glucose Metabolism.
abstract: A pandemic of diabetes and obesity has been developing worldwide in close association with excessive nutrient intake and a sedentary lifestyle. Variations in the protein content of the diet have a direct impact on glucose homeostasis because amino acids (AAs) are powerful modulators of insulin action. In this work we review our recent findings on how elevations in the concentration of the circulating AAs leucine and proline activate a metabolic mechanism located in the mediobasal hypothalamus of the brain that sends a signal to the liver via the vagus nerve, which curtails glucose output. This neurogenic signal is strictly dependent on the metabolism of leucine and proline to acetyl-coenzyme A (CoA) and the subsequent production of malonyl-CoA; the signal also requires functional neuronal ATP-sensitive potassium channels. The liver then responds by lowering the rate of gluconeogenesis and glycogenolysis, ultimately leading to a net decrease in glucose production and in concentrations of circulating glucose. Furthermore, we review here how our work with proline suggests a new role of astrocytes in the central regulation of glycemia. Last, we outline how factors such as the consumption of fat-rich diets can interfere with glucoregulatory mechanisms and, in the long term, may contribute to the development of hyperglycemia, a hallmark of type 2 diabetes.
authors.affiliation: Department of Basic Research, National Institute of Geriatrics, Mexico City, Mexico; and.
authors.forename: Isabel
authors.initials: I
authors.lastname: Arrieta-Cruz
authors.affiliation: Department of Medicine and Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY roger.gutierrez@einstein.yu.edu.
authors.forename: Roger
authors.initials: R
authors.lastname: Gutiérrez-Juárez
mesh_terms: D000596:Amino Acids / Q000097:blood*; D000818:Animals; D001253:Astrocytes / Q000502:physiology; D001786:Blood Glucose / Q000032:analysis; D004041:Dietary Fats / Q000008:administration & dosage; D005943:Gluconeogenesis / Q000502:physiology; D005947:Glucose / Q000378:metabolism*; D050261:Glycogenolysis / Q000502:physiology; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D007031:Hypothalamus / Q000502:physiology*; D007930:Leucine; D008099:Liver / Q000294:innervation / Q000378:metabolism*; D009474:Neurons / Q000502:physiology; D011392:Proline / Q000097:blood; D014630:Vagus Nerve / Q000502:physiology
chemical_list: D000596:Amino Acids; D001786:Blood Glucose; D004041:Dietary Fats; D011392:Proline; D007930:Leucine; D005947:Glucose
keywords: amino acids; branched-chain amino acids; glucose homeostasis; hyperglycemia; hypothalamus; insulin action; leucine; liver; nutrient sensing; proline