It is unclear how hepatic adiponectin resistance and sensitivity mediated by the adiponectin receptor, AdipoR2, contributes to the progression of nonalcoholic steatohepatitis (NASH). The aim of this study was to examine the roles of hepatic AdipoR2 in NASH, using an animal model. We fed C57BL/6 mice a methionine-deficient and choline-deficient (

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. Combination therapy with PPAR␥ and PPAR␣ agonists increases glucose-stimulated insulin secretion in db/db mice. Am J Physiol Endocrinol Metab 284: E966-E971, 2003; 10.1152/ ajpendo.00149.2002.-Although peroxisome proliferator-activated receptor (PPAR)␥ agonists ameliorate insulin resistance, they sometimes cause body weight gain, and the effect of PPAR agonists on insulin secretion is unclear. We evaluated the effects of combination therapy with a PPAR␥ agonist, pioglitazone, and a PPAR␣ agonist, bezafibrate, and a dual agonist, KRP-297, for 4 wk in male C57BL/6J mice and db/db mice, and we investigated glucose-stimulated insulin secretion (GSIS) by in situ pancreatic perfusion. Body weight gain in db/db mice was less with KRP-297 treatment than with pioglitazone or pioglitazone ϩ bezafibrate treatment. Plasma glucose, insulin, triglyceride, and nonesterified fatty acid levels were elevated in untreated db/db mice compared with untreated C57BL/6J mice, and these parameters were significantly ameliorated in the PPAR␥ agonist-treated groups. Also, PPAR␥ agonists ameliorated the diminished GSIS and insulin content, and they preserved insulin and GLUT2 staining in db/db mice. GSIS was further increased by PPAR␥ and -␣ agonists. We conclude that combination therapy with PPAR␥ and PPAR␣ agonists may be more useful with respect to body weight and pancreatic GSIS in type 2 diabetes with obesity.peroxisome proliferator-activated receptor; glucose-stimulated insulin secretion; glucolipotoxicity; insulin resistance; type 2 diabetes with obesity PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPAR)␥ agonists have been used for the treatment of type 2 diabetic patients, especially those with obesity, all over the world. They ameliorate insulin resistance of peripheral tissues, such as skeletal muscle, liver, and adipocytes, by various suggested mechanisms. Although some literature has suggested effects of PPAR␥ agonists on the pancreas (13, 32), only a few studies have investigated this issue (23,29,30). Because the expression of PPAR␥ is confirmed not only in rodent (1) but also in human islets (5), an effect of PPAR␥ agonists on the pancreas has been suggested.On the other hand, fibrates are PPAR␣ agonists and have been used for patients with dyslipidemia. Some literature has reported that PPAR␣ agonists also ameliorated insulin resistance (6,7,14,19,24,28,36), but the effect on insulin secretion is unclear. Dual agonists of PPAR␥ and -␣, 25,26) and , have been developed, and their utility for diabetes and/or metabolic syndrome has been suggested. However, studies of combination therapy with a PPAR␥ agonist and a PPAR␣ agonist are rare (2, 21), and their effect on insulin secretion has not been reported.We hypothesized that combination therapy with PPAR␥ and -␣ agonists would be useful for reducing lipotoxicity (10, 20, 37) in type 2 diabetes with obesity by augmenting the lipid-lowering effects. We used the PPAR␥ agonist pioglitazone (PIO), combination therapy with the PPAR␥ agonist PIO and the PPAR␣ agonist bezabibrate (P...

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