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Molecular Pathology in the Obese Spontaneous Hypertensive Koletsky Rat: A Model of Syndrome X
Author(s) -
ERNSBERGER PAUL,
KOLETSKY RICHARD J.,
FRIEDMAN JACOB E.
Publication year - 1999
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.1999.tb07801.x
Subject(s) - endocrinology , medicine , insulin resistance , hyperinsulinemia , moxonidine , insulin receptor , insulin , hypertriglyceridemia , metabolic syndrome , spontaneously hypertensive rat , biology , diabetes mellitus , receptor , blood pressure , agonist , triglyceride , cholesterol
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 fa K , and is allelic with the Zucker fatty trait ( fa ), but of distinct origin. The fa K 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.