Hypothalamic MC4R regulates glucose homeostasis through adrenaline-mediated control of glucose reabsorption via renal GLUT2 in mice

• Published in: Diabetologia Vol. 64; no. 1; pp. 181 - 194
• Main Authors: de Souza Cordeiro, Leticia Maria, Elsheikh, Arwa, Devisetty, Nagavardhini, Morgan, Donald A., Ebert, Steven N., Rahmouni, Kamal, Chhabra, Kavaljit H.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-01-2021; Springer Nature B.V
• Subjects: Animals; Beta cells; Blood Glucose - metabolism; Body weight; Crosses, Genetic; Diabetes; Epinephrine; Epinephrine - deficiency; Epinephrine - physiology; Glucose; Glucose tolerance; Glucose Tolerance Test; Glucose transporter; Glucose Transporter Type 2 - physiology; Glycosuria - physiopathology; Hexoses - metabolism; Homeostasis; Homeostasis - physiology; Human Physiology; Hyperglycemia; Hypothalamus; Hypothalamus - chemistry; Insulin; Insulin - blood; Insulin resistance; Insulin Resistance - physiology; Internal Medicine; Intravenous administration; Kidney - innervation; Kidney - metabolism; Kidneys; Medicine; Medicine & Public Health; Melanocortin; Melanocortin MC4 receptors; Metabolic Diseases; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular modelling; Obesity; Obesity - physiopathology; Paraventricular nucleus; Phenotypes; Reabsorption; Receptor, Melanocortin, Type 4 - deficiency; Receptor, Melanocortin, Type 4 - physiology; Renal plexus; Rodents; Schiff Bases - metabolism; Sympathetic nerves; Sympathetic nervous system; Sympathetic Nervous System - physiopathology; Western blotting; Obesity; Mouse model; Melanocortin 4 receptor; Diabetes; Hypothalamus; Endocrinology
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-020-05289-z

Aims/hypothesis
Melanocortin 4 receptor (MC4R) mutation is the most common cause of known monogenic obesity in humans. Unexpectedly, humans and rodents with MC4R deficiency do not develop hyperglycaemia despite chronic obesity and insulin resistance. To explain the underlying mechanisms for this phenotype, we determined the role of MC4R in glucose homeostasis in the presence and absence of obesity in mice.
Methods
We used global and hypothalamus-specific MC4R-deficient mice to investigate the brain regions that contribute to glucose homeostasis via MC4R. We performed oral, intraperitoneal and intravenous glucose tolerance tests in MC4R-deficient mice that were either obese or weight-matched to their littermate controls to define the role of MC4R in glucose regulation independently of changes in body weight. To identify the integrative pathways through which MC4R regulates glucose homeostasis, we measured renal and adrenal sympathetic nerve activity. We also evaluated glucose homeostasis in adrenaline (epinephrine)-deficient mice to investigate the role of adrenaline in mediating the effects of MC4R in glucose homeostasis. We employed a graded [
13
C
6
]glucose infusion procedure to quantify renal glucose reabsorption in MC4R-deficient mice. Finally, we measured the levels of renal glucose transporters in hypothalamus-specific MC4R-deficient mice and adrenaline-deficient mice using western blotting to ascertain the molecular mechanisms underlying MC4R control of glucose homeostasis.
Results
We found that obese and weight-matched MC4R-deficient mice exhibited improved glucose tolerance due to elevated glucosuria, not enhanced beta cell function. Moreover, MC4R deficiency selectively in the paraventricular nucleus of the hypothalamus (PVH) is responsible for reducing the renal threshold for glucose as measured by graded [
13
C
6
]glucose infusion technique. The MC4R deficiency suppressed renal sympathetic nerve activity by 50% in addition to decreasing circulating adrenaline and renal GLUT2 levels in mice, which contributed to the elevated glucosuria. We further report that adrenaline-deficient mice recapitulated the increased excretion of glucose in urine observed in the MC4R-deficient mice. Restoration of circulating adrenaline in both the MC4R- and adrenaline-deficient mice reversed their phenotype of improved glucose tolerance and elevated glucosuria, demonstrating the role of adrenaline in mediating the effects of MC4R on glucose reabsorption.
Conclusions/interpretation
These findings define a previously unrecognised function of hypothalamic MC4R in glucose reabsorption mediated by adrenaline and renal GLUT2. Taken together, our findings indicate that elevated glucosuria due to low sympathetic tone explains why MC4R deficiency does not cause hyperglycaemia despite inducing obesity and insulin resistance.
Graphical abstract