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

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)194-204
Number of pages11
JournalMolecular Metabolism
Volume20
DOIs
StatePublished - Feb 2019

Bibliographical note

Publisher Copyright:
© 2018 The Authors

Funding

This study was supported by NIH grants K01 DK113115 to K.H.C; R01 DK066604 and DK068400 to M.J.L. This work utilized services of the Michigan Mouse Metabolic Phenotyping Center funded by NIH grant U2CDK110768 .

FundersFunder number
National Institutes of Health (NIH)DK068400, U2CDK110768, R01 DK066604
National Institutes of Health (NIH)
National Institute of Diabetes and Digestive and Kidney DiseasesK01DK113115
National Institute of Diabetes and Digestive and Kidney Diseases

    Keywords

    • Diabetes
    • Hypoglycemia counterregulation
    • Hypothalamus
    • Melanocortin 4 receptor (MC4R)
    • Pro-opiomelanocortin (POMC)

    ASJC Scopus subject areas

    • Molecular Biology
    • Cell Biology

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