Visceral Obesity without Insulin Resistance in Late-Onset Obesity Rats

We describe a line of transgenic rats in which the males develop a unique autosomal dominant, late-onset obesity (LOB) phenotype. LOB males gradually accumulate fat specifically in visceral, but not peripheral, fat depots despite a normal intake of a low fat diet. LOB females normally develop only m...

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Bibliographic Details
Published in:	Endocrinology (Philadelphia) Vol. 145; no. 6; pp. 2666 - 2679
Main Authors:	Bains, Randip K, Wells, Sara E, Flavell, Dave M, Fairhall, Keith M, Strom, Molly, Le Tissier, Paul, Robinson, Iain C. A. F
Format:	Journal Article
Language:	English
Published:	Bethesda, MD Endocrine Society 01-06-2004 Oxford University Press
Subjects:	Absorption Adiponectin Adipose tissue Animals Animals, Genetically Modified Biological and medical sciences Body Temperature Corticosterone Diet Dietary Fats - pharmacokinetics Dietary intake Disease Susceptibility Eating Estradiol - pharmacology Estrogens Female Females Fundamental and applied biological sciences. Psychology Gene deletion Genotype & phenotype Glucose Glucose - pharmacology Glucose tolerance Growth Hormone - pharmacology Hormone replacement therapy Hypoglycemic Agents - pharmacology Insulin Insulin - pharmacology Insulin Resistance Low fat diet Male Males Nutrient deficiency Obesity Obesity - etiology Obesity - physiopathology Obesity - prevention & control Ovariectomy Phenotype Phenotypes Rats Rats, Wistar Rosiglitazone Thiazolidinediones - pharmacology Time Factors Transgenes Vertebrates: endocrinology Viscera Target tissue resistance Vertebrata Late Mammalia Rat Animal Rodentia Visceral obesity
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Summary:	We describe a line of transgenic rats in which the males develop a unique autosomal dominant, late-onset obesity (LOB) phenotype. LOB males gradually accumulate fat specifically in visceral, but not peripheral, fat depots despite a normal intake of a low fat diet. LOB females normally develop only mild obesity with advanced age. However, the phenotype can be induced rapidly in young females by ovariectomy and prevented by estrogen replacement. LOB males are highly sensitive to dietary fat. Young, nonobese LOB males gain more weight on a 30% fat diet and lose more weight when treated with the lipase inhibitor, Orlistat, than their nontransgenic littermates. Remarkably, despite severe visceral obesity, LOB rats have normal fasting blood glucose, insulin, and corticosterone; show normal or increased insulin sensitivity in glucose and insulin tolerance tests; have increased plasma adiponectin levels; and display a heightened response to treatment with rosiglitazone. Their visceral adiposity reflects a specific increase in visceral adipocyte number, not size. Analysis of the transgene in LOB rats revealed a deletion in the gene encoding the S26 subunit of the mitochondrial ribosome that results in the production of a truncated protein, which we show to be imported into mitochondria. However, the transgene integrant is complex, so whether this is the sole molecular disruption underlying this phenotype remains to be established. Nevertheless, LOB rats provide a valuable new model of late-onset, male-preponderant, visceral-specific obesity, clearly dissociated from insulin resistance.
ISSN:	0013-7227 1945-7170
DOI:	10.1210/en.2003-1608