The role of beta3-adrenergic receptors in control of brown and white adipose tissues and of energy balance: Reversal of obesity by CL 316,243, a new beta3-adrenergic agonist.

Obesity is a prevalent health hazard that is associated with other metabolic disorders, in particular with insulin resistance and non-insulin-dependent diabetes mellitus. Treatment of obesity requires an increase in energy expenditure or a decrease in energy intake or both of these. One target for raising energy expenditure in the treatment of obesity with drugs is the $\beta$3-adrenergic receptor in brown and white adipose tissues. Selective $\beta$3-adrenergic receptor agonists have been developed that will stimulate both the mobilization of fat from white adipose tissue, the site of triacylglycerol storage in the body, and the oxidation of this fat in brown adipose tissue, a site of thermogenesis. The principal objectives of the work described in this thesis were to find out whether a selective $\beta$3-adrenergic receptor agonist could reverse obesity and insulin-resistance in rats and to elucidate the mechanisms involved. Two models of obesity were studied: young Sprague-Dawley rats which became obese because they were eating a high-fat diet and continued to eat this diet during the treatment (diet-induced obesity) and old Zucker fa/fa rats (genetic obesity). Rats were treated by continuous subcutaneous infusion of the selective $\beta$3-adrenergic receptor agonist, CL 316,243; control rats received infusion of saline. Lean rats of the same age and strain were similarly treated. Rats with diet-induced obesity had a hypertrophic obesity (enlarged white adipocytes but no increase in number of adipocytes) while rats with genetic obesity had a hyperplastic obesity (increase in number of white adipocytes). Treatment with CL 316,243 reversed obesity in both animal models. Reduction in fat stores was associated with shrinking of enlarged animal models. Reduction in fat white adipocytes but no reduction in their number, even when this was elevated as in the genetically obese fa/fa rats. Reversal of obesity was associated with a large increase in energy expenditure. This was associated not only with growth of the presumed site of this increase in energy expenditure, brown adipose tissue, but also with appearance of abundant brown adipocytes in white adipose tissues, a site in which they do not normally occur. Reversal of obesity was not associated with any reduction in energy intake, except in the genetically obese rats in which the hyperphagia was reversed. Treatment reduced the concentration of leptin in serum when this was elevated, as in the rats with diet-induced obesity and in the moderately obese old control Zucker rats. Treatment did not, however, reduce the elevated level of leptin in the blood of fa/fa rats. There was thus no correlation of drug-induced changes in leptin concentration with changes in food intake. Studied only in fa/fa rats, treatment improved insulin resistance, decreasing both hyperglycaemia and hyperinsulinaemia. This improvement was correlated with a reduction of expression of a suggested mediator of insulin resistance, tumour necrosis factor $\alpha$, in white adipose tissues. Results show that CL 316,243, a selective agonist for rodent $\beta$3-adrenergic receptors, is an effective anti-obesity agent in rat models of obesity. Future development of similar compounds that are selective for human $\beta$3-adrenergic receptors will be needed before this approach to treatment of obesity and insulin resistance can be useful in humans