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Publication
Hypothalamic POMC Deficiency Improves Glucose Tolerance Despite Insulin
Resistance by Increasing Glycosuria.
Authors Chhabra KH, Adams JM, Fagel B, Lam DD, Qi N, Rubinstein M, Low MJ
Submitted By Submitted Externally on 1/10/2022
Status Published
Journal Diabetes
Year 2016
Date Published 3/1/2016
Volume : Pages 65 : 660 - 72
PubMed Reference 26467632
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.




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