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

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          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.

          Graphical abstract

          Highlights

          • •

            Hypothalamic POMC as well as MC4R is necessary to counteract hypoglycemia.

          • •

            Type 1 diabetic mice exhibit a reduced Pomc and Mc4r expression in the hypothalamus.

          • •

            Insulin treatment does not restore Pomc and Mc4r expression in diabetic mice.

          • •

            MC4R agonist improves hypoglycemia counterregulation in diabetic mice.

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          Most cited references45

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          Obesity-induced hypertension: role of sympathetic nervous system, leptin, and melanocortins.

          John E Hall, Alexandre da Silva, Jussara M do Carmo … (2010)
          Excess weight gain contributes to increased blood pressure in most patients with essential hypertension. Although the mechanisms of obesity hypertension are not fully understood, increased renal sodium reabsorption and impaired pressure natriuresis play key roles. Several mechanisms contribute to altered kidney function and hypertension in obesity, including activation of the sympathetic nervous system, which appears to be mediated in part by increased levels of the adipocyte-derived hormone leptin, stimulation of pro-opiomelanocortin neurons, and subsequent activation of central nervous system melanocortin 4 receptors.
          Article 0 comments Cited 147 times – based on 0 reviews     Review now
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            Hypoglycaemia in diabetes mellitus: epidemiology and clinical implications.

            Brian M. Frier (2014)
            Hypoglycaemia is a frequent adverse effect of treatment of diabetes mellitus with insulin and sulphonylureas. Fear of hypoglycaemia alters self-management of diabetes mellitus and prevents optimal glycaemic control. Mild (self-treated) and severe (requiring help) hypoglycaemia episodes are more common in type 1 diabetes mellitus but people with insulin-treated type 2 diabetes mellitus are also exposed to frequent hypoglycaemic events, many of which occur during sleep. Hypoglycaemia can disrupt many everyday activities such as driving, work performance and leisure pursuits. In addition to accidents and physical injury, the morbidity of hypoglycaemia involves the cardiovascular and central nervous systems. Whereas coma and seizures are well-recognized neurological sequelae of hypoglycaemia, much interest is currently focused on the potential for hypoglycaemia to cause dangerous and life-threatening cardiac complications, such as arrhythmias and myocardial ischaemia, and whether recurrent severe hypoglycaemia can cause permanent cognitive impairment or promote cognitive decline and accelerate the onset of dementia in middle-aged and elderly people with diabetes mellitus. Prevention of hypoglycaemia is an important part of diabetes mellitus management and strategies include patient education, glucose monitoring, appropriate adjustment of diet and medications in relation to everyday circumstances including physical exercise, and the application of new technologies such as real-time continuous glucose monitoring, modified insulin pumps and the artificial pancreas.
            Article 0 comments Cited 146 times – based on 0 reviews     Review now
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              Modulation of blood pressure by central melanocortinergic pathways.

              I. Sadaf Farooqi, Joan W. Miller, J H Satterwhite … (2009)
              Weight gain and weight loss are associated with changes in blood pressure through unknown mechanisms. Central melanocortinergic signaling is implicated in the control of energy balance and blood pressure in rodents, but there is no information regarding such an association with blood pressure in humans. We assessed blood pressure, heart rate, and urinary catecholamines in overweight or obese subjects with a loss-of-function mutation in MC4R, the gene encoding the melanocortin 4 receptor, and in equally overweight control subjects. We also examined the effects of an MC4R agonist administered for 7 days in 28 overweight or obese volunteers. The prevalence of hypertension was markedly lower in the MC4R-deficient subjects than in the control subjects (24% vs. 53%, P=0.009). After the exclusion of subjects taking antihypertensive medications, blood-pressure levels were significantly lower in MC4R-deficient subjects than in control subjects, with mean (+/-SE) systolic blood pressures of 123+/-14 mm Hg and 131+/-12 mm Hg, respectively (P=0.02), and mean diastolic blood pressures of 73+/-10 mm Hg and 79+/-7 mm Hg, respectively (P=0.03). As compared with control subjects, MC4R-deficient subjects had a lower increase in heart rate on waking (P=0.007), a lower heart rate during euglycemic hyperinsulinemia (P<0.001), and lower 24-hour urinary norepinephrine excretion (P=0.04). The maximum tolerated daily dose of 1.0 mg of the MC4R agonist led to significant increases of 9.3+/-1.9 mm Hg in systolic blood pressure and of 6.6+/-1.1 mm Hg in diastolic blood pressure (P<0.001 for both comparisons) at 24 hours, as compared with placebo. Differences in blood pressure were not explained by changes in insulin levels; there were no significant adverse events. Results of our genetic and pharmacologic studies implicate melanocortinergic signaling in the control of human blood pressure through an insulin-independent mechanism. 2009 Massachusetts Medical Society
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                Author and article information

                Contributors
                Malcolm J. Low
                Kavaljit H. Chhabra
                Journal
                Journal ID (nlm-ta): Mol Metab
                Journal ID (iso-abbrev): Mol Metab
                Title: Molecular Metabolism
                Publisher: Elsevier
                ISSN (Electronic): 2212-8778
                Publication date PMC-release: 20 November 2018
                Publication date Collection: February 2019
                Publication date (Electronic): 20 November 2018
                Volume: 20
                Pages: 194-204
                Affiliations
                [1 ]Case Western Reserve University, Cleveland, OH, USA
                [2 ]Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA
                [3 ]Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA
                [4 ]Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI, USA
                [5 ]Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan Medical School, Ann Arbor, MI, USA
                [6 ]Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
                Author notes
                [∗ ]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. Kavaljit_Chhabra@ 123456URMC.Rochester.Edu
                [∗∗ ]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. mjlow@ 123456umich.edu
                [7]

                Co-senior authors.

                Article
                Publisher ID: S2212-8778(18)30957-8
                DOI: 10.1016/j.molmet.2018.11.004
                PMC ID: 6358536
                PubMed ID: 30503832
                SO-VID: d4422411-cd23-4d2f-b796-44487ddd1cc8
                Copyright © © 2018 The Authors
                License:

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 9 October 2018
                Date revision received : 9 November 2018
                Date accepted : 14 November 2018
                Categories
                Subject: Original Article

                Keywords: hypothalamus,pro-opiomelanocortin (pomc),melanocortin 4 receptor (mc4r),hypoglycemia counterregulation,diabetes
                Data availability:
                Keywords: hypothalamus, pro-opiomelanocortin (pomc), melanocortin 4 receptor (mc4r), hypoglycemia counterregulation, diabetes

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