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Cited by 69Diabetes, Cardiovascular Risks, and LipoproteinsAdipokines, Inflammation, and Metabolic DiseasesRegulation of Appetite and Obesity

Molecular Pathology in the Obese Spontaneous Hypertensive Koletsky Rat: A Model of Syndrome X

ERNSBERGER, PAUL, KOLETSKY, RICHARD J., FRIEDMAN, JACOB E.·1999·Annals of the New York Academy of Sciences
DOI 10.1111/j.1749-6632.1999.tb07801.x
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Abstract

ABSTRACT: The SHROB rat is a unique strain with genetic obesity, hypertriglyceridemia, hyperinsulinemia, renal disease with proteinuria, and genetically determined hypertension, characteristics paralleling human Syndrome X. The obese phenotype results from a single homozygous recessive trait, designated faK, and is allelic with the Zucker fatty trait (fa), but of distinct origin. The faK mutation is a premature stop codon in the extracellular domain of the leptin receptor, resulting in a natural receptor knockout. The SHROB are glucose intolerant compared to heterozygous or wild‐type SHR, but retain fasting euglycemia even on a high sucrose diet, suggesting that diabetes requires polygenic interaction with additional modifier genes. Insulin‐stimulated phosphorylation of tyrosine residues on the insulin receptor and on the associated docking protein IRS‐1 are reduced in skeletal muscle and liver compared to SHR, due mainly to diminished expression of insulin receptor and IRS‐1 proteins. Despite multiple metabolic derangements and severe insulin resistance, hypertension is not exacerbated in SHROB compared to SHR. Thus, insulin resistance and hypertension are independent in this model. Increased activity of the sympathetic nervous system may be a common factor leading by separate pathways to hypertension and to insulin resistance. We studied the chronic effects of sympathetic inhibition with moxonidine on glucose metabolism in SHROB. Moxoni‐dine (8 mg/kg/day), a selective I 1‐imidazoline receptor agonist, not only reduced blood pressure but also ameliorated glucose intolerance. Moxonidine reduced fasting insulin by 47% and plasma free fatty acids by 30%. Moxonidine enhanced expression and insulin‐stimulated phosphorylation of IRS‐1 in skeletal muscle by 74 and 27%, respectively. Thus, central sympatholytic therapy not only counters hypertension but also insulin resistance, glucose tolerance, and hyperlipidemia in the SHROB model of Syndrome X.

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Crossref · 10.1111/j.1749-6632.1999.tb07801.x

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  • Mice with genetic leptin deficiency or leptin receptor deficiency exhibit hyperphagia, obesity, insulin resistance, and diabetes.

    “Such animals exhibit not only hyperphagia and obesity, but insulin resistance and diabetes as well (37, 57, 181, 212).”

    From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [57]

  • Koletsky fak/fak rats are characterized by obesity, hyperphagia, insulin resistance, and glucose intolerance but are not hyperglycemic.

    “These animals are characterized by obesity, hyperphagia, insulin resistance and glucose intolerance but are not hyperglycemic (57).”

    From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [57]

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Authors
ERNSBERGER, P., KOLETSKY, R. J., & FRIEDMAN, J. E.
Affiliations
Case Western Reserve University (US)
Corresponding author
FRIEDMAN, JACOB E.
ORCID
Venue
Annals of the New York Academy of Sciences
Publisher
Wiley
Published
1999-11
Volume
892
Issue
1
Pages
272-288
ISSN
  • 0077-8923 (ISSN-L)
  • 1749-6632
DOI
10.1111/j.1749-6632.1999.tb07801.x
OpenAlex
W2128806783
Cited by
69
References
28
Citations by year
2026: 1 · 2021: 2 · 2019: 2 · 2018: 5 · 2017: 1 · 2016: 2 · 2015: 3 · 2014: 4 · 2013: 5 · 2012: 3
FWCI
1.59
Type
journal article
Language
en
Open access
closed
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor, 2289 d)
Locations
  • Annals of the New York Academy of Sciences (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
Keywords
metabolic syndrome, genetic obesity, leptin receptor, insulin resistance, insulin receptor tyrosine phosphorylation, IRS-1, moxonidine, imidazoline I1 receptor, sympathetic nervous system, impaired glucose tolerance, hypertriglyceridemia, hyperinsulinemia, hypertension, free fatty acids, skeletal muscle
MeSH terms
Animals, Carrier Proteins, Disease Models, Animal, Endocrine System, Female, Hyperinsulinism, Hyperlipidemias, Hypertension, Imidazoles, Insulin Resistance, Kidney Diseases, Male, Obesity, Phenotype, Phosphoproteins, Phosphorylation, Rats, Mutant Strains, Receptors, Cell Surface, Receptor, Insulin, Anti-Obesity Agents, Leptin, Rats, Receptors, Leptin, Insulin Receptor Substrate Proteins

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