Increased sensitivity of the genetically obese mouse to corticosterone

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Abstract
Adrenalectomy normalizes many abnormalities of the obese (ob/ob) mouse. The high corticosterone concentration in blood may account in part for development of obesity and other abnormalities in the ob/ob mouse. Our objective was to determine dose-response relationships for the effect of corticosterone on the obesity. Lean and ob/ob mice were adrenalectomized or sham-operated at 4.5 wk of age. Adrenalectomized mice received 100 mg implants of cholesterol containing corticosterone (0, 2, 5, 20, or 50 mg) at 8.5 wk of age and were killed at 10.5 wk of age. In ob/ob mice, but not in lean mice, low physiological levels of serum corticosterone (up to 10 .mu.g/dl) markedly increased body weight gain, food intake, and serum insulin. They also increased white and brown adipose tissue weights and decreased brown adipose tissue mitochondrial GDP binding. Higher levels of corticosterone (12-22 .mu.g/dl) increased body weight gain, white and brown adipose tissue weights, and serum insulin and suppressed brown adipose tissue mitochondrial GDP binding in lean mice also, although in most cases to a lesser extent than in ob/ob mice, but were still without effect on food intake. Only very high levels of corticosterone (.apprx. 30 .mu.g/dl) increased food intake in lean mice. Hyperglycemia was induced in ob/ob, but not lean, mice only at concentrations of corticosterone > 17 .mu.g/dl. Thermoregulation was unaffected by serum corticosterone at levels from 0 to 30 .mu.g/dl in both ob/ob and lean mice. Thus, the ob/ob mouse is excessively sensitive and responsive to an effect of physiological levels of corticosterone that results in hyperphagia, hyperinsulinemia, and increased weight gain. Other abnormalities, such as pronounced suppression of brown adipose tissue thermogenic state, and hyperglycemia, are related to high levels of corticosterone. The thermoregulatory abnormality of the ob/ob mouse persists in the adrenalectomized state and must account for part of the high metabolic efficiency of this animal; it is unrelated to any action of corticosterone.