Skeletal Muscle PPARδ Research Articles

Fimasartan Ameliorates Deteriorations in Glucose Metabolism in a High Glucose State by Regulating Skeletal Muscle and Liver Cells.

PurposeSince diabetes and hypertension frequently occur together, it is thought that these conditions may have a common pathogenesis. This study was designed to evaluate the anti-diabetic function of the anti-hypertensive drug fimasartan on C2C12 mouse skeletal muscle and HepG2 human liver cells in a high glucose state.Materials and MethodsThe anti-diabetic effects and mechanism of fimasartan were identified using Western blot, glucose uptake tests, oxygen consumption rate (OCR) analysis, adenosine 5′-triphosphate (ATP) enzyme-linked immunosorbent assay (ELISA), and immunofluorescence staining for diabetic biomarkers in C2C12 cells. Protein biomarkers for glycogenolysis and glycogenesis were evaluated by Western blotting and ELISA in HepG2 cells.ResultsThe protein levels of phosphorylated 5′ adenosine monophosphate-activated protein kinase (p-AMPK), p-AKT, insulin receptor substrate-1 (IRS-1), and glucose transporter type 4 (Glut4) were elevated in C2C12 cells treated with fimasartan. These increases were reversed by peroxisome proliferator-activated receptor delta (PPARδ) antagonist. ATP, OCR, and glucose uptake were increased in cells treated with 200 µM fimasartan. Protein levels of glycogen phosphorylase, glucose synthase, phosphorylated glycogen synthase, and glycogen synthase kinase-3 (GSK-3) were decreased in HepG2 cells treated with fimasartan. However, these effects were reversed following the addition of the PPARδ antagonist GSK0660.ConclusionIn conclusion, fimasartan ameliorates deteriorations in glucose metabolism as a result of a high glucose state by regulating PPARδ in skeletal muscle and liver cells.

Production of Functional Peptide with Anti-obesity Effect from Defatted Tenebrio molitor Larvae Using Proteolytic Enzyme

This study was conducted to investigate the anti-obesity effect of peptides derived from defatted mealworm (Tenebrio molitor larvae) and to determine the expression level of obesity-related membrane-associated proteins in the rat muscle. The production of functional peptide was produced by hydrolysis of mealworm protein using commercial enzymes. To evaluate anti-obesity effects through animal feeding experiments, a total of thirty-two rats were randomly divided into control diet (CD), 5% mealworm peptide supplemented control diet (CT), high-fat diet (HD), and 5% mealworm peptide supplemented high-fat diet group (HT). The weight loss of HT was confirmed by mealworm peptides feeding. The weights of fat tissues (perirenal and epididymal) of HT were significantly decreased, however, soleus muscle weight of HT was significantly increased compared to those of the HD, respectively. The expression levels of obesity-related membrane-associated proteins (FABPpm, PGC-1α, and PPAR) in HT group involved in fatty acid transport and utilization were significantly higher than that of the HD. From these results, mealworm peptide supplement showed an anti-obesity effect by stimulation of FABPpm, PGC-1α, and PPAR-δ in skeletal muscle and then showed an increase in muscle weight along with body weight loss in HT group.

Increase in muscle endurance in mice by dietary Yamabushitake mushroom (Hericium erinaceus) possibly via activation of PPARδ.

Skeletal muscle fiber is largely classified into two types: type 1 (slow‐twitch) and type 2 (fast‐twitch) fibers. Meat quality and composition of fiber types are thought to be closely related. Previous research showed that overexpression of constitutively active peroxisome proliferator‐activated receptor (PPAR)δ, a nuclear receptor present in skeletal muscle, increased type 1 fibers in mice. In this study, we found that hexane extracts of Yamabushitake mushroom (Hericium erinaceus) showed PPARδ agonistic activity in vitro. Eight‐week‐old C57BL/6J mice were fed a diet supplemented with 5% (w/w) freeze‐dried Yamabushitake mushroom for 24 hr. After the treatment period, the extensor digitorum longus (EDL) muscles were excised. The Yamabushitake‐supplemented diet up‐regulated the PPARδ target genes Pdk4 and Ucp3 in mouse skeletal muscles in vivo. Furthermore, feeding the Yamabushitake‐supplemented diet to mice for 8 weeks resulted in a significant increase in muscle endurance. These results indicate that Yamabushitake mushroom contains PPARδ agonistic ligands and that dietary intake of Yamabushitake mushroom could activate PPARδ in skeletal muscle of mice. Unexpectedly, we observed no significant alterations in composition of muscle fiber types between the mice fed control and Yamabushitake‐supplemented diets.

Estrogen and voluntary exercise attenuate cardiometabolic syndrome and hepatic steatosis in ovariectomized rats fed a high-fat high-fructose diet.

The prevalence of cardiometabolic syndrome (CMS) is increased in women after menopause. While hormone replacement therapy has been prescribed to relieve several components of CMS in postmenopausal women, some aspects of cardiometabolic dysfunction cannot be completely restored. The present study examined the effectiveness of estrogen replacement alone and in combination with exercise by voluntary wheel running (VWR) for alleviating the risks of CMS, insulin-mediated skeletal muscle glucose transport, and hepatic fat accumulation in ovariectomized Sprague-Dawley rats fed a high-fat high-fructose diet (OHFFD). We compared a sham-operated group with OHFFD rats that were subdivided into a sedentary, estradiol replacement (E2), and E2 plus VWR for 12 wk. E2 prevented the development of insulin resistance in skeletal muscle glucose transport and decreased hepatic fat accumulation in OHFFD rats. Furthermore, E2 treatment decreased visceral fat mass and low-density lipoprotein (LDL)-cholesterol in OHFFD rats, while VWR further decreased LDL-cholesterol and increased the ratio of high-density lipoprotein-cholesterol to total cholesterol to a greater extent. Although E2 treatment alone did not reduce serum triglyceride levels in OHFFD rats, the combined intervention of E2 and VWR lowered serum triglycerides in E2-treated OHFFD rats. The addition of VWR to E2-treated OHFFD rats led to AMPK activation and upregulation of peroxisome proliferator-activated receptor-γ (PPARγ) coactivator-1α and PPARδ in skeletal muscle along with increased fatty acid oxidation and suppressed fatty acid synthesis in the liver. Collectively, our findings indicate that, to achieve greater health benefits, physical exercise is required for E2-treated individuals under ovarian hormone deprivation with high-energy consumption.

MicroRNA‑29a is involved lipid metabolism dysfunction and insulin resistance in C2C12 myotubes by targeting PPARδ.

MicroRNA‑29a (miR‑29a) expression has been reported to be closely associated with skeletal muscle insulin resistance and type 2 diabetes. The present study investigated the effect of miR‑29a on palmitic acid (PA)‑induced lipid metabolism dysfunction and insulin resistance in C2C12 myotubes via overexpressing or silencing of miR‑29a expression. Mouse C2C12 myoblasts were cultured, differentiated and transfected with miR‑29a or miR‑29a inhibitor lentiviral with or without subsequent palmitic acid (PA) treatment. Reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and western blot analysis were performed to assess the mRNA and protein levels of related genes, respectively. PA treatment increased the expression of miR‑29a in a time‑ and dose‑ dependent manner. miR‑29a silencing improved insulin‑induced glucose uptake and increased glucose transporter‑4 (GLUT4) transportation to the plasma membrane by upregulating its target peroxisome proliferator‑activated receptor δ (PPARδ). Furthermore, it was observed that miR‑29a regulated the expression of genes associated with lipid metabolism, including pyruvate dehydrogenase kinase isoform, mitochondrial uncoupling protein (UCP)2, UCP3, long chain specific acyl‑CoA dehydrogenase, mitochondrial and fatty acid transport protein 2. The results confirmed that silencing miR‑29a induced a decrease in glucose transport and affected lipid metabolism in PA‑treated C2C12 cells, and therefore may be involved in insulin resistance by targeting PPARδ in skeletal muscle. Therefore, the inhibition of miR‑29a may be a potential novel strategy for treating insulin resistance and type 2 diabetes.

Skeletal Muscle PPARδ Increases Acutely with Resistance Exercise Inversely Proportional to Body Fat Percentage

PurposePPARδ expression in skeletal muscle has been shown to increase in response to resistance exercise training in our laboratory. However, it is unclear whether PPARδ expression is affected by a single bout of resistance exercise. Since dyslipidemia is associated with excess body fat, we examined the relationship between the change of PPARδ content and percent body fat in response to one bout of whole body resistance exercise.MethodsEleven untrained young men (N=4) and women (N=7) performed one bout of whole body resistance exercise that included leg press and leg extension for emphasis on quadriceps femoris muscles. Body fat percentage was measured by DEXA before exercise. Muscle biopsies were performed on the vastus lateralis muscles 24 hours before and 24 hours after the exercise. Western Blotting was conducted to quantify the PPARδ content.ResultsWith body fat percentage as a covariate, PPARδ levels increased by 49.1% (p<0.001) after one bout of resistance exercise. The amount of changes in PPARδ was inversely proportional to the body fat percentage (R2=0.769, P=0.001).ConclusionOur data suggest that when adjusted for body fat percentage, resistance exercise may acutely increase PPARδ content, which may be a key factor of lipid metabolism.Support or Funding Information1. The Sydney & J.L. Huffines Institute for Sports Medicine & Human Performance 2. American College of Sports Medicine‐ Texas Chapter (TACSM) 3. Department of Health and Kinesiology, Texas A&M University 4. College of Education and Human Development, Texas A&M University

Peroxisome proliferator-activated receptor delta activation leads to increased transintestinal cholesterol efflux

Peroxisome proliferator-activated receptor delta (PPARdelta) is involved in regulation of energy homeostasis. Activation of PPARdelta markedly increases fecal neutral sterol secretion, the last step in reverse cholesterol transport. This phenomenon can neither be explained by increased hepatobiliary cholesterol secretion, nor by reduced cholesterol absorption. To test the hypothesis that PPARdelta activation leads to stimulation of transintestinal cholesterol efflux (TICE), we quantified it by intestine perfusions in FVB mice treated with PPARdelta agonist GW610742. To exclude the effects on cholesterol absorption, mice were also treated with cholesterol absorption inhibitor ezetimibe or ezetimibe/GW610742. GW601742 treatment had little effect on plasma lipid levels but stimulated both fecal neutral sterol excretion ( approximately 200%) and TICE ( approximately 100%). GW610742 decreased intestinal Npc1l1 expression but had no effect on Abcg5/Abcg8. Interestingly, expression of Rab9 and LIMPII, encoding proteins involved in intracellular cholesterol trafficking, was increased upon PPARdelta activation. Although treatment with ezetimibe alone had no effect on TICE, it reduced the effect of GW610742 on TICE. These data show that activation of PPARdelta stimulates fecal cholesterol excretion in mice, primarily by the two-fold increase in TICE, indicating that this pathway provides an interesting target for the development of drugs aiming at the prevention of atherosclerosis.

Haploinsufficiency of the retinoblastoma protein gene reduces diet-induced obesity, insulin resistance, and hepatosteatosis in mice

Brown adipose tissue activity dissipates energy as heat, and there is evidence that lack of the retinoblastoma protein (pRb) may favor the development of the brown adipocyte phenotype in adipose cells. In this work we assessed the impact of germ line haploinsufficiency of the pRb gene (Rb) on the response to high-fat diet feeding in mice. Rb(+/-) mice had body weight and adiposity indistinguishable from that of wild-type (Rb(+/+)) littermates when maintained on a standard diet, yet they gained less body weight and body fat after long-term high-fat diet feeding coupled with reduced feed efficiency and increased rectal temperature. Rb haploinsufficiency ameliorated insulin resistance and hepatosteatosis after high-fat diet in male mice, in which these disturbances were more marked than in females. Compared with wild-type littermates, Rb(+/-) mice fed a high-fat diet displayed higher expression of peroxisome proliferator-activated receptor (PPAR)gamma as well as of genes involved in mitochondrial function, cAMP sensitivity, brown adipocyte determination, and tissue vascularization in white adipose tissue depots. Furthermore, Rb(+/-) mice exhibited signs of enhanced activation of brown adipose tissue and higher expression levels of PPARalpha in liver and of PPARdelta in skeletal muscle, suggestive of an increased capability for fatty acid oxidation in these tissues. These findings support a role for pRb in modulating whole body energy metabolism and the plasticity of the adipose tissues in vivo and constitute first evidence that partial deficiency in the Rb gene protects against the development of obesity and associated metabolic disturbances.

Transgenic expression of a mutated cyclin-dependent kinase 4 (CDK4/R24C) in pancreatic β-cells prevents progression of diabetes in db/ db mice

In an attempt to rectify the hyperglycemic state in obese insulin resistant db/ db mice, a transgenic line was generated ( db/ db-CDK4 R24C ) that expresses a constitutively active form of cyclin-dependent kinase 4 (CDK4/R24C) under the control of the insulin promoter. Compared with non-transgenic db/ db littermates, adult db/ db-CDK4 R24C mice show near-complete glycemic normalization and improved plasma lipid concentrations, but are also more susceptible to weight gain and have significantly lower plasma adiponection levels. They have striking islet hypertrophy and β-cell hyperplasia, and retain an insulin secretory response during the glucose tolerance test. We examined the expression of several key regulatory transcription factor genes involved in lipid and glucose metabolism in insulin target tissues of db/ db-CDK4 R24C as well as db/ db mice, and found that the expression levels of members of the peroxisome proliferator-activated receptor ( PPAR) family are highly associated with metabolic alterations in a gene- and tissue-specific manner. We show for the first time that the Ppar-δ in skeletal muscle and white adipose tissues is transcriptionally down-regulated in db/ db mice. The db/ db-CDK4 R24C mice present a novel model of leptin-resistant obesity with compensatory hyperinsulinemia and normalized blood glucose levels, and thus may be useful for future studies that aim to dissect relationships between insulin and leptin signaling.

Are Peroxisome Proliferator-Activated Receptors Involved in Skeletal Muscle Wasting during Experimental Cancer Cachexia? Role of β2-Adrenergic Agonists

Implantation of the Yoshida AH-130 ascites hepatoma to rats resulted in a decrease in muscle weight 7 days after the inoculation of the tumor. These changes were associated with increases in the mRNA content for both peroxisome proliferator-activated receptor (PPAR) gamma and PPAR delta in skeletal muscle. The increase in gene expression for these transcription factors was related to increases in the expression of several genes involved in fatty acid transport, activation, and oxidation. Tumor burden also resulted in increases in PPAR gamma coactivator-1 alpha gene expression and pyruvate dehydrogenase kinase 4. All these changes in lipid metabolism genes suggest that a metabolic shift occurs in skeletal muscle of tumor-bearing rats toward a more oxidative phenotype. Formoterol treatment to tumor-bearing rats resulted in an amelioration of all the changes observed as a result of tumor burden. Administration of this beta(2)-adrenergic agonist also resulted in a decrease in mRNA content of muscle PPAR alpha, PPAR delta, and PPAR gamma, as well as in mRNA levels of many of the genes involved in both lipid and mitochondrial metabolism. All these results suggest an involvement of the different PPARs as transcription factors related with muscle wasting and also indicate that a possible mode of action of the anticachectic compound formoterol may involve a normalization of the levels of these transcription factors.