PHARMACOLOGICAL MANIPULATION OF OB EXPRESSION IN A DIETARY MODEL OF OBESITY

Mutation of the obese (ob) gene results in severe hereditary obesity a nd 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 fa t) without mutation of the ob gene, and in four genetic models of obes ity in mice: ob/ob, db/db, tubby, and fat, Several white and brown adi pose depots were examined (epididymal, subcutaneous, perirenal, and in terscapular), Northern blot analysis shows that levels of ob mRNA are increased in all adipose depots examined in every model of obesity, Th e 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 d iet-induced A/J), Moreover, we found that the expression of the ob gen e could be manipulated by pharmacologically blocking the development o f 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 fa t-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 contain ed 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 a s 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 o f any effects on food intake.