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The development of alcoholic fatty liver is associated with reduced adipocyte-derived adiponectin levels, decreased hepatic adiponectin receptors, and deranged hepatic adiponectin signaling in animals. Peroxisomal proliferator-activated receptor-[gamma] (PPAR-[gamma]) plays a key role in the regulation of adiponectin in adipose tissue. The aim of the present study was to test the ability of rosiglitazone, a known PPAR-[gamma] agonist, to reverse the inhibitory effects of ethanol on adiponectin expression and its hepatic signaling, and to attenuate alcoholic liver steatosis in mice. Mice were fed modified Lieber-DeCarli ethanol-containing liquid diets for 4 wk or pair-fed control diets. Four groups of mice were given a dose of either 3 or l0 mg x kg body [w.sup.-1] x [day.sup.-1] of rosiglitazone with or without ethanol in their diets for the last 2 wk of the feeding study. Coadministration of rosiglitazone and ethanol increased the expression and circulating levels of adiponectin and enhanced the expression of hepatic adiponectin receptors (AdipoRs) in mice. These increases correlated closely with the activation of a hepatic sirtuin 1 (SIRT1)-AMP-activated kinase (AMPK) signaling system. In concordance with stimulated SIRT1-AMPK signaling, rosiglitazone administration enhanced expression of fatty acid oxidation enzymes, normalized lipin 1 expression, and blocked elevated expression of genes encoding lipogenic enzymes which, in turn, led to increased fatty acid oxidation, reduced lipogenesis, and alleviation of steatosis in the livers of ethanol-fed mice. Enhanced hepatic adiponectin-SIRT1-AMPK signaling contributes, at least in part, to the protective action of rosiglitazone against alcoholic fatty liver in mice. lipid metabolism; signal transduction; transcriptional regulators; acetylation doi:10.1152/ajpgi.00456.2009.

We investigated the mechanisms whereby peroxisome proliferator-activated receptor-[gamma], (PPAR[gamma]) agonism affects glucose and lipid metabolism in brown adipose tissue (BAT) by studying the impact of PPAR[gamma] activation on BAT glucose uptake and metabolism, lipogenesis, and mRNA levels plus activities of enzymes involved in triacylglycerol (TAG) synthesis. Interscapular BAT of rats treated or not with rosiglitazone (15 mg x [kg.sup.-1] x [day.sup.-1], 7 days) was evaluated in vivo for glucose uptake and lipogenesis and in vitro for glucose metabolism, gene expression, and activities of glycerolphosphate acyltransferase (GPAT), phosphatidate phosphatase-1 (PAP or lipin-1), and diacylglycerol acyltransferase (DGAT). Rosiglitazone increased BAT mass without affecting whole tissue glucose uptake. BAT glycogen content (-80%), its synthesis from glucose (-50%), and mRNA levels of UDP-glucose pyrophosphorylase (-40%), which generates UDP-linked glucose for glycogen synthesis, were all reduced by rosiglita-zone. In contrast, BAT TAG-glycerol synthesis in vivo and glucose incorporation into TAG-glycerol in vitro were stimulated by the agonist along with the activities and mRNA levels of glycerol 3-phosphate-generating phosphoenolpyruvate carboxykinase and glycerokinase. Furthermore, rosiglitazone markedly increased the activities of GPAT and DGAT but not those of lipin-l-mediated PAP-l, enzymes involved in the sequential acylation of glycerol 3-phosphate and TAG synthesis. Because an adequate supply of fatty acids is essential for BAT nonshivering thermogenesis, the enhanced ability of BAT to synthesize TAG under PPAR[gamma] activation may constitute an important mechanism by which lipid substrates are stored in preparation for an eventual thermogenic activation. glycogen; glycerokinase; phosphoenolpyruvate carboxykinase; glycerolphosphate acyltransferase; lipin; diacylglycerol acyltransferase; peroxisome proliferator-activated receptor-[gamma]

Women with systemic lupus erythematosus (SLE) exhibit a high prevalence of hypertension and renal injury. Rosiglitazone (Rosi), a peroxisome proliferator activator receptor gamma ([PPAR.sub.[gamma]]) agonist, has renal protective and antihypertensive effects. We tested whether Rosi ameliorates hypertension and renal injury in a female mouse model of SLE (NZBWF1). Thirty-week-old SLE and control (NZW/LacJ) mice (n [greater than or equal to] 6/group) were fed Rosi (5 mg x [kg.sup.-1] x [day.sup.-1] in standard chow) or standard chow for 4 wk. SLE mice had increased blood pressure (BP in mmHg) compared with controls (139 [+ or -] 4 vs. 111 [+ or -] 4, P < 0.05). Rosi treatment lowered BP in SLE mice (127 [+ or -] 4, P < 0.05) but not in controls (111 [+ or -] 4). Urinary albumin ([micro]g/mg creatinine) was increased in SLE mice compared with controls (12,396 [+ or -] 6,525 vs. 50 [+ or -] 6) and reduced with Rosi treatment (148 [+ or -] 117). Glomerulosclerosis (% of glomeruli with sclerosis) was reduced in Rosi-treated SLE mice (4.2 [+ or -] 1.6 vs. 0.4 [+ or -] 0.3, P < 0.05). Renal monocyte/ macrophage numbers (cell number/1,320 points counted) were reduced in SLE mice treated with Rosi (32.6 [+ or -] 11.0 vs. 10.6 [+ or -] 3.6, P < 0.05) but unchanged in controls (3.7 [+ or -] 1.6 vs. 3.7 [+ or -] 2.0). Renal osteopontin expression, a cytokine-regulating macrophage recruitment, was reduced in Rosi-treated SLE mice. Urinary endothelin (in pg/mg creatinine) was increased in SLE mice compared with controls (1.9 [+ or -] 0.59 vs. 0.6 [+ or -] 0.04, P < 0.05) and reduced in SLE mice treated with Rosi (0.8 [+ or -] 0.11, P < 0.05). [PPAR.sup.[gamma]]/protein expression in the renal cortex was significantly lower in SLE mice compared with controls and was unaffected by Rosi. These data suggest that Rosi may be an important therapeutic option for the treatment of SLE hypertension and renal injury. lupus; inflammation; endothelin; glomerulosclerosis; proliferator activated receptor gamma

Peroxisome proliferator-activated receptor-[gamma](PPAR-[gamma]) agonists, such as the thiazolidinediones (TZDs), decrease acute inflammation in both pancreatic cell lines and mouse models of acute pancreatitis. Since PPAR-[gamma] agonists have been shown to exert some of their actions independent of PPAR-[gamma] the role of PPAR-[gamma] in pancreatic inflammation has not been directly tested. Furthermore, the differential role of PPAR-[gamma] in endodermal derivatives (acini, ductal cells, and islets) as opposed to the endothelial or inflammatory cells is unknown. To determine whether the effects of a TZD, rosiglitazone, on caerulein-induced acute pancreatitis are dependent on PPAR-[gamma] in the endoderreal derivatives, we created a cell-type specific knock out of PPAR-[gamma] in pancreatic acini, ducts, and islets. PPAR-[gamma] knockout animals show a greater response in some inflammatory genes after caerulein challenge. The anti-inflammatory effect of rosiglitazone on edema, macrophage infiltration, and expression of the proinflammatory cytokines is significantly decreased in pancreata of the knockout animals compared with control animals. However, rosiglitazone retains its effect in the lungs of the pancreatic-specific PPAR-[gamma] knockout animals, likely due to direct anti-inflammatory effect on lung parenchyma. These data show that the PPAR-[gamma] in the pancreatic epithelia and islets is important in suppressing inflammation and is required for the anti-inflammatory effects of TZDs in acute pancreatitis. peroxisome proliferator-activated receptor-[gamma]; caerulein-induced acute pancreatitis; pancreatic epithelial cell-type specific PPAR-[gamma] knockout; proinflammatory cytokines; rosiglitazone doi:10.1152/ajpgi.00056.2007

Dysfunctional cross talk between adipose tissue and liver tissue results in metabolic and inflammatory disorders. As an insulin sensitizer, rosiglitazone (Rosi) improves insulin resistance yet causes increased adipose mass and weight gain in mice and humans. Conjugated linoleic acid (CLA) reduces adipose mass and body weight gain but induces hepatic steatosis in mice. We examined the combined effects of Rosi and CLA on adiposity, insulin sensitivity, and hepatic steatosis in high-fat-fed male C57B1/6 mice. CLA alone suppressed weight gain and adipose mass but caused hepatic steatosis. Addition of Rosi attenuated CLA-induced insulin resistance and dysregulation of adipocytokines. In adipose, CLA significantly suppressed lipoprotein lipase and fatty acid translocase (FAT/CD36) mRNA, suggesting inhibition of fatty acid uptake into adipose; addition of Rosi completely rescued this effect. In addition, CLA alone increased markers of macrophage infiltration, F4/80, and CD68 mRNA levels, without inducing TNF-[alpha] in epididymal adipose tissue. The ratio of Bax to Bcl2, a marker of apoptosis, was significantly increased in adipose of the CLA-alone group and was partially prevented by treatment of Rosi. Immunohistochemistry of F4/80 demonstrates a proinflammatory response induced by CLA in epididymal adipose. In the liver, CLA alone induced microsteatotic liver but surprisingly increased the rate of very-low-density lipoprotein-triglyceride production without inducing inflammatory mediator-TNF-[alpha] and markers of macrophage infiltration. These changes were accompanied by significantly increased mRNA levels of stearoyl-CoA desaturase, FAT/CD36, and fatty acid synthase. The combined administration of CLA and Rosi reduced hepatic liver triglyceride content as well as lipogenic gene expression compared with CLA alone. In summary, dietary CLA prevented weight gain in Rosi-treated mice without attenuating the beneficial effects of Rosi on insulin sensitivity. Rosi ameliorated CLA-induced lipodystrophic disorders that occurred in parallel with rescued expression of adipocytokine and adipocytes-abundant genes. doi:10.1152/ajpgi.00523.2006

Pregnancy decreases baroreflex gain, but the underlying mechanism is unclear. Insulin resistance, which has been associated with reduced transport of insulin into the brain, is a consistent feature of many conditions exhibiting impaired baroreflex gain, including pregnancy. Therefore, using conscious pregnant and nonpregnant rabbits, we tested the novel hypothesis that the pregnancy-induced impairment in baroreflex gain is due to insulin resistance and reduced brain insulin. Baroreflex gain was determined by quantifying changes in heart rate in response to stepwise steady-state changes in arterial pressure, secondary to infusion of nitroprusside and phenylephrine. We found that insulin sensitivity and baroreflex gain were strongly correlated in nonpregnant and term pregnant rabbits ([r.sup.2] = 0.59). The decrease in insulin sensitivity and in baroreflex gain exhibited similar time courses throughout pregnancy, reaching significantly lower levels at 3 wk of gestation and remaining reduced at 4 wk (term is 31 days). Treatment of rabbits with the insulin-sensitizing drug rosiglitazone during pregnancy almost completely normalized baroreflex gain. Finally, pregnancy significantly lowered cerebrospinal fluid insulin concentrations. These data identify insulin resistance as a mechanism underlying pregnancy-induced baroreflex impairment and suggest, for the first time in any condition, that decreased brain insulin concentrations may be the link between reductions in peripheral insulin sensitivity and baroreflex gain. conscious rabbits; rosiglitazone; cerebrospinal fluid; insulin sensitivity doi:10.1152/ajpregu.00614.2006

Obesity and weight gain are characterized by increased adipose tissue mass due to an increase in the size of individual adipocytes and the generation of new adipocytes. New adipocytes are [...]

The detrimental effect of elevated free fatty acids (FFAs) on insulin sensitivity can be improved by thiazolidinediones (TZDs) in patients with type 2 diabetes mellitus. It is unknown whether this salutary action of TZD is associated with altered release of the insulin-mimetic adipocytokine visfatin. In this study, we investigated whether visfatin concentrations are altered by FFA and TZD treatment. In a randomized, double-blind, placebo-controlled, parallel-group study 16 healthy volunteers received an infusion of triglycerides/heparin to increase plasma FFA after 3 wk of treatment with rosiglitazone (8 mg/day, n = 8) or placebo (n = 8), and circulating plasma visfatin was measured. As a corollary, human adipocytes were incubated with synthetic fatty acids and rosiglitazone to assess visfatin release in vitro. The results were that rosiglitazone treatment increased systemic plasma visfatin concentrations from 0.6 [+ or -] 0.1 to 1.7 [+ or -] 0.2 ng/ml (P < 0.01). Lipid infusion caused a marked elevation of plasma FFA but had no effect on circulating visfatin in controls. In contrast, elevated visfatin concentrations in subjects receiving rosiglitazone were normalized by lipid infusion. In isolated adipocytes, visfatin was released into supernatant medium by acute addition and long-term treatment of rosiglitazone. This secretion was blocked by synthetic fatty acids and by inhibition of phosphatidylinositol 3-kinase or Akt. In conclusion, release of the insulin-mimetic visfatin may represent a major mechanism of metabolic TZD action. The presence of FFA antagonizes this action, which may have implications for visfatin bioactivity.

It has been suggested that changes in adiponectin levels may contribute to improved insulin sensitivity in insulin-resistant individuals both after weight loss and after treatment with thiazolidinedione compounds. If this is correct, then changes in total circulating adiponectin and/or distribution of its multimeric complexes should coincide with improvements in insulin sensitivity after both interventions. To address this issue, fasting adiponectin concentrations and distribution of adiponectin complexes were measured in plasma samples in 24 insulin-resistant, nondiabetic subjects before and after 3-4 mo of treatment with either rosiglitazone or caloric restriction. The degree of insulin resistance in each group of 12 subjects was equal at baseline and improved to a similar extent (~30%) after each therapy. Whereas total adiponectin levels increased by nearly threefold and the relative amount of several higher molecular weight adiponectin complexes increased significantly in the rosiglitazone treatment group, there were no discernible changes in adiponectin levels or in the distribution between high or low molecular weight complexes in the weight loss group. These data indicate that, although changes in total adiponectin and several specific adiponectin complexes paralleled improvements in insulin resistance in thiazolidinedione-treated subjects, neither circulating adiponectin concentrations nor multimeric complexes changed in association with enhanced insulin sensitivity after moderate weight loss in 12 insulin-resistant, obese individuals. thiazolidinedione; adiponectin multimers: high molecular weight complexes

The article discusses whether the plans by the pharmaceutical company GlaxoSmithKline (GSK) regarding the unbinding of the RECORD trial for the drug rosiglitazone are appropriate and beneficial or not. Some of the other problems of the RECORD trial are highlighted.

A molecule that coordinates the body's response to low oxygen, HIF1?, may underlie heart failure (Cell Metab. 9, 512-524). Hearts enlarge to compensate for damage such as a heart attack [...]