Hypothalamic POMC or MC4R deficiency impairs counterregulatory responses to hypoglycemia in mice

Benjamin P. Tooke; Hui Yu; Jessica M. Adams; Graham L. Jones; Talisha Sutton-Kennedy; Lakshmi Mundada; Nathan R. Qi; Malcolm J. Low; Kavaljit H. Chhabra

Molecular Metabolism (Feb 2019)

Hypothalamic POMC or MC4R deficiency impairs counterregulatory responses to hypoglycemia in mice

Benjamin P. Tooke,
Hui Yu,
Jessica M. Adams,
Graham L. Jones,
Talisha Sutton-Kennedy,
Lakshmi Mundada,
Nathan R. Qi,
Malcolm J. Low,
Kavaljit H. Chhabra

Affiliations

Benjamin P. Tooke: Case Western Reserve University, Cleveland, OH, USA; Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA
Hui Yu: Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA
Jessica M. Adams: Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA
Graham L. Jones: Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA; Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI, USA
Talisha Sutton-Kennedy: Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA
Lakshmi Mundada: Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA
Nathan R. Qi: Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan Medical School, Ann Arbor, MI, USA
Malcolm J. Low: Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan Medical School, Ann Arbor, MI, USA; Corresponding author. David F. Bohr Collegiate Professor of Physiology, Professor of Physiology and Internal Medicine, Department of Molecular & Integrative Physiology, University of Michigan Medical School, Brehm Tower, Rm. 6116, 1000 Wall St., Ann Arbor, MI 48105, USA.
Kavaljit H. Chhabra: Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA; Corresponding author. Assistant Professor, Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Rochester Medical Center, 601 Elmwood Ave/Box 693, Rochester, NY 14642, USA.

Journal volume & issue: Vol. 20
pp. 194 – 204

Abstract

Read online

Objective: Life-threatening hypoglycemia is a major limiting factor in the management of diabetes. While it is known that counterregulatory responses to hypoglycemia are impaired in diabetes, molecular mechanisms underlying the reduced responses remain unclear. Given the established roles of the hypothalamic proopiomelanocortin (POMC)/melanocortin 4 receptor (MC4R) circuit in regulating sympathetic nervous system (SNS) activity and the SNS in stimulating counterregulatory responses to hypoglycemia, we hypothesized that hypothalamic POMC as well as MC4R, a receptor for POMC derived melanocyte stimulating hormones, is required for normal hypoglycemia counterregulation. Methods: To test the hypothesis, we induced hypoglycemia or glucopenia in separate cohorts of mice deficient in either POMC or MC4R in the arcuate nucleus (ARC) or the paraventricular nucleus of the hypothalamus (PVH), respectively, and measured their circulating counterregulatory hormones. In addition, we performed a hyperinsulinemic-hypoglycemic clamp study to further validate the function of MC4R in hypoglycemia counterregulation. We also measured Pomc and Mc4r mRNA levels in the ARC and PVH, respectively, in the streptozotocin-induced type 1 diabetes mouse model and non-obese diabetic (NOD) mice to delineate molecular mechanisms by which diabetes deteriorates the defense systems against hypoglycemia. Finally, we treated diabetic mice with the MC4R agonist MTII, administered stereotaxically into the PVH, to determine its potential for restoring the counterregulatory response to hypoglycemia in diabetes. Results: Stimulation of epinephrine and glucagon release in response to hypoglycemia or glucopenia was diminished in both POMC- and MC4R-deficient mice, relative to their littermate controls. Similarly, the counterregulatory response was impaired in association with decreased hypothalamic Pomc and Mc4r expression in the diabetic mice, a phenotype that was not reversed by insulin treatment which normalized glycemia. In contrast, infusion of an MC4R agonist in the PVH restored the counterregulatory response in diabetic mice. Conclusion: In conclusion, hypothalamic Pomc as well as Mc4r, both of which are reduced in type 1 diabetic mice, are required for normal counterregulatory responses to hypoglycemia. Therefore, enhancing MC4R function may improve hypoglycemia counterregulation in diabetes. Keywords: Hypothalamus, Pro-opiomelanocortin (POMC), Melanocortin 4 receptor (MC4R), Hypoglycemia counterregulation, Diabetes

Published in Molecular Metabolism

ISSN: 2212-8778 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Internal medicine
Website: https://www.journals.elsevier.com/molecular-metabolism/

About the journal