The discovery that peroxisome proliferator-activated receptor (PPAR)-gamma was the molecular target of the thiazolidinedione class of antidiabetic agents suggested a key role for PPAR-gamma in the regulation of carbohydrate and lipid metabolism. Through the use of high-throughput biochemical assays, GW1929, a novel N-aryl tyrosine activator of human PPAR-gamma, was identified. Chronic oral administration of GW1929 or troglitazone to Zucker diabetic fatty (ZDF) rats resulted in dose-dependent decreases in daily glucose, free fatty acid, and triglyceride exposure compared with pretreatment values, as well as significant decreases in glycosylated hemoglobin. Whole body insulin sensitivity, as determined by the euglycemic-hyperinsulinemic clamp technique, was significantly increased in treated animals. Comparison of the magnitude of glucose lowering as a function of serum drug concentrations showed that GW1929 was 2 orders of magnitude more potent than troglitazone in vivo. These data were consistent with the relative in vitro potencies of GW1929 and troglitazone. Isolated perfused pancreas studies performed at the end of the study confirmed that pancreata from vehicle-treated rats showed no increase in insulin secretion in response to a step change in glucose from 3 to 10 mmol/l. In contrast, pancreata from animals treated with GW1929 showed a first- and second-phase insulin secretion pattern. Consistent with the functional data from the perfusion experiments, animals treated with the PPAR-gamma agonist had more normal islet architecture with preserved insulin staining compared with vehicle-treated ZDF rats. This is the first demonstration of in vivo efficacy of a novel nonthiazolidinedione identified as a high-affinity ligand for human PPAR-gamma. The increased potency of GW1929 compared with troglitazone both in vitro and in vivo may translate into improved clinical efficacy when used as monotherapy in type 2 diabetic patients. In addition, the significant improvement in daily meal tolerance may impact cardiovascular risk factor management in these patients.

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)...

In certain pathologic states, cytokine production may become spatially and temporally dysregulated, leading to their inappropriate production and potentially detrimental consequences. Tumor necrosis factor-a (TNF-a), interleukin (IL)-1, lL-6, and transforming growth factor-/I (TGF-/3) mediate a range of host responses affecting multiple cell types. To study the role of cytokines in the early stages of brain injury, we examined alterations in the 17-day-old mouse hippocampus during trimethyltin-induced neurodegeneration characterized by neuronal necrosis, microglia activation in the dentate, and astrocyte reactivity throughout the hippocampus. By 24 h after dosing, elevations in mRNA levels for TNF-a, IL-la, IL-i/I, and IL-6 mRNA were seen. TGF-~3lmRNA was elevated at 72 h. In situ hybridization showed that TNF-a and IL-la were localized to the microglia, whereas TGF-/3i was expressed predominantly in hippocampal pyramidal cells. Intercellular adhesion molecule-i, EB-22, Mac-i, and glial fibrillary acidic protein mRNA levels were elevated within the first 3 days of exposure in the absence of increased inducible nitric oxide synthetase and interferon-y mRNA. These data suggest that pro-inflammatory cytokines contribute to the progression and pattern of neuronal degeneration in the hippocampus.

These data suggest 1) RXR and PPARgamma agonists decrease islet degeneration, cardiovascular risk and cachexia during later stages of diabetes, 2) RXR agonists are less effective than PPARgamma agonists at decreasing serum lipids and causing weight gain and 3) RXR agonists have a more pronounced effect on liver metabolism (e.g. peroxisome accumulation and hepatomegaly) than PPARgamma agonists.