The Effect of Adrenalectomy on the Development of the Obese-Hyperglycemic Syndrome in OB/OB Mice

Adrenalectomy in the male and female obese-hyperglycemic mouse at 2 months of age significantly lowers blood glucose and body weight. In the ob/ob mouse the response to fasting is appropriate, glucose tolerance is improved, and insulin resistance is significantly reduced after adrenalectomy. {Endocrinology 93: 510, 1973) T^/TANY laboratories have suggested that the •"•'• adrenal plays a role in both the pancreatic islet cell hypertrophy and adiposity seen in some obese hyperglycemic syndromes of laboratory rodents (1,2,3,4,5). Indeed, hyperadrenalcortism is one of the major methods used to produce experimental obesities (6,7,8,9,10). In NH, ob/ob, Aa obese mice, adiposity is associated with some form of adrenal hypertrophy (S). It is of interest that adrenalectomy, before the onset of obesity, prevents both excess weight gain and islet hypertrophy in NH and yellow obese mice (1,3). Intraocular transplantation of adrenals from lean mice maintains excess weight gain in adrenalectomized NH mice (5). Adrenalectomized ob/ob mice gain less weight than controls (11). In the ob/ob mouse the blood glucose is reduced after adrenalectomy, and it is reported (5) that blood sugar levels correlate with adrenal hypertrophy in these mice. In an investigation of the role of the adrenal cortex in the etiology of the obese-hyperglycemic syndrome in ob/ob mice, Hellerstrom et at. (12) found that all zones of the adrenal cortex were markedly hypertrophied in the obese, but not in the lean animals. They also found that the adrenal hypertrophy was directly related to the adiposity, i.e., if the body weight of obese mice was kept within normal ranges by restricted Received August 29, 1972. 1 Supported in part by Grants-in-aid from the National Institutes of Arthritis and Metabolic Diseases (A-2911), National Institutes of Health, U.S. Public Health Service, Bethesda, Maryland; and the fund for Research and Teaching of the Department of Nutrition, Harvard University School of Public Health, Boston, Massachusetts. 2 Present address: Department of Biology, Boston College, Chestnut Hill, Massachusetts, 02167. diet, there was no adrenal enlargement. Age also seems to play a role in the effect of the adrenals on adiposity. In the NH, Aa, and ob/ob mouse adrenal hypertrophy increases with age, as does the adiposity and hyperglycemia (5). Biochemical evidence that the adrenals of ob/ob mice are hyperactive has been shown by increased glucose 6-phosphate dehydrogenase activity (4) and by increased sensitivity to ACTH (13). Thus, the possibility that the adrenals are involved in the expression of the ob/ob genome prompted us to explore the effect of adrenalectomy on young male and female mice. Materials and Methods Male and female C57BL/6J-ob/ob mice obtained from the Jackson Memorial Laboratories were randomized into 2 groups at 2 months of age. Fourteen were bilaterally adrenalectomized; 10 served as unoperated controls. Body weights and blood glucose levels for both groups were obtained one day before, and periodically from 6 to 90 days after the adrenalectomy date. Fourteen lean littermates were similarly randomized into 2 groups: 8 adrenalectomized and 6 unoperated controls. In all groups, body weights and blood sugar levels were determined the day before, and periodically following the adrenalectomy date. All animals were maintained on ad lib food (Purina lab chow) and water. Adrenalectomized animals were also given the choice of 1% salt in drinking water. In order to approximate the functional capacity of the pancreas all animals were fasted overnight 70 days (obese) and 71 days (lean) after adrenalectomy date. A blood sample was obtained from the fasting mice and then 50 mg of glucose ip was administered to the obese mice. Fasting lean mice received 20 mg glucose. Blood samples were drawn 30, 60, and 360 min later to determine glucose tolerance. The insulin sensitivity of adrenalectomized mice and their controls was studied by collecting blood