American Diabetes Association Annual Meeting, 1997: Obesity, diabetes prevention, and type 1 diabetes

Obesity Alan Shuldiner, Baltimore, MD, discussed the use of p3-agonists for treatment of obesity. Obesity is associated with diabetes, hypertension, dyslipidemia, coronary disease, thromboembolic disease, gall bladder disease, pulmonary disease, and certain malignancies, and the goal in treating obesity should be to improve "metabolic fitness," even if only modest weight loss is achieved. Throughout biological evolution, however, for hundreds of millions of years, energy requirements have exceeded food availability. Thus, there are diverse and redundant systems to maintain and increase body weight. Over the past few hundred years, an epidemic of obesity has begun because of the availability of excess food, leading to one third of Americans currently being obese. We need new therapeutic agents as well as new genetic tests to determine the causes of obesity and evaluate individual susceptibility, so that we can direct therapy for specific patients. Targets of treatment include the appetite/satiety system, the manipulation of which will require understanding the roles of leptin, neuropeptide Y (NPY), melanocortin, galanin, opioids, glucagon-like peptide I, and cholecystokinin, among other hormonal controls; the energy-expenditure system, for which leptin, 33-agonists, uncoupling protein, and the thyroid hormone axis are relevant; and other mediators of adipocyte growth, including cytokines, peroxisome proliferation activated receptor, and growth hormone. The f$3-adrenergic receptor is a cell-surface protein expressed almost exclusively in adipocytes. It is coupled to G-protein, activation of which leads to increased intracellular cyclic AMP levels, which activate protein kinase C and result in lipolysis. In white adipose tissue, free fatty acids are released, while in brown adipose tissue (BAT), in the presence of uncoupling protein, free fatty acids are metabolized, with stimulation of thermogenesis. In other adrenergic systems, chronic stimulation downregulates receptor expression, but chronic stimulation of the p3-adrenergic receptor upregulates its expression, as well as that of the uncoupling protein. The Lederle compound CL 316,243 potently stimulates lipolysis, thermogenesis, hypertrophy of BAT, and weight loss in rodents. This compound is not, however, effective in humans as a (33-agonist. A Merck compound, L739,574, has been studied in Rhesus monkeys, but may cause flush and tachycardia. The question of whether the use of (33-agonists will be applicable to human obesity is not yet fully answered. There is little BAT in adult humans, and p3-adrenergic receptor expression is low in subcutaneous fat, while there is expression in the heart and gallbladder, suggesting the possibility of adverse actions at these sites. However, chronic sympathetic stimulation does cause BAT hypertrophy in humans, and [^-adrenergic receptors are present in visceral fat and are upregulated, rather than downregulated, by chronic stimulation. In addition, it appears that a genetic (33-receptor variant is associated with lower resting metabolic rate and increased risk of the insulin resistance syndrome, further suggesting a potential role of |33-agonists in the treatment of obesity Fujisawa et al. (675; references in parentheses are to abstract numbers from the Abstracts of the 57th Annual Meeting and