Peroxisome proliferator-activated receptor (PPAR)α and PPARγ agonists lower lipid accumulation in muscle and liver by different mechanisms. We investigated whether benefits could be achieved on insulin sensitivity and lipid metabolism by the dual PPARα/γ agonist ragaglitazar in high fat-fed rats. Ragaglitazar completely eliminated high-fat feeding-induced liver triglyceride accumulation and visceral adiposity, like the PPARα agonist Wy-14643 but without causing hepatomegaly. In contrast, the PPARγ agonist rosiglitazone only slightly lessened liver triglyceride without affecting visceral adiposity. Compared with rosiglitazone or Wy-14643, ragaglitazar showed a much greater effect (79%, P< 0.05) to enhance insulin's suppression of hepatic glucose output. Whereas all three PPAR agonists lowered plasma triglyceride levels and lessened muscle long-chain acyl-CoAs, ragaglitazar and rosiglitazone had greater insulin-sensitizing action in muscle than Wy-14643, associated with a threefold increase in plasma adiponectin levels. There was a significant correlation of lipid content and insulin action in liver and particularly muscle with adiponectin levels ( P < 0.01). We conclude that the PPARα/γ agonist ragaglitazar has a therapeutic potential for insulin-resistant states as a PPARγ ligand, with possible involvement of adiponectin. Additionally, it can counteract fatty liver, hepatic insulin resistance, and visceral adiposity generally associated with PPARα activation, but without hepatomegaly.

Chronic treatment with compounds activating peroxisome proliferator-activated receptor (PPAR)␥ and -␣ influences body energy stores, but the underlying mechanisms are only partially known. In a chronic-dosing study, equiefficacious antihyperglycemic doses of the PPAR␥ agonist pioglitazone and PPAR␣/␥ dual activator ragaglitazar were administered to obesity-prone male rats. The PPAR␣ agonist fenofibrate had no effect on insulin sensitivity. Pioglitazone transiently increased and fenofibrate transiently decreased food intake, whereas ragaglitazar had no impact on feeding. As a result, body adiposity increased in pioglitazone-treated rats and decreased in fenofibrate-treated rats. PPAR␥ compounds markedly increased feed efficiency, whereas PPAR␣ agonist treatment decreased feed efficiency. In fenofibrate-treated rats, plasma acetoacetate was significantly elevated. Plasma levels of this potentially anorectic ketone body were unaffected in pioglitazoneand ragaglitazar-treated rats. High-fat feeding markedly increased visceral fat pads, and this was prevented by pioglitazone and ragaglitazar treatment. Pioglitazone treatment enlarged subcutaneous adiposity in high-fatfed rats. In conclusion, PPAR␥ activation increases both food intake and feed efficiency, resulting in net accumulation of subcutaneous body fat. The impact of PPAR␥ activation on feeding and feed efficiency appears to be partially independent because the PPAR␣ component of ragaglitazar completely counteracts the orexigenic actions of PPAR␥ activation without marked impact on feed efficiency. Diabetes 52:2249 -2259, 2003 T he nuclear receptors, peroxisome proliferatoractivated receptors (PPARs), constitute a family of three genes, PPAR␣, -␥, and -␤(␦), all of which are involved in control of energy homeostasis (1,2). Unequivocal evidence of endogenous ligands for PPAR␣ and -␥ is lacking, but a number of synthetic PPAR activating ligands exist, of which hypolipidemic fibric acids are typical examples of PPAR␣ activators while hypoglycemic thiazolidinediones are typical examples of PPAR␥ activators.The antidiabetic effects of PPAR␥ agonists are partly mediated via increased insulin sensitivity of adipose tissue and skeletal muscle. From clinical experience, PPAR␥ agonists are associated with weight gain, whereas PPAR␣ agonists appear body weight neutral (3). Part of the body weight increase may be caused by their oedema-inducing class effect, but activators of PPAR␥ also induce adipogenesis (4,5). They act preferentially on subcutaneous adipocytes, which in comparison to intrabdominal adipocytes express higher levels of PPAR␥ (6). The long-term metabolic consequences of the increased fat accumulation accompanying treatment with PPAR␥ agonists are not fully elucidated. Intrabdominal body fat accumulation is one of several hallmarks typifying the metabolic syndrome and, as such, an independent risk factor of type 2 diabetes (7-9). Many clinical trials of oral antidiabetic agents (including PPAR␥ agonists) are conspicuous by their absence of obese test subjec...

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Peroxisome proliferator-activated receptors (PPARs) are activated by a variety of fatty acids, eicosanoids, and hypolipidemic and insulin-sensitizing drugs. Many of these compounds bind avidly to members of a family of small lipid-binding proteins, the fatty acid-binding proteins (FABPs). Fatty acids are activated to CoA esters, which bind with high affinity to the acyl-CoA-binding protein (ACBP). Thus, the availability of known and potential PPAR ligands may be regulated by lipid-binding proteins. In this report we show by transient transfection of CV-1 cells that coexpression of ACBP and adipocyte lipid-binding protein (ALBP) exerts a ligand-and PPAR subtype-specific attenuation of PPAR-mediated trans -activation, suggesting that lipid-binding proteins, when expressed at high levels, may function as negative regulators of PPAR activation by certain ligands. Expression of ACBP, ALBP, and keratinocyte lipid-binding protein (KLBP) is induced during adipocyte differentiation, a process during which PPAR ␥ plays a prominent role. We present evidence that endogenous ACBP, ALBP, and KLBP not only localize to the cytoplasm but also exhibit a prominent nuclear localization in 3T3-L1 adipocytes. In addition, forced expression of ACBP, ALBP, and KLBP in CV-1 cells resulted in a substantial accumulation of all three proteins in the nucleus.These results suggest that lipid-binding proteins, contrary to the general assumption, may exert their action in the nucleus as well as in the cytoplasm.