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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 pheno-types, 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 cotrans-porter 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. © 2016 by the American Diabetes Association.

Registro:

Documento: Artículo
Título:Hypothalamic POMC deficiency improves glucose tolerance despite insulin resistance by increasing Glycosuria
Autor:Chhabra, K.H.; Adams, J.M.; Fagel, B.; Lam, D.D.; Qi, N.; Rubinstein, M.; Low, M.J.
Filiación:Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, United States
Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI, United States
Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan Medical School, Ann Arbor, MI, United States
Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, Consejo Nacional de Investigaciones Científicas y Técnicas, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
Palabras clave:adrenalin; brain protein; catecholamine; glucose; glycogen; insulin; melanotan II; noradrenalin; proopiomelanocortin; sodium glucose cotransporter 2; agouti related protein; alpha intermedin; cyclopeptide; epinephrine; glucose blood level; glucose transporter 2; melanocortin receptor; melanotan-II; noradrenalin; proopiomelanocortin; Slc2a2 protein, mouse; adrenalin urine level; animal cell; animal experiment; animal model; animal tissue; arcuate nucleus; Article; controlled study; female; genotype; gluconeogenesis; glucose blood level; glucose tolerance; glucose urine level; glucosuria; glycogen liver level; hyperglycemia; hyperinsulinemia; hypothalamic proopiomelanocortin deficiency; hypothalamus disease; impaired glucose tolerance; insulin blood level; insulin resistance; insulin sensitivity; insulin tolerance test; intravenous glucose tolerance test; male; mouse; nonhuman; noradrenalin urine level; obesity; oral glucose tolerance test; priority journal; protein deficiency; sympathetic innervation; sympathetic tone; turnover time; wild type; adrenergic system; agonists; analogs and derivatives; animal; antagonists and inhibitors; deficiency; drug effects; genetics; glucose tolerance test; hypothalamus; insulin resistance; intracerebroventricular drug administration; kidney; knockout mouse; metabolism; renal diabetes; Western blotting; Agouti-Related Protein; alpha-MSH; Animals; Arcuate Nucleus of Hypothalamus; Blood Glucose; Blotting, Western; Epinephrine; Glucose Tolerance Test; Glucose Transporter Type 2; Glycosuria, Renal; Hypothalamus; Injections, Intraventricular; Insulin Resistance; Kidney; Mice; Mice, Knockout; Norepinephrine; Obesity; Peptides, Cyclic; Pro-Opiomelanocortin; Receptors, Melanocortin; Sympathetic Nervous System
Año:2016
Volumen:65
Número:3
Página de inicio:660
Página de fin:672
DOI: http://dx.doi.org/10.2337/db15-0804
Título revista:Diabetes
Título revista abreviado:Diabetes
ISSN:00121797
CODEN:DIAEA
CAS:glucose, 50-99-7, 84778-64-3; glycogen, 9005-79-2; insulin, 9004-10-8; melanotan II, 121062-08-6; noradrenalin, 1407-84-7, 51-41-2; proopiomelanocortin, 66796-54-1; epinephrine, 51-43-4, 55-31-2, 6912-68-1; glucose transporter 2, 357693-20-0; Agouti-Related Protein; alpha-MSH; Blood Glucose; Epinephrine; Glucose Transporter Type 2; melanotan-II; Norepinephrine; Peptides, Cyclic; Pro-Opiomelanocortin; Receptors, Melanocortin; Slc2a2 protein, mouse
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00121797_v65_n3_p660_Chhabra

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Citas:

---------- APA ----------
Chhabra, K.H., Adams, J.M., Fagel, B., Lam, D.D., Qi, N., Rubinstein, M. & Low, M.J. (2016) . Hypothalamic POMC deficiency improves glucose tolerance despite insulin resistance by increasing Glycosuria. Diabetes, 65(3), 660-672.
http://dx.doi.org/10.2337/db15-0804
---------- CHICAGO ----------
Chhabra, K.H., Adams, J.M., Fagel, B., Lam, D.D., Qi, N., Rubinstein, M., et al. "Hypothalamic POMC deficiency improves glucose tolerance despite insulin resistance by increasing Glycosuria" . Diabetes 65, no. 3 (2016) : 660-672.
http://dx.doi.org/10.2337/db15-0804
---------- MLA ----------
Chhabra, K.H., Adams, J.M., Fagel, B., Lam, D.D., Qi, N., Rubinstein, M., et al. "Hypothalamic POMC deficiency improves glucose tolerance despite insulin resistance by increasing Glycosuria" . Diabetes, vol. 65, no. 3, 2016, pp. 660-672.
http://dx.doi.org/10.2337/db15-0804
---------- VANCOUVER ----------
Chhabra, K.H., Adams, J.M., Fagel, B., Lam, D.D., Qi, N., Rubinstein, M., et al. Hypothalamic POMC deficiency improves glucose tolerance despite insulin resistance by increasing Glycosuria. Diabetes. 2016;65(3):660-672.
http://dx.doi.org/10.2337/db15-0804