Reduced renal sympathetic nerve activity contributes to elevated glycosuria and improved glucose tolerance in hypothalamus-specific Pomc knockout mice

Kavaljit H Chhabra; Donald A Morgan; Benjamin P Tooke; Jessica M Adams; Kamal Rahmouni; Malcolm J Low

doi:10.1016/j.molmet.2017.07.005

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Reduced renal sympathetic nerve activity contributes to elevated glycosuria and improved glucose tolerance in hypothalamus-specific Pomc knockout mice

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Reduced renal sympathetic nerve activity contributes to elevated glycosuria and improved glucose tolerance in hypothalamus-specific Pomc knockout mice

Kavaljit H Chhabra, Donald A Morgan, Benjamin P Tooke, Jessica M Adams, Kamal Rahmouni and Malcolm J Low

Molecular metabolism (Germany), Vol.6(10), pp.1274-1285

10/2017

DOI: 10.1016/j.molmet.2017.07.005

PMCID: PMC5641634

PMID: 29031726

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Abstract

Hypothalamic arcuate nucleus-specific pro-opiomelanocortin deficient (ArcPomc ) mice exhibit improved glucose tolerance despite massive obesity and insulin resistance. We demonstrated previously that their improved glucose tolerance is due to elevated glycosuria. However, the underlying mechanisms that link glucose reabsorption in the kidney with ArcPomc remain unclear. Given the function of the hypothalamic melanocortin system in controlling sympathetic outflow, we hypothesized that reduced renal sympathetic nerve activity (RSNA) in ArcPomc mice could explain their elevated glycosuria and consequent enhanced glucose tolerance. We measured RSNA by multifiber recording directly from the nerves innervating the kidneys in ArcPomc mice. To further validate the function of RSNA in glucose reabsorption, we denervated the kidneys of WT and diabetic db/db mice before measuring their glucose tolerance and urine glucose levels. Moreover, we performed western blot and immunohistochemistry to determine kidney GLUT2 and SGLT2 levels in either ArcPomc mice or the renal-denervated mice. Consistent with our hypothesis, we found that basal RSNA was decreased in ArcPomc mice relative to their wild type (WT) littermates. Remarkably, both WT and db/db mice exhibited elevated glycosuria and improved glucose tolerance after renal denervation. The elevated glycosuria in obese ArcPomc , WT and db/db mice was due to reduced renal GLUT2 levels in the proximal tubules. Overall, we show that renal-denervated WT and diabetic mice recapitulate the phenotype of improved glucose tolerance and elevated glycosuria associated with reduced renal GLUT2 levels observed in obese ArcPomc mice. Hence, we conclude that ArcPomc is essential in maintaining basal RSNA and that elevated glycosuria is a possible mechanism to explain improved glucose tolerance after renal denervation in drug resistant hypertensive patients.

Glycosuria - physiopathology

Glucose Tolerance Test

Arcuate Nucleus of Hypothalamus - metabolism

Male

Glucose Transporter Type 2 - metabolism

Glycosuria - metabolism

Mice, Knockout

Obesity - metabolism

Pro-Opiomelanocortin - metabolism

Insulin - metabolism

Kidney - metabolism

Animals

Hypothalamus - metabolism

Sympathetic Nervous System - physiology

Insulin Resistance - physiology

Diabetes Mellitus, Experimental

Glucose - metabolism

Female

Kidney - innervation

Mice, Obese

Pro-Opiomelanocortin - deficiency

Mice

Pro-Opiomelanocortin - genetics

Glycosuria - urine

Details

Title: Subtitle: Reduced renal sympathetic nerve activity contributes to elevated glycosuria and improved glucose tolerance in hypothalamus-specific Pomc knockout mice
Creators: Kavaljit H Chhabra - Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA
Donald A Morgan - Department of Pharmacology, University of Iowa, Iowa City, IA, USA
Benjamin P Tooke - Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA; Case Western Reserve University, Cleveland, OH, USA
Jessica M Adams - Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI, USA
Kamal Rahmouni - Department of Pharmacology, University of Iowa, Iowa City, IA, USA
Malcolm J Low - Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan Medical School, Ann Arbor, MI, USA. Electronic address: mjlow@umich.edu
Resource Type: Journal article
Publication Details: Molecular metabolism (Germany), Vol.6(10), pp.1274-1285
DOI: 10.1016/j.molmet.2017.07.005
PMID: 29031726
PMCID: PMC5641634
NLM abbreviation: Mol Metab
ISSN: 2212-8778
eISSN: 2212-8778
Publisher: Germany
Grant note: R01 DK066604 / NIDDK NIH HHS P30 DK020572 / NIDDK NIH HHS T32 NS076401 / NINDS NIH HHS K01 DK113115 / NIDDK NIH HHS R01 DK068400 / NIDDK NIH HHS T32 GM008322 / NIGMS NIH HHS P01 HL084207 / NHLBI NIH HHS P30 DK089503 / NIDDK NIH HHS
Language: English
Date published: 10/2017
Academic Unit: Iowa Neuroscience Institute; Neuroscience and Pharmacology; Internal Medicine
Record Identifier: 9984040357902771

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