We have investigated the antidiabetic action of troglitazone in aP2/DTA mice, whose white and brown fat was virtually eliminated by fat-specific expression of diphtheria toxin A chain. aP2/DTA mice had markedly suppressed serum leptin levels and were hyperphagic, but did not gain excess weight. aP2/DTA mice fed a control diet were hyperlipidemic, hyperglycemic, and had hyperinsulinemia indicative of insulin-resistant diabetes. Treatment with troglitazone alleviated the hyperglycemia, normalized the tolerance to intraperitoneally injected glucose, and significantly decreased elevated insulin levels. Troglitazone also markedly decreased the serum levels of cholesterol, triglycerides, and free fatty acids both in wild-type and aP2/DTA mice. The decrease in serum triglycerides in aP2/DTA mice was due to a marked reduction in VLDL-and LDL-associated triglyceride. In skeletal muscle, triglyceride levels were decreased in aP2/DTA mice compared with controls, but glycogen levels were increased. Troglitazone treatment decreased skeletal muscle, but not hepatic triglyceride and increased hepatic and muscle glycogen content in wild-type mice. Troglitazone decreased muscle glycogen content in aP2/DTA mice without affecting muscle triglyceride levels. The levels of peroxisomal proliferator-activated receptor ␥ mRNA in liver increased slightly in aP2/DTA mice and were not changed by troglitazone treatment. The results demonstrate that insulin resistance and diabetes can occur in animals without significant adipose deposits. Furthermore, troglitazone can alter glucose and lipid metabolism independent of its effects on adipose tissue. ( J. Clin. Invest. 1997. 100:2900-2908.)

Brown adipose tissue (BAT) functions in non-shivering and diet-induced thermogenesis via its capacity for uncoupled mitochondrial respiration. BAT dysfunction in rodents is associated with severe defects in energy homeostasis, resulting in obesity and hyperglycemia. Here, we report that the nuclear receptor peroxisome proliferator-activated receptor ␥ (PPAR␥), a prostaglandin-activated transcription factor recently implicated as a central regulator of white adipose tissue differentiation, also regulates brown adipocyte function. PPAR␥ is abundantly expressed in both embryonic and adult BAT. Treatment of CD-1 rats with the PPAR␥-selective ligand BRL49653, an anti-diabetic drug of the thiazolidinedione class, results in marked increases in the mass of interscapular BAT. In vitro, BRL49653 induces the terminal differentiation of the brown preadipocyte cell line HIB-1B as judged by both changes in cell morphology and expression of uncoupling protein and other adipocyte-specific mRNAs. These data demonstrate that PPAR␥ is a key regulatory factor in brown adipocytes and suggest that PPAR␥ functions not only in the storage of excess energy in white adipose tissue but also in its dissipation in BAT.Two types of adipose tissue have been described. White adipose tissue (WAT) 1 is specialized to store triglycerides and to release free fatty acids in response to changing energy requirements. A second type of adipose tissue, termed brown adipose tissue (BAT), is involved in the dissipation of energy via the generation of heat (see below). This unique thermogenic activity of BAT is tightly regulated and can be induced in response to either cold exposure or hyperphagia (1, 2). In rodents, several lines of evidence suggest that BAT plays a central role in maintaining energy balance. First, by increasing energy expenditure in response to increased food intake, BAT thermogenesis acts to prevent (or deter) the development of obesity (3). Second, transgenic ablation of BAT in mice is sufficient to induce obesity as well as insulin resistance and other metabolic disorders that, as a whole, closely resemble human non-insulindependent diabetes mellitus (5-7). Third, defects in BAT function are thought to play a significant role in the development of obesity and diabetes in several animal models (8,9). These data suggest a tight link between BAT function and the regulation of glucose and lipid metabolism.The unique thermogenic activity of BAT results from the action of a BAT-specific protein termed uncoupling protein (UCP). UCP is a mitochondrial proton translocator that uncouples fatty acid oxidation from ATP synthesis, releasing the energy as heat (10, 11). Analysis of the UCP gene has resulted in the identification of a 220-bp enhancer located from Ϫ2.5 to Ϫ2.3 kilobase pairs upstream of the UCP gene that is responsible for brown adipocyte-specific gene expression in cell culture models (12,13). This enhancer region contains a cAMP response element as well as thyroid hormone receptor and retinoid receptor response elements (12-15)...