Adipose PPARγ Research Articles

Overexpression of Plg-RKT protects against adipose dysfunction and dysregulation of glucose homeostasis in diet-induced obese mice

ABSTRACT The plasminogen receptor, Plg-RKT, is a unique cell surface receptor that is broadly expressed in cells and tissues throughout the body. Plg-RKT localizes plasminogen on cell surfaces and promotes its activation to the broad-spectrum serine protease, plasmin. In this study, we show that overexpression of Plg-RKT protects mice from high fat diet (HFD)-induced adipose and metabolic dysfunction. During the first 10 weeks on the HFD, the body weights of mice that overexpressed Plg-RKT (Plg-RKT-OEX) were lower than those of control mice (CagRosaPlgRKT). After 10 weeks on the HFD, CagRosaPlgRKT and Plg-RKT-OEX mice had similar body weights. However, Plg-RKT-OEX mice showed a more metabolically favourable body composition phenotype. Plg-RKT-OEX mice also showed improved glucose tolerance and increased insulin sensitivity. We found that the improved metabolic functions of Plg-RKT-OEX mice were mechanistically associated with increased energy expenditure and activity, decreased proinflammatory adipose macrophages and decreased inflammation, elevated brown fat thermogenesis, and higher expression of adipose PPARγ and adiponectin. These findings suggest that Plg-RKT signalling promotes healthy adipose function via multiple mechanisms to defend against obesity-associated adverse metabolic phenotypes.

Diet Modifies Pioglitazone's Influence on Hepatic PPARγ-Regulated Mitochondrial Gene Expression.

Pioglitazone (Pio) is a thiazolidinedione (TZD) insulin-sensitizing drug whose effects result predominantly from its modulation of the transcriptional activity of peroxisome proliferator-activated-receptor-gamma (PPARγ). Pio is used to treat human insulin-resistant diabetes and also frequently considered for treatment of nonalcoholic steatohepatitis (NASH). In both settings, Pio's beneficial effects are believed to result primarily from its actions on adipose PPARγ activity, which improves insulin sensitivity and reduces the delivery of fatty acids to the liver. Nevertheless, a recent clinical trial showed variable efficacy of Pio in human NASH. Hepatocytes also express PPARγ, and such expression increases with insulin resistance and in nonalcoholic fatty liver disease (NAFLD). Furthermore, mice that overexpress hepatocellular PPARγ and Pio-treated mice with extrahepatic PPARγ gene disruption develop features of NAFLD. Thus, Pio's direct impact on hepatocellular gene expression might also be a determinant of this drug's ultimate influence on insulin resistance and NAFLD. Previous studies have characterized Pio's PPARγ-dependent effects on hepatic expression of specific adipogenic, lipogenic, and other metabolic genes. However, such transcriptional regulation has not been comprehensively assessed. The studies reported here address that consideration by genome-wide comparisons of Pio's hepatic transcriptional effects in wildtype (WT) and liver-specific PPARγ-knockout (KO) mice given either control or high-fat (HFD) diets. The results identify a large set of hepatic genes for which Pio's liver PPARγ-dependent transcriptional effects are concordant with its effects on RXR-DNA binding in WT mice. These data also show that HFD modifies Pio's influence on a subset of such transcriptional regulation. Finally, our findings reveal a broader influence of Pio on PPARγ-dependent hepatic expression of nuclear genes encoding mitochondrial proteins than previously recognized. Taken together, these studies provide new insights about the tissue-specific mechanisms by which Pio affects hepatic gene expression and the broad scope of this drug's influence on such regulation.

Prorenin receptor regulates lipid metabolism via distinct actions on PPARγ and SREBP‐2 in liver of male mice

Introduction and objectivesThe epidemic of obesity is currently affecting more than 35% of the population in the United States. Non‐alcoholic fatty liver disease (NAFLD) is strongly associated with obesity and metabolic syndrome. Our laboratory previously demonstrated that adipose prorenin receptor (PRR) KO mice developed lipodystrophy and liver steatosis associated with elevated hepatic triglycerides (TG) levels. Interestingly, hepatic PRR and PPARγ expression were up‐regulated in HF‐fed adipose PRR KO mice. Since body of evidence indicated that PPARγ becomes elevated in fatty livers and since we showed that PRR regulated PPARγ in adipose, we sought to investigate whether PRR regulated TG contents in liver through a PPARγ‐dependent mechanism.Methods and resultsPRR floxed male mice fed a standard diet were injected with a single dose of an adeno‐associated virus thyroxine‐binding globulin Cre (Liver PRR KO, n=5) or saline (Veh, n=6). Body weights were measured weekly for 3 weeks. The deletion of PRR in liver did not change body weight curves. Hepatic levels of TG were significantly decreased in liver PRR KO mice compared with control mice injected with saline (Veh, 53.22 ± 15.4 mg/g liver; AAV, 10.79 ± 1.61 mg/g liver, P<0.05). The deletion of PRR induced a significant decrease of PPARγ gene expression whereas SREBP‐1c expression was unchanged suggesting that PRR regulated TG contents through a PPARγ‐dependent mechanism. Surprisingly, liver weights were significantly higher in liver PRR KO mice compared to control mice injected with saline (Veh, 1.82 ± 0.12 g; Liver PRR KO, 2.37 ± 0.08g, P<0.05). Plasma cholesterol levels (Veh, 143 ± 10 mg/dL; Liver PRR KO, 383 ± 14g mg/dL, P<0.05) and hepatic total cholesterol levels (Veh, 3.64 ± 0.09 mg/g liver; Liver PRR KO, 10.47 ± 0.55 mg/g liver) were elevated in liver PRR KO mice. Interestingly, the increase in total cholesterol content in liver was associated with an increase in SREBP‐2 and HMGCoA‐reductase gene expression suggesting that the deletion of PRR stimulated cholesterol synthesis. Additionally, ABCG5 gene expression was increased, reflecting an increased cholesterol efflux.ConclusionTaken together our results demonstrated for the first time that PRR is an important modulator of lipid metabolism in liver. In agreement with our hypothesis, hepatic PRR positively regulated TG contents through a PPARγ‐dependent mechanism. Interestingly, the deletion of hepatic PRR stimulates cholesterol synthesis via SREBP‐2 up‐regulation indicating that PRR acts at the crossroad between triglycerides and cholesterol metabolism.Support or Funding Information COBRE ‐ P20 GM103527 American Heart Association ‐ 13SDG17230008 University of Kentucky, Center for Clinical and Translational Sciences, CCTS pilot grant, CCTS small grant, NIH T32HL091812 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Gestational diabetes mellitus is associated with decreased adipose and placenta peroxisome proliferator-activator receptor γ expression in a Chinese population.

Peroxisome proliferator-activated receptors γ (PPARγ) is a member of nuclear receptor superfamily, and studies have demonstrated that dysregulation of PPARγ was associated with gestational diabetes mellitus (GDM), which is one of the most common metabolic abnormalities occurring during pregnancy. However, the results regarding the associations between PPARγ and GDM were conflicting among different studies. The present study aimed to determine the expression of PPARγ in adipose and placenta from GDM women in a Chinese population and to further explore the role of PPARγ in GDM women. The adipose and placenta tissues were isolated from GDM women and healthy pregnant women at term. The mRNA and protein expressions of PPARγ in adipose and placenta tissues were determined by qRT-PCR and western blot, respectively. Univariate correlation analysis was used to analyze the relationship between PPARγ expression and clinical characteristics of patients. The levels of tryglycerides and HbA1c were significantly higher, while the levels of low density lipoprotein (LDL) cholesterol, adiponectin and insulin were significantly lower in the GDM women than that in the healthy pregnant women. The mRNA and protein expression of PPARγ in both adipose and placenta from GDM women were significantly lower than that from healthy pregnant women. PPARγ mRNA expression in both adipose and placenta positively correlated with LDL cholesterol and adiponectin levels, and negatively correlated with tryglycerides and glucose levels at 0 h, 1 h and 2 h of 75 g oral glucose tolerance test. In summary, our results suggest that PPARγ may be a key modulator in the development of GDM, due to the roles of PPARγ in glucose homeostasis and adipose tissue development and function.

Vitamin D deficiency impairs glucose-stimulated insulin secretion and increases insulin resistance by reducing PPAR-γ expression in nonobese Type 2 diabetic rats

Human studies have provided relatively strong associations of poor vitamin D status with Type 2 diabetes but do not explain the nature of the association. Here, we explored the physiological pathways that may explain how vitamin D status modulates energy, lipid and glucose metabolisms in nonobese Type 2 diabetic rats. Goto-Kakizaki (GK) rats were fed high-fat diets containing 25 (VD-low), 1000 (VD-normal) or 10,000 (VD-high) cholecalciferol-IU/kg diet for 8 weeks. Energy expenditure, insulin resistance, insulin secretory capacity and lipid metabolism were measured. Serum 25-OH-D levels, an index of vitamin D status, increased dose dependently with dietary vitamin D. VD-low resulted in less fat oxidation without a significant difference in energy expenditure and less lean body mass in the abdomen and legs comparison to the VD-normal group. In comparison to VD-low, VD-normal had lower serum triglycerides and intracellular fat accumulation in the liver and skeletal muscles which was associated with down-regulation of the mRNA expressions of sterol regulatory element binding protein-1c and fatty acid synthase and up-regulation of gene expressions of peroxisome proliferator-activated receptors (PPAR)-α and carnitine palmitoyltransferase-1. In euglycemic hyperinsulinemic clamp, whole-body and hepatic insulin resistance was exacerbated in the VD-low group but not in the VD-normal group, possibly through decreasing hepatic insulin signaling and PPAR-γ expression in the adipocytes. In 3T3-L1 adipocytes 1,25-(OH)2-D (10 nM) increased triglyceride accumulation by elevating PPAR-γ expression and treatment with a PPAR-γ antagonist blocked the triglyceride deposition induced by 1,25-(OH)2-D treatment. VD-low impaired glucose-stimulated insulin secretion in hyperglycemic clamp and decreased β-cell mass by decreasing β-cell proliferation. In conclusion, vitamin D deficiency resulted in the dysregulation of glucose metabolism in GK rats by simultaneously increasing insulin resistance by decreasing adipose PPAR-γ expression and deteriorating β-cell function and mass.

Black elderberry extract attenuates inflammation and metabolic dysfunction in diet-induced obese mice.

Dietary anthocyanins have been shown to reduce inflammation in animal models and may ameliorate obesity-related complications. Black elderberry is one of the richest sources of anthocyanins. We investigated the metabolic effects of anthocyanin-rich black elderberry extract (BEE) in a diet-induced obese C57BL/6J mouse model. Mice were fed either a low-fat diet (n 8), high-fat lard-based diet (HFD; n 16), HFD+0·25 % (w/w) BEE (0·25 %-BEE; n 16) or HFD+1·25 % BEE (1·25 %-BEE; n 16) for 16 weeks. The 0·25 % BEE (0·034 % anthocyanin, w/w) and 1·25 % BEE (0·17 % anthocyanin, w/w) diets corresponded to estimated anthocyanin doses of 20-40 mg and 100-200 mg per kg of body weight, respectively. After 16 weeks, both BEE groups had significantly lower liver weights, serum TAG, homoeostasis model assessment and serum monocyte chemoattractant protein-1 compared with HFD. The 0·25 %-BEE also had lower serum insulin and TNFα compared with HFD. Hepatic fatty acid synthase mRNA was lower in both BEE groups, whereas PPARγ2 mRNA and liver cholesterol were lower in 1·25 %-BEE, suggesting decreased hepatic lipid synthesis. Higher adipose PPARγ mRNA, transforming growth factor β mRNA and adipose tissue histology suggested a pro-fibrogenic phenotype that was less inflammatory in 1·25 %-BEE. Skeletal muscle mRNA expression of the myokine IL-6 was higher in 0·25 %-BEE relative to HFD. These results suggest that BEE may have improved some metabolic disturbances present in this mouse model of obesity by lowering serum TAG, inflammatory markers and insulin resistance.

Reciprocal Regulation of Hepatic and Adipose Lipogenesis by Liver X Receptors in Obesity and Insulin Resistance

Liver X receptors (LXRs) regulate lipogenesis and inflammation, but their contribution to the metabolic syndrome is unclear. We show that LXRs modulate key aspects of the metabolic syndrome in mice. LXRαβ-deficient-ob/ob (LOKO) mice remain obese but show reduced hepatic steatosis and improved insulin sensitivity compared to ob/ob mice. Impaired hepatic lipogenesis in LOKO mice is accompanied by reciprocal increases in adipose lipid storage, reflecting tissue-selective effects on the SREBP, PPARγ, and ChREBP lipogenic pathways. LXRs are essential for obesity-driven SREBP-1c and ChREBP activity in liver, but not fat. Furthermore, loss of LXRs in obesity promotes adipose PPARγ and ChREBP-β activity, leading to improved insulin sensitivity. LOKO mice also exhibit defects in β cell mass and proliferation despite improved insulin sensitivity. Our data suggest that sterol sensing by LXRs in obesity is critically linked with lipid and glucose homeostasis and provide insight into the complex relationships between LXR and insulin signaling.

INTERLEUKIN‐10 DEFICIENCY LIMITS THE DEVELOPMENT OF OBESITY AND INSULIN RESISTANCE PRODUCED BY A HIGH FAT DIET

The goal of this study was to test the hypothesis that deficiency of immune‐regulating cytokine interleukin‐10 (IL‐10) promotes the development of obesity and insulin resistance. Male C57BL/6 (wild‐type, WT) and IL‐10 deficient (IL‐10−/−) mice were fed either 10% (control) or 60% kcal high fat diet (HFD) for 36 wks. A HFD produced obesity and increased adiposity in both WT and IL‐10−/− mice, however the increases were markedly less (P<0.05) in IL‐10−/−. In addition, the increase in adipocyte size with HFD was less in IL‐10−/− mice as compared to WT. A HFD was associated with the development of insulin resistance in WT mice but not IL‐10−/− mice (eg, glucose levels in WT HFD and IL‐10−/− HFD were 187±47 and 70±44 mg/dl at 120 min following a glucose challenge, respectively). Fasting plasma insulin levels were also higher in WT HFD compared to IL‐10−/− HFD mice (2.6±0.9 vs. 1.0±0.3 ng/ml, respectively). Expression of GLUT4, IRS‐1 and PPARγ in adipose was reduced to a similar extent in response to a HFD in both WT and IL‐10−/− mice. GLUT4 and IRS‐1 expression in skeletal muscle was unaffected by genotype and HFD. Contrary to our hypothesis, these data suggest that IL‐10 contributes to insulin resistance and adiposity produced by a HFD. NIH HL‐089884 & HL‐107632.

Activation of peroxisome proliferator-activated receptor-γ by rosiglitazone improves lipid homeostasis at the adipose tissue-liver axis in ethanol-fed mice.

The development of alcohol-induced fatty liver is associated with a reduction of white adipose tissue (WAT). Peroxisome proliferator-activated receptor (PPAR)-γ prominently distributes in the WAT and plays a crucial role in maintaining adiposity. The present study investigated the effects of PPAR-γ activation by rosiglitazone on lipid homeostasis at the adipose tissue-liver axis. Adult C57BL/6 male mice were pair fed liquid diet containing ethanol or isocaloric maltose dextrin for 8 wk with or without rosiglitazone supplementation to ethanol-fed mice for the last 3 wk. Ethanol exposure downregulated adipose PPAR-γ gene and reduced the WAT mass in association with induction of inflammation, which was attenuated by rosiglitazone. Ethanol exposure stimulated lipolysis but reduced fatty acid uptake capacity in association with dysregulation of lipid metabolism genes. Rosiglitazone normalized adipose gene expression and corrected ethanol-induced lipid dyshomeostasis. Ethanol exposure induced steatosis and upregulated inflammatory genes in the liver, which were attenuated by rosiglitazone. Hepatic peroxisomal fatty acid β-oxidation was suppressed by ethanol in associated with inhibition of acyl-coenzyme A oxidase 1. Rosiglitazone elevated plasma adiponectin level and normalized peroxisomal fatty acid β-oxidation rate. However, rosiglitazone did not affect ethanol-reduced very low-density lipoprotein secretion from the liver. These results demonstrated that activation of PPAR-γ by rosiglitazone reverses ethanol-induced adipose dysfunction and lipid dyshomeostasis at the WAT-liver axis, thereby abrogating alcoholic fatty liver.

Effects of conjugated linoleic acid, fish oil and soybean oil on PPARs (α & γ) mRNA expression in broiler chickens and their relation to body fat deposits.

An experiment was conducted on broiler chickens to study the effects of different dietary fats (Conjugated linoleic acid (CLA), fish oil, soybean oil, or their mixtures, as well as palm oil, as a more saturated fat), with a as fed dose of 7% for single fat and 3.5 + 3.5% for the mixtures, on Peroxisome Proliferator-Activated Receptors (PPARs) gene expression and its relation with body fat deposits. The CLA used in this experiment was CLA LUTA60 which contained 60% CLA, so 7% and 3.5% dietary inclusions of CLA LUTA60 were equal to 4.2% and 2.1% CLA, respectively. Higher abdominal fat pad was found in broiler chickens fed with a diet containing palm oil compared to chickens in the other experimental groups (P ≤ 0.05). The diets containing CLA resulted in an increased fat deposition in the liver of broiler chickens (P ≤ 0.05). The only exception was related to the birds fed with diets containing palm oil or fish oil + soybean oil, where contents of liver fat were compared to the CLA + fish oil treatment. PPARγ gene in adipose tissue of chickens fed with palm oil diet was up-regulated compared to other treatments (P ≤ 0.001), whereas no significant differences were found in adipose PPARγ gene expression between chickens fed with diets containing CLA, fish oil, soybean oil or the mixture of these fats. On the other hand, the PPARα gene expression in liver tissue was up-regulated in response to the dietary fish oil inclusion and the differences were also significant for both fish oil and CLA + fish oil diets compared to the diets with palm oil, soybean oil or CLA as the only oil source (P ≤ 0.001). In conclusion, the results of present study showed that there was a relationship between the adipose PPARγ gene up-regulation and abdominal fat pad deposition for birds fed with palm oil diet, while no deference was detected in n-3 and n-6 fatty acids, as well as CLA on PPARγ down regulation in comparison to a more saturated fat. When used on its own, fish oil was found to be a more effective fat in up-regulating hepatic PPARα gene expression and this effect was related to a less fat deposition in liver tissue. A negative correlation coefficient (−0.3) between PPARα relative gene expression and liver tissue fat content confirm the anti-lipogenic effect of PPARα, however, the change in these parameters was not completely parallel.

Azilsartan treatment improves insulin sensitivity in obese spontaneously hypertensive Koletsky rats

Hypertension often coexists with insulin resistance. However, most metabolic effects of the antihypertensive agents have been investigated in nomotensive animals, in which different conclusions may arise. We investigated the metabolic effects of the new angiotensin II type 1 receptor blocker azilsartan using the obese Koletsky rats superimposed on the background of the spontaneously hypertensive rats. Male Koletsky rats were treated with azilsartan (2 mg/kg/day) over 3 weeks. Blood pressure was measured by tail-cuff. Blood biochemical and hormonal parameters were determined by enzymatic or ELISA methods. Gene expression was assessed by RT-PCR. In Koletsky rats, azilsartan treatment lowered blood pressure, basal plasma insulin concentration and the homeostasis model assessment of insulin resistance index, and inhibited over-increase of plasma glucose and insulin concentrations during oral glucose tolerance test. These effects were accompanied by decreases in both food intake and body weight (BW) increase. Although two treatments showed the same effect on BW gain, insulin sensitivity was higher after azilsartan treatment than pair-feeding. Azilsartan neither affected plasma concentrations of triglyceride and free fatty acids, nor increased adipose mRNA levels of peroxisome proliferator-activated receptor (PPAR)γ and its target genes such as adiponectin, aP2. In addition, azilsartan downregulated 11β-hydroxysteroid dehydrogenase type 1 expression. These results show the insulin-sensitizing effect of azilsartan in obese Koletsky rats. This effect is independent of decreases in food intake and BW increase or of the activation of adipose PPARγ. Our findings indicate the possible usefulness of azilsartan in the treatment of metabolic syndrome.

17β-Estradiol inhibition of PPARγ-induced adipogenesis and adipocyte-specific gene expression

To investigate the molecular interaction of peroxisome proliferator-activated receptor γ (PPARγ) with 17β-estradiol (E) in the regulation of adipogenesis. Female ovariectomized (OVX) mice and differentiated 3T3-L1 adipocytes were treated with combinations of the PPARγ agonist troglitazone or E, and the variables and determinants of adipogenesis were measured using in vivo and in vitro approaches. Troglitazone (250 mg·kg(-1)·d(-1) for 13 weeks) decreased the size of adipocytes without the change in white adipose tissue (WAT) mass and increased the expression of adipocyte-specific genes, such as PPARγ, adipocyte fatty acid binding protein, and lipoprotein lipase, compared with OVX control mice. E (0.05 mg/pellet, sc implanted) significantly reduced WAT mass, adipocyte size, and adipose marker gene expression. When mice were concomitantly treated with troglitazone and E, E blunted the effects of troglitazone on WAT mass, adipocyte size, and adipose PPARγ target gene expression. Consistent with the in vivo data, E (10 μmol/L) treatment inhibited lipid accumulation and the expression of adipocyte-specific genes caused by troglitazone (10 μmol/L) in 3T3-L1 cells. E (10 μmol/L) also decreased troglitazone-induced PPARγ reporter activity through both estrogen receptor (ER) α and ERβ. Mechanistic studies indicated that E (0.1 μmol/L) decreased the DNA binding of PPARγ induced by troglitazone (1 μmol/L) and inhibited the recruitment of the PPARγ coactivator CREB-binding protein. These results suggest that in vivo and in vitro treatment of E interferes with the actions of PPARγ on adipogenesis by down-regulating adipogenesis-related genes, which are mediated through the inhibition of PPARγ coactivator recruitment. In addition, it is likely that the activities of PPARγ activators may be enhanced in estrogen-deficient states.

Eriobotrya japonica improves hyperlipidemia and reverses insulin resistance in high‐fat‐fed mice

The effect of Eriobotrya japonica Lindl. (loquat) on insulin resistance was examined in mice fed a high-fat (HF) diet. First, the mice were divided randomly into two groups: the control (CON) group was fed a low-fat diet, whereas the experimental group was fed with a 45% HF diet for 10 weeks. After 6 weeks of induction, the HF group was subdivided into five groups and was given orally loquat or not for 4 weeks afterward. It was demonstrated that loquat was effective in ameliorating the HF diet-induced hyperglycemia, hyperleptinemia, hyperinsulinemia and hypertriglyceridemia, as well as in decreasing the levels of free fatty acid (FFA), but increasing the adipose PPARγ (peroxisomal proliferator-activated receptor γ) and hepatic PPARα mRNA levels. Loquat significantly decreased the body weight gain, weights of white adipose tissue and visceral fat accompanying the suppressed leptin mRNA levels. Loquat not only suppressed the hepatic mRNA levels of enzymes involved in fatty acid and triacylglycerol synthesis and lowered the sterol regulatory element binding protein-1c (SREBP-1c) mRNA level, but also affected fatty acid oxidation enzyme levels. These regulations may contribute to triacylglycerol accumulation in white adipose tissue. The findings provide a nutritional basis for the use of loquat as a functional food factor that may have benefits for the prevention of hyperlipidemia and diabetes.

Differential effects of high MUFA with high or low P/S ratio (polyunsaturated to saturated fatty acids) on improving hepatic lipolytic enzymes and mediating PPARγ related with lipoprotein lipase and hormone-sensitive lipase of white adipose tissue in diet-induced obese hamster

The aim of this study was to assess the relationship between high monounsaturated fatty acids (MUFAs) with different levels of polyunsaturated-to-saturated fatty acid (P/S) ratios and body fat loss in diet-induced obesity (DIO) models. Male Golden Syrian hamsters were randomly assigned to the control group (n=12) and obesity group (n=24) for 4 weeks of the high-fat DIO period; afterward, six hamsters from each group were killed. The remaining control hamsters were still fed a low-fat diet. For an additional 8 weeks, the remaining obesity hamsters were switched to a low-fat diet and subdivided into three subgroups (n=6/group): the obesity-control (ObC) group, high MUFA with high P/S ratio oil (HMHR) group and olive oil (OO) group. Serum insulin and leptin concentrations were measured, and hepatic fatty acid metabolic enzymes and adipose differentiation markers were determined using enzyme activities analysis, western blot and semiquantification reverse-transcription PCR. No difference was observed in the mean energy intake through all study periods. After the DIO period, the obesity group increased in weight gain and epididymal fat weight compared with the control group. DIO hamsters in the HMLR group had significant reductions in white adipose tissue deposition and plasma leptin levels, suppression in adipose peroxisome proliferator-activated receptor-γ (PPARγ) and lipoprotein lipase (LPL) mRNA expressions and increases in hepatic acyl-CoA oxidase and carnitine palmitoyltransferase-I activities and mRNA levels compared with those in the ObC group. The HMHR group had upregulated phosphorylation of hormone-sensitive lipase (HSL) relative to total HSL protein levels compared with the OO group. However, the OO group had significantly elevated hepatic de novo lipogenesis compared with the HMHR group. HMHR seemed to be beneficial in depleting white adipose tissue accumulation by decreasing adipose PPARγ and LPL mRNA expressions and mediating phosphorylation of HSL, and by improving hepatic lipolytic enzyme activities and mRNA expressions involved in β-oxidation in DIO hamsters.

Effects of Momordica charantia on insulin resistance and visceral obesity in mice on high-fat diet

We examined the preventive effect of Momordica charantia L. fruit (bitter melon) on hyperglycemia and insulin resistance in C57BL/6J mice fed with a high-fat (HF) diet. Firstly, mice were divided randomly into two groups: the control group was fed low-fat (LF) diet, whereas the experimental group was fed with a 45% HF diet last for 12 weeks. After 8 week of induction, the HF group was subdivided into six groups and was given orally with or without M. charantia or rosiglitazone 4 weeks afterward. We demonstrated that bitter melon was effective in ameliorating the HF diet-induced hyperglycemia, hyperleptinemia, and decreased the levels of blood glycated hemoglobin (HbA1c) and free fatty acid (FFA) ( P < 0.01, P < 0.05, P < 0.05, respectively), whereas increased the adipose PPARγ and liver PPARα mRNA levels. Additionally, bitter melon significantly decreased the weights of epididymal white adipose tissue and visceral fat, and decreased the adipose leptin and resistin mRNA levels. It is tempting to speculate that at least a portion of bitter melon effects is due to be through PPARγ-mediated pathways, resulting in lowering glucose levels and improving insulin resistance, and partly be through PPARα-mediated pathways to improve plasma lipid profiles. This is the first report demonstrating that bitter melon, is a food factor, but not a medicine, itself could influence dual PPARα/PPARγ expression and the mediated gene expression, is effective in ameliorating insulin resistance and visceral obesity.

RNA interference of PPARγ using fiber-modified adenovirus vector efficiently suppresses preadipocyte-to-adipocyte differentiation in 3T3-L1 cells

The peroxisome proliferator-activated receptor (PPAR) γ is regarded as a “master regulator” of adipocyte differentiation and is abundantly expressed in adipose. To understand the biological role of PPARγ in adipose, RNA interference (RNAi) of PPARγ should be a powerful tool. 3T3-L1 cell line serves an excellent model to investigate the mechanism of preadipocyte-to-adipocyte differentiation. However, this cell line is difficult to transfect by plasmid vectors and viral vectors. We optimized the transduction of both 3T3-L1 preadipocytes and adipocytes by means of fiber-modified adenovirus (Ad) vectors. Among the various vectors tested, polylysine modification of the C-terminal of the fiber knob most markedly improved the transduction efficiency in both 3T3-L1 preadipocytes and adipocytes. Then, we examined whether fiber-modified Ad vectors with polylysine peptides expressing the small interfering RNA (siRNA) for PPARγ inhibit the differentiation of 3T3-L1 preadipocytes into adipocytes. Oil red O staining and measurement of glycerol-3-phosphate dehydrogenase (GPDH) activity indicated that the vectors effectively suppressed the differentiation of 3T3-L1 preadipocytes to adipocytes. These results suggested that the combination of fiber-modified Ad vectors containing polylysine peptides and RNAi is an effective tool for the study of the biological and physiological mechanism of adipogenesis in adiposity and diabetes using 3T3-L1 models. Ad vector-mediated RNAi for PPARγ should also be useful to clarify the biological role of the PPARγ pathway in various tissues in addition to adipose and for therapeutic application to a variety of diseases, including adiposity and diabetes.

PPARγ-mediated insulin sensitization: the importance of fat versus muscle

Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a nuclear hormone receptor that functions as a transcriptional regulator in a variety of tissues. PPARgamma activation, e.g., through binding of the synthetic glitazones or thiazolidinediones (TZD), results in a marked improvement in type 2 diabetic patients of insulin and glucose parameters resulting from an improvement of whole body insulin sensitivity. The role of different metabolic tissues (fat, skeletal muscle, liver) in mediating PPARgamma function in glucose and insulin homeostasis is still unclear. Recently, the function of PPARgamma in adipose tissue and skeletal muscle has been intensively characterized by using targeted deletion of PPARgamma in those tissues. In those studies, adipose PPARgamma has been identified as an essential mediator for the maintainance of whole body insulin sensitivity. Two major mechanisms have been described. 1) Adipose PPARgamma protects nonadipose tissue against excessive lipid overload and maintains normal organ function (liver, skeletal muscle); and 2) adipose PPARgamma guarantees a balanced and adequate production of secretion from adipose tissue of adipocytokines such as adiponectin and leptin, which are important mediators of insulin action in peripheral tissues. In contrast to studies in adipose-specific PPARgamma-deficient mice, the data in muscle-specific PPARgamma(-/-) mice demonstrate that whole body insulin sensitivity is, at least in part, relying on an intact PPARgamma system in skeletal muscle. Finally, these early and elegant studies using tissue-specific PPARgamma knockout mouse models pinpoint adipose tissue as the major target of TZD-mediated improvement of hyperlipidemia and insulin sensitization.

Expression of the chicken peroxisome proliferator-activated receptor-γ gene is influenced by aging, nutrition, and agonist administration

Peroxisome proliferatior-activated receptor-γ (PPARγ) is a transcription factor that modulates lipid and glucose metabolism in mammals. The aim of the present study was to investigate whether chicken PPARγ is expressed in tissues in a similar manner to mammalian PPAR and whether it is involved in the regulation of lipid metabolism, particularly in the regulation of fat accumulation in adipose tissue and ovaries. In 30-wk-old chickens, PPARγ mRNA was detected in most tissues that were examined. Of those tissues expressing chicken PPARγ mRNA, the lowest expression levels were found in adipose tissue, the tissue that in mammals was shown to express the highest levels of PPARγ mRNA. Chicken PPARγ mRNA expression in abdominal adipose tissue tended to increase with age, as shown by higher expression levels at 6 wk than at 1 and 2 wk of age. With regard to nutritional modulation, PPARγ mRNA levels in abdominal adipose tissue were significantly higher in broiler chickens fed for 7 d a diet containing 8% safflower oil (18:2-rich) or linseed oil (18:3-rich) compared with chickens fed a diet containing olive oil (18:1-rich). In contrast, feeding a 3% cholesterol-supplemented diet for 7 d resulted in no changes to adipose PPARγ mRNA expression. In broiler chickens orally administered troglitazone, a PPARγ ligand, abdominal fat pad weight and PPARγ and lipoprotein lipase (LPL) mRNA levels were significantly increased relative to those of control chickens. Levels of PPARγ mRNA in liver, skeletal muscle, and ovaries were increased with the onset of egg laying, whereas in adipose tissue the level of PPARγ mRNA was decreased. These findings suggest that PPARγ plays an important role in the regulation of fat deposition and egg production and the characteristic pattern of PPARγ mRNA expression may be indicative of specific differences in the lipid and glucose metabolism of chickens compared with mammals.

Effect of reduced maternal protein consumption during pregnancy in the rat on plasma lipid concentrations and expression of peroxisomal proliferator–activated receptors in the liver and adipose tissue of the offspring

The effect of protein consumption during pregnancy on peroxisomal proliferator-activated receptor (PPAR) expression and plasma lipid concentrations in the offspring were determined in the rat. Rats were fed isocaloric diets containing either 18% (w/w) (control) or 9% (w/w) casein throughout pregnancy, and chow during lactation. Maternal protein intake did not alter fetal hepatic PPARα and γ expression at 20/21 days gestation ( n = 5/group). Liver PPARα expression was 69% greater ( P < 0.0001) in the 9% group, whereas PPARγ was not altered, in the offspring 6 days after weaning ( n = 5/group). Adipose PPARγ expression was 59% lower ( P < 0.01) in the 9% group after weaning. This was accompanied by an increase (35%, P < 0.02) in plasma triacylglycerol and nonesterified fatty acid concentrations (55%, ( P < 0.01) in the 9% group after weaning. These data show that maternal protein intake during pregnancy alters the regulation of PPAR expression, which represents a potential mechanism to explain impaired lipid homeostasis in the offspring.