Pharmacologic manipulation of ob expression in a dietary model of obesity.
Mutation of the obese (ob) gene results in severe hereditary obesity and diabetes in the C57BL/6J and related strains of mice. In this study we examined the expression of the ob gene in a dietary model in which moderate obesity develops in response to fat (58% of calories from fat) without mutation of the ob gene, and in four genetic models of obesity in mice: ob/ob, db/db, tubby, and fat. Several white and brown adipose depots were examined (epididymal, subcutaneous, perirenal, and interscapular). Northern blot analysis shows that levels of ob mRNA are increased in all adipose depots examined in every model of obesity. The average fold increases were 12.0 +/ 2.1 (ob/ob), 4.8 +/- 1.5 (db/db), 2.8 +/- 0.1 (tubby), 2.4 +/- 0.3 (fat), and 2.1 +/- 0.2 (high fat diet-induced A/J). Moreover, we found that the expression of the ob gene could be manipulated by pharmacologically blocking the development of diet-induced obesity. Supplementation of a high fat diet with a beta 3-adrenergic receptor agonist (CL316,243) prevented obesity, but not hyperphagia associated with high fat feeding (body weights of high fat-fed A/J mice = 34.0 +/- 1.0 g; high fat plus CL316,243-fed mice = 26.8 +/- 0.5 g; n = 10). CL316,243-treated, high fat-fed animals contained levels of ob mRNA in all adipose depots that were equal to or less than levels in low fat-fed mice (average levels in high fat plus CL316,243-fed mice relative to low fat-fed mice: 0.93 +/- 0.09). Inasmuch as fat cell size, but not number, was increased in a previous study in diet-induced obese A/J mice, these results indicate that expression of the ob gene serves as a sensor of fat cell hypertrophy, independent of any effects on food intake.
Collins
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Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina 27710, USA.
Surwit
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D000273:Adipose Tissue; D002001:Adipose Tissue, Brown; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D017931:DNA Primers; D004041:Dietary Fats; D004149:Dioxoles / Q000494:pharmacology; D002149:Energy Intake; D015870:Gene Expression / Q000187:drug effects; D020738:Leptin; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008969:Molecular Sequence Data; D009765:Obesity / Q000235:genetics* / Q000503:physiopathology*; D009928:Organ Specificity; D016133:Polymerase Chain Reaction; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D013045:Species Specificity
D000318:Adrenergic beta-Agonists; D017931:DNA Primers; D004041:Dietary Fats; D004149:Dioxoles; D020738:Leptin; D011506:Proteins; D012333:RNA, Messenger; C076126:disodium (R,R)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)-amino)propyl)-1,3-benzodioxole-2,3-dicarboxylate