Suppression of plasma free fatty acids upregulates peroxisome proliferator-activated receptor (PPAR) α and δ and PPAR coactivator 1α in human skeletal muscle, but not lipid regulatory genes

Skeletal Muscle Research Laboratory, School of Medical Sciences, Royal Melbourne Institute of Technology, PO Box 27, Bundoora 3083, Victoria, Australia.
Journal of Molecular Endocrinology (Impact Factor: 3.08). 10/2004; 33(2):533-44. DOI: 10.1677/jme.1.01499
Source: PubMed


Fatty acids are an important ligand for peroxisome proliferator-activated receptor (PPAR) activation and transcriptional regulation of metabolic genes. To examine whether reduced plasma free fatty acid (FFA) availability affects the mRNA content of proteins involved in fuel metabolism in vivo, the skeletal muscle mRNA content of various transcription factors, transcriptional coactivators and genes encoding for lipid regulatory proteins were examined before and after 3 h of cycle exercise with (NA) and without (CON) pre-exercise ingestion of nicotinic acid (NA). NA resulted in a marked (3- to 6-fold) increase (P<0.05) in PPARalpha, PPARdelta and PPAR coactivator 1alpha (PGC1alpha) mRNA, but was without effect on nuclear respiratory factor-1 and Forkhead transcription factor, fatty acid transcolase/CD36, carnitine palmitoyl transferase 1, hormone sensitive lipase (HSL) and pyruvate dehydrogenase kinase 4. Exercise in CON was associated with increased (P<0.05) PPARalpha, PPARdelta and PGC1alpha mRNA, which was similar in magnitude to levels observed with NA at rest. Exercise was generally without effect on the mRNA content of lipid regulatory proteins in CON and did not affect the mRNA content of the measured subset of transcription factors, transcriptional co-activators and lipid regulatory proteins during NA. To determine the possible mechanisms by which NA might affect PGC1alpha expression, we measured p38 MAP kinase (MAPK) and plasma epinephrine. Phosphorylation of p38 MAPK was increased (P<0.05) by NA treatment at rest, and this correlated (r2=0.84, P<0.01) with increased PGC1alpha. Despite this close relationship, increasing p38 MAPK in human primary myotubes was without effect on PGC1alpha mRNA content. Plasma epinephrine was elevated (P<0.05) by NA at rest (CON: 0.27+/-0.06, NA: 0.72+/-0.11 nM) and throughout exercise. Incubating human primary myotubes with epinephrine increased PGC1alpha independently of changes in p38 MAPK phosphorylation. Hence, despite the fact that NA ingestion decreased FFA availability, it promoted the induction of PPARalpha/delta and PGC1alpha gene expression to a similar degree as prolonged exercise. We suggest that the increase in PGC1alpha may be due to the elevated plasma epinephrine levels. Despite these changes in transcription factors/coactivators, the mRNA content of lipid regulatory proteins was generally unaffected by plasma FFA availability.

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Available from: Mark A Febbraio, Feb 22, 2014
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    • "This is based on several complimentary observations: PLIN5 is highly expressed in oxidative and not glycolytic tissues [9]–[11]; lipid droplets and the mitochondria are spatially associated in muscle and PLIN5 is located near both organelles [14]; PLIN5 may recruit mitochondria to lipid droplets [40]; and overexpression of PLIN5 may promote an oxidative phenotype [27], although the latter point is not supported by several other studies [14], [41], [42]. We reasoned that acute moderate intensity exercise, which increases fatty acid oxidation rates by ∼5-10-fold (calculated from [43]), would provide an ideal platform to test this hypothesis. Our data show that the PLIN5/mitochondria colocation is not different between resting and exercise conditions, indicating that PLIN5 is unlikely to be mediating marked changes in lipid droplet-mitochondria flux due to increased abundance at the mitochondria. "
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    ABSTRACT: Lipolysis involves the sequential breakdown of fatty acids from triacylglycerol and is increased during energy stress such as exercise. Adipose triglyceride lipase (ATGL) is a key regulator of skeletal muscle lipolysis and perilipin (PLIN) 5 is postulated to be an important regulator of ATGL action of muscle lipolysis. Hence, we hypothesized that non-genomic regulation such as cellular localization and the interaction of these key proteins modulate muscle lipolysis during exercise. PLIN5, ATGL and CGI-58 were highly (>60%) colocated with Oil Red O (ORO) stained lipid droplets. PLIN5 was significantly colocated with ATGL, mitochondria and CGI-58, indicating a close association between the key lipolytic effectors in resting skeletal muscle. The colocation of the lipolytic proteins, their independent association with ORO and the PLIN5/ORO colocation were not altered after 60 min of moderate intensity exercise. Further experiments in cultured human myocytes showed that PLIN5 colocation with ORO or mitochondria is unaffected by pharmacological activation of lipolytic pathways. Together, these data suggest that the major lipolytic proteins are highly expressed at the lipid droplet and colocate in resting skeletal muscle, that their localization and interactions appear to remain unchanged during prolonged exercise, and, accordingly, that other post-translational mechanisms are likely regulators of skeletal muscle lipolysis.
    Full-text · Article · Jul 2014 · PLoS ONE
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    • "With regard to other effects of niacin, which may contribute to its lipid-lowering efficacy, it is noteworthy that acute administration of niacin causes an increase of the mRNA levels of peroxisome proliferator-activated receptor (PPAR)α, PPARδ and the PPAR co-activator PGC-1α in tissues of male healthy subjects [7]. PPARα and PPARδ are ligand-dependent transcription factors which act as important metabolic regulators, especially in fatty acid catabolism, and are therefore abundantly expressed in tissues with high rates of fatty acid oxidation such as liver and skeletal muscle [8]. "
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    ABSTRACT: Background Activation of peroxisome proliferator-activated receptor (PPAR)α and PPARδ causes an elevation of tissue carnitine concentrations through induction of genes involved in carnitine uptake [novel organic cation transporter 2, (OCTN2)], and carnitine biosynthesis [γ-butyrobetaine dioxygenase (BBD), 4-N-trimethyl-aminobutyraldehyde dehydrogenase (TMABA-DH)]. Recent studies showed that administration of the plasma lipid-lowering drug niacin causes activation of PPARα and/or PPARδ in tissues of obese Zucker rats, which have a compromised carnitine status and an impaired fatty acid oxidation capacity. Thus, we hypothesized that niacin administration to obese Zucker rats is also able to improve the diminished carnitine status of obese Zucker rats through PPAR-mediated stimulation of genes involved in carnitine uptake and biosynthesis. Methods To test this hypothesis, we used plasma, muscle and liver samples from a recent experiment with obese Zucker rats, which were fed either a niacin-adequate diet (30 mg niacin/kg diet) or a diet with a pharmacological niacin dose (780 mg niacin/kg diet), and determined concentrations of carnitine in tissues and mRNA and protein levels of genes critical for carnitine homeostasis (OCTN2, BBD, TMABA-DH). Statistical data analysis of all data was done by one-way ANOVA, and Fisher’s multiple range test. Results Rats of the obese niacin group had higher concentrations of total carnitine in plasma, skeletal muscle and liver, higher mRNA and protein levels of OCTN2, BBD, and TMABA-DH in the liver and higher mRNA and protein levels of OCTN2 in skeletal muscle than those of the obese control group (P < 0.05), whereas rats of the obese control group had lower concentrations of total carnitine in plasma and skeletal muscle than lean rats (P < 0.05). Conclusion The results show for the first time that niacin administration stimulates the expression of genes involved in carnitine uptake and biosynthesis and improves the diminished carnitine status of obese Zucker rats. We assume that the induction of genes involved in carnitine uptake and biosynthesis by niacin administration is mediated by PPAR-activation.
    Full-text · Article · Jul 2014 · BMC pharmacology & toxicology
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    • "However, less well-documented niacin treatment also causes significant changes in gene expression in other tissues than adipose tissue, like skeletal muscle [2], a tissue which due to its great mass is particularly important for whole body fatty acid utilization. Noteworthy, it has been recently shown in humans that niacin administration induces the expression of two transcription factors, peroxisome proliferator-activated receptor δ (PPARδ, encoded by PPARD) and PPARγ coactivator-1α (PGC-1α, encoded by PPARGC1A) in skeletal muscle [3]. Both transcription factors are key regulators of muscle fiber composition and the muscle’s metabolic phenotype because they control genes involved in muscle fiber switching, fatty acid utilization, oxidative phosphorylation, mitochondrial biogenesis and function [4,5], and angiogenesis [6]. "
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    ABSTRACT: It was recently shown that niacin supplementation counteracts the obesity-induced muscle fiber transition from oxidative type I to glycolytic type II and increases the number of type I fibers in skeletal muscle of obese Zucker rats. These effects were likely mediated by the induction of key regulators of fiber transition, PPARdelta (encoded by PPARD), PGC-1alpha (encoded by PPARGC1A) and PGC-1beta (encoded by PPARGC1B), leading to type II to type I fiber transition and upregulation of genes involved in oxidative metabolism. The aim of the present study was to investigate whether niacin administration also influences fiber distribution and the metabolic phenotype of different muscles [M. longissimus dorsi (LD), M. semimembranosus (SM), M. semitendinosus (ST)] in sheep as a model for ruminants. For this purpose, 16 male, 11 wk old Rhoen sheep were randomly allocated to two groups of 8 sheep each administered either no (control group) or 1 g niacin per day (niacin group) for 4 wk. After 4 wk, the percentage number of type I fibers in LD, SM and ST muscles was greater in the niacin group, whereas the percentage number of type II fibers was less in niacin group than in the control group (P < 0.05). The mRNA levels of PPARGC1A, PPARGC1B, and PPARD and the relative mRNA levels of genes involved in mitochondrial fatty acid uptake (CPT1B, SLC25A20), tricarboxylic acid cycle (SDHA), mitochondrial respiratory chain (COX5A, COX6A1), and angiogenesis (VEGFA) in LD, SM and ST muscles were greater (P < 0.05) or tended to be greater (P < 0.15) in the niacin group than in the control group. The study shows that niacin supplementation induces muscle fiber transition from type II to type I, and thereby an oxidative metabolic phenotype of skeletal muscle in sheep as a model for ruminants. The enhanced capacity of skeletal muscle to utilize fatty acids in ruminants might be particularly useful during metabolic states in which fatty acids are excessively mobilized from adipose tissue, such as during the early lactating period in high producing cows.
    Full-text · Article · Nov 2013 · Acta Veterinaria Scandinavica
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