Hypothalamic POMC deficiency improves glucose tolerance despite insulin resistance by increasing Glycosuria
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...
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| Acceso en línea: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00121797_v65_n3_p660_Chhabra http://hdl.handle.net/20.500.12110/paper_00121797_v65_n3_p660_Chhabra |
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paper:paper_00121797_v65_n3_p660_Chhabra2023-06-08T14:35:21Z Hypothalamic POMC deficiency improves glucose tolerance despite insulin resistance by increasing Glycosuria Rubinstein, Marcelo 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 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. Fil:Rubinstein, M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. 2016 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00121797_v65_n3_p660_Chhabra http://hdl.handle.net/20.500.12110/paper_00121797_v65_n3_p660_Chhabra |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
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 |
| spellingShingle |
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 Rubinstein, Marcelo Hypothalamic POMC deficiency improves glucose tolerance despite insulin resistance by increasing Glycosuria |
| topic_facet |
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 |
| description |
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. |
| author |
Rubinstein, Marcelo |
| author_facet |
Rubinstein, Marcelo |
| author_sort |
Rubinstein, Marcelo |
| title |
Hypothalamic POMC deficiency improves glucose tolerance despite insulin resistance by increasing Glycosuria |
| title_short |
Hypothalamic POMC deficiency improves glucose tolerance despite insulin resistance by increasing Glycosuria |
| title_full |
Hypothalamic POMC deficiency improves glucose tolerance despite insulin resistance by increasing Glycosuria |
| title_fullStr |
Hypothalamic POMC deficiency improves glucose tolerance despite insulin resistance by increasing Glycosuria |
| title_full_unstemmed |
Hypothalamic POMC deficiency improves glucose tolerance despite insulin resistance by increasing Glycosuria |
| title_sort |
hypothalamic pomc deficiency improves glucose tolerance despite insulin resistance by increasing glycosuria |
| publishDate |
2016 |
| url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00121797_v65_n3_p660_Chhabra http://hdl.handle.net/20.500.12110/paper_00121797_v65_n3_p660_Chhabra |
| work_keys_str_mv |
AT rubinsteinmarcelo hypothalamicpomcdeficiencyimprovesglucosetolerancedespiteinsulinresistancebyincreasingglycosuria |
| _version_ |
1768545033450946560 |