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Hypothalamic POMC Deficiency Improves Glucose Tolerance Despite Insulin Resistance by Increasing Glycosuria.
- Source :
-
Diabetes [Diabetes] 2016 Mar; Vol. 65 (3), pp. 660-72. Date of Electronic Publication: 2015 Oct 14. - Publication Year :
- 2016
-
Abstract
- Hypothalamic proopiomelanocortin (POMC) is essential for the physiological regulation of energy balance; however, its role in glucose homeostasis remains less clear. We show that hypothalamic arcuate nucleus (Arc)POMC-deficient mice, which develop severe obesity and insulin resistance, unexpectedly exhibit improved glucose tolerance and remain protected from hyperglycemia. To explain these paradoxical phenotypes, we hypothesized that an insulin-independent pathway is responsible for the enhanced glucose tolerance. Indeed, the mutant mice demonstrated increased glucose effectiveness and exaggerated glycosuria relative to wild-type littermate controls at comparable blood glucose concentrations. Central administration of the melanocortin receptor agonist melanotan II in mutant mice reversed alterations in glucose tolerance and glycosuria, whereas, conversely, administration of the antagonist Agouti-related peptide (Agrp) to wild-type mice enhanced glucose tolerance. The glycosuria of ArcPOMC-deficient mice was due to decreased levels of renal GLUT 2 (rGLUT2) but not sodium-glucose cotransporter 2 and was associated with reduced renal catecholamine content. Epinephrine treatment abolished the genotype differences in glucose tolerance and rGLUT2 levels, suggesting that reduced renal sympathetic nervous system (SNS) activity is the underlying mechanism for the observed glycosuria and improved glucose tolerance in ArcPOMC-deficient mice. Therefore, the ArcPOMC-SNS-rGLUT2 axis is potentially an insulin-independent therapeutic target to control diabetes.<br /> (© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)
- Subjects :
- Agouti-Related Protein pharmacology
Animals
Blood Glucose drug effects
Blotting, Western
Epinephrine metabolism
Glucose Tolerance Test
Glucose Transporter Type 2 metabolism
Glycosuria, Renal metabolism
Hypothalamus metabolism
Injections, Intraventricular
Mice
Mice, Knockout
Norepinephrine metabolism
Obesity metabolism
Peptides, Cyclic pharmacology
Pro-Opiomelanocortin deficiency
Pro-Opiomelanocortin metabolism
Receptors, Melanocortin agonists
Receptors, Melanocortin antagonists & inhibitors
alpha-MSH analogs & derivatives
alpha-MSH pharmacology
Arcuate Nucleus of Hypothalamus metabolism
Blood Glucose metabolism
Glucose Transporter Type 2 genetics
Glycosuria, Renal genetics
Insulin Resistance genetics
Kidney metabolism
Obesity genetics
Pro-Opiomelanocortin genetics
Sympathetic Nervous System metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1939-327X
- Volume :
- 65
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Diabetes
- Publication Type :
- Academic Journal
- Accession number :
- 26467632
- Full Text :
- https://doi.org/10.2337/db15-0804