scholarly journals Downregulation of peroxisome proliferator-activated receptor α and its coactivators in liver and skeletal muscle mediates the metabolic adaptations during lactation in mice

2009 ◽  
Vol 43 (6) ◽  
pp. 241-250 ◽  
Author(s):  
Anke Gutgesell ◽  
Robert Ringseis ◽  
Eileen Schmidt ◽  
Corinna Brandsch ◽  
Gabriele I Stangl ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Target Genes ◽  
Fatty Acid Uptake ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Acid Uptake ◽  
Wild Type ◽  
Peroxisome Proliferator Activated Receptor ◽  
Metabolic Adaptations

Previous studies have shown that genes involved in fatty acid uptake, fatty acid oxidation, and thermogenesis are downregulated in liver and skeletal muscle of rats during lactation. However, biochemical mechanisms underlying these important metabolic adaptations during lactation have not yet been elucidated. As all these genes are transcriptionally regulated by peroxisome proliferator-activated receptor α (Pparα), we hypothesized that their downregulation is mediated by a suppression of Pparα during lactation. In order to investigate this hypothesis, we performed an experiment with lactating and nonlactating Pparα knockout and corresponding wild-type mice. In wild-type mice, lactation led to a considerable downregulation of Pparα, Ppar coactivators Pgc1α and Pgc1β, and Pparα target genes involved in fatty acid uptake, fatty acid oxidation, and thermogenesis in liver and skeletal muscle (P<0.05). Pparα knockout mice had generally a lower expression of all these Pparα target genes in liver and skeletal muscle. However, in those mice, lactation did not lower the expression of genes involved in fatty acid utilization and thermogenesis in liver and skeletal muscle. Expression levels of Pparα target genes in lactating wild-type mice were similar than in lactating or nonlactating Pparα knockout mice. In conclusion, the present findings suggest that downregulation of Pparα and its coactivators in tissues with high rates of fatty acid catabolism is responsible for the reduced utilization of fatty acids in liver and skeletal muscle and the reduced thermogenesis occurring in the lactating animal, which aim to conserve energy and metabolic substrates for milk production in the mammary gland.

scholarly journals Estrogen-Related Receptor α Directs Peroxisome Proliferator-Activated Receptor α Signaling in the Transcriptional Control of Energy Metabolism in Cardiac and Skeletal Muscle

2004 ◽  
Vol 24 (20) ◽  
pp. 9079-9091 ◽  
Author(s):  
Janice M. Huss ◽  
Inés Pineda Torra ◽  
Bart Staels ◽  
Vincent Giguère ◽  
Daniel P. Kelly
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Target Genes ◽  
Cellular Fatty Acid ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Oxidation Rates

ABSTRACT Estrogen-related receptors (ERRs) are orphan nuclear receptors activated by the transcriptional coactivator peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1α (PGC-1α), a critical regulator of cellular energy metabolism. However, metabolic target genes downstream of ERRα have not been well defined. To identify ERRα-regulated pathways in tissues with high energy demand such as the heart, gene expression profiling was performed with primary neonatal cardiac myocytes overexpressing ERRα. ERRα upregulated a subset of PGC-1α target genes involved in multiple energy production pathways, including cellular fatty acid transport, mitochondrial and peroxisomal fatty acid oxidation, and mitochondrial respiration. These results were validated by independent analyses in cardiac myocytes, C2C12 myotubes, and cardiac and skeletal muscle of ERRα−/− mice. Consistent with the gene expression results, ERRα increased myocyte lipid accumulation and fatty acid oxidation rates. Many of the genes regulated by ERRα are known targets for the nuclear receptor PPARα, and therefore, the interaction between these regulatory pathways was explored. ERRα activated PPARα gene expression via direct binding of ERRα to the PPARα gene promoter. Furthermore, in fibroblasts null for PPARα and ERRα, the ability of ERRα to activate several PPARα targets and to increase cellular fatty acid oxidation rates was abolished. PGC-1α was also shown to activate ERRα gene expression. We conclude that ERRα serves as a critical nodal point in the regulatory circuitry downstream of PGC-1α to direct the transcription of genes involved in mitochondrial energy-producing pathways in cardiac and skeletal muscle.

scholarly journals Peroxisome Proliferator-Activated Receptor γ Decouples Fatty Acid Uptake from Lipid Inhibition of Insulin Signaling in Skeletal Muscle

2012 ◽  
Vol 26 (6) ◽  
pp. 977-988 ◽  
Author(s):  
Shanming Hu ◽  
Jianrong Yao ◽  
Alexander A. Howe ◽  
Brandon M. Menke ◽  
William I. Sivitz ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Insulin Signaling ◽  
Fatty Acid Uptake ◽  
Peroxisome Proliferator ◽  
Acid Uptake ◽  
Peroxisome Proliferator Activated Receptor

scholarly journals The Peroxisome Proliferator-Activated Receptor N-Terminal Domain Controls Isotype-Selective Gene Expression and Adipogenesis

2006 ◽  
Vol 20 (6) ◽  
pp. 1261-1275 ◽  
Author(s):  
Sarah Hummasti ◽  
Peter Tontonoz
Keyword(s):  
Gene Expression ◽  
Fatty Acid ◽  
Target Genes ◽  
Biological Effects ◽  
Binding Domain ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
N Terminus

Abstract Peroxisome proliferator-activated receptors (PPARγ, PPARα, and PPARδ) are important regulators of lipid metabolism. Although they share significant structural similarity, the biological effects associated with each PPAR isotype are distinct. For example, PPARα and PPARδ regulate fatty acid catabolism, whereas PPARγ controls lipid storage and adipogenesis. The different functions of PPARs in vivo can be explained at least in part by the different tissue distributions of the three receptors. The question of whether the receptors have different intrinsic activities and regulate distinct target genes, however, has not been adequately explored. We have engineered cell lines that express comparable amounts of each receptor. Transcriptional profiling of these cells in the presence of selective agonists reveals partially overlapping but distinct patterns of gene regulation by the three PPARs. Moreover, analysis of chimeric receptors points to the N terminus of each receptor as the key determinant of isotype-selective gene expression. For example, the N terminus of PPARγ confers the ability to promote adipocyte differentiation when fused to the PPARδ DNA binding domain and ligand binding domain, whereas the N terminus of PPARδ leads to the inappropriate expression of fatty acid oxidation genes in differentiated adipocytes when fused to PPARγ. Finally, we demonstrate that the N terminus of each receptor functions in part to limit receptor activity because deletion of the N terminus leads to nonselective activation of target genes. A more detailed understanding of the mechanisms by which the individual PPARs differentially regulate gene expression should aid in the design of more effective drugs, including tissue- and target gene-selective PPAR modulators.

scholarly journals Endogenous Peroxisome Proliferator-Activated Receptor-γ Augments Fatty Acid Uptake in Oxidative Muscle

Endocrinology ◽  
2008 ◽  
Vol 149 (11) ◽  
pp. 5374-5383 ◽  
Author(s):  
Andrew W. Norris ◽  
Michael F. Hirshman ◽  
Jianrong Yao ◽  
Niels Jessen ◽  
Nicolas Musi ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Uptake ◽  
Transport Protein ◽  
Fatty Acid Transport ◽  
Peroxisome Proliferator ◽  
Acid Uptake ◽  
Acid Transport ◽  
Peroxisome Proliferator Activated Receptor ◽  
Nonesterified Fatty Acids ◽  
Fatty Acid Transport Protein

In the setting of insulin resistance, agonists of peroxisome proliferator-activated receptor (PPAR)-γ restore insulin action in muscle and promote lipid redistribution. Mice with muscle-specific knockout of PPARγ (MuPPARγKO) develop excess adiposity, despite reduced food intake and normal glucose disposal in muscle. To understand the relation between muscle PPARγ and lipid accumulation, we studied the fuel energetics of MuPPARγKO mice. Compared with controls, MuPPARγKO mice exhibited significantly increased ambulatory activity, muscle mitochondrial uncoupling, and respiratory quotient. Fitting with this latter finding, MuPPARγKO animals compared with control siblings exhibited a 25% reduction in the uptake of the fatty acid tracer 2-bromo-palmitate (P &lt; 0.05) and a 13% increase in serum nonesterified fatty acids (P = 0.05). These abnormalities were associated with no change in AMP kinase (AMPK) phosphorylation, AMPK activity, or phosphorylation of acetyl-CoA carboxylase in muscle and occurred despite increased expression of fatty acid transport protein 1. Palmitate oxidation was not significantly altered in MuPPARγKO mice despite the increased expression of several genes promoting lipid oxidation. These data demonstrate that PPARγ, even in the absence of exogenous activators, is required for normal rates of fatty acid uptake in oxidative skeletal muscle via mechanisms independent of AMPK and fatty acid transport protein 1. Thus, when PPARγ activity in muscle is absent or reduced, there will be decreased fatty acid disposal leading to diminished energy utilization and ultimately adiposity.

scholarly journals Loss of Hepatocyte-Specific PPARγ Expression Ameliorates Early Events of Steatohepatitis in Mice Fed the Methionine and Choline-Deficient Diet

PPAR Research ◽  
2020 ◽  
Vol 2020 ◽  
pp. 1-13 ◽  
Author(s):  
Jose Cordoba-Chacon
Keyword(s):  
Fatty Acid ◽  
Molecular Mechanisms ◽  
Fatty Acid Uptake ◽  
Peroxisome Proliferator ◽  
Acid Uptake ◽  
Deficient Diet ◽  
Peroxisome Proliferator Activated Receptor ◽  
Nonalcoholic Fatty Liver ◽  
Cd36 Expression ◽  
Pparγ Expression

The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide. To date, there is not a specific and approved treatment for NAFLD yet, and therefore, it is important to understand the molecular mechanisms that lead to the progression of NAFLD. Methionine- and choline-deficient (MCD) diets are used to reproduce some features of NAFLD in mice. MCD diets increase the expression of hepatic peroxisome proliferator-activated receptor gamma (PPARγ, Pparg) and the fatty acid translocase (CD36, Cd36) which could increase hepatic fatty acid uptake and promote the progression of NAFLD in mice and humans. In this study, we assessed the contribution of hepatocyte-specific PPARγ and CD36 expression to the development of early events induced by the MCD diet. Specifically, mice with adult-onset, hepatocyte-specific PPARγ knockout with and without hepatocyte CD36 overexpression were fed a MCD diet for three weeks. Hepatocyte PPARγ and/or CD36 expression did not contribute to the development of steatosis induced by the MCD diet. However, the expression of inflammatory and fibrogenic genes seems to be dependent on the expression of hepatocyte PPARγ and CD36. The expression of PPARγ and CD36 in hepatocytes may be relevant in the regulation of some features of NAFLD and steatohepatitis.

scholarly journals Hyperglycemia- and hyperinsulinemia-induced alteration of adiponectin receptor expression and adiponectin effects in L6 myoblasts

2005 ◽  
Vol 35 (3) ◽  
pp. 465-476 ◽  
Author(s):  
X Fang ◽  
R Palanivel ◽  
X Zhou ◽  
Y Liu ◽  
A Xu ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Muscle Cells ◽  
Fatty Acid Uptake ◽  
Receptor Expression ◽  
Skeletal Muscle Cells ◽  
Adiponectin Receptor ◽  
Acid Oxidation ◽  
Acid Uptake ◽  
Rat Skeletal Muscle

Adiponectin has been shown to regulate glucose and fatty acid uptake and metabolism in skeletal muscle. Here we investigated the role of the recently cloned adiponectin receptor (AdipoR) isoforms in mediating effects of both globular (gAd) and full-length (fAd) adiponectin, and their regulation by hyperglycemia (25 mM, 20 h) and hyperinsulinemia (100 nM, 20 h). We used L6 rat skeletal muscle cells, which were found to express both AdipoR1 and AdipoR2 mRNA in a ratio of over 6:1 respectively. Hyperglycemia and hyperinsulinemia both decreased AdipoR1 receptor expression by approximately 50%, while the latter induced an increase of approximately threefold in AdipoR2 expression. The ability of gAd to increase GLUT4 myc translocation, glucose uptake, fatty acid uptake and oxidation, as well as AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) phosphorylation, was decreased by both hyperglycemia and hyperinsulinemia. Interestingly, hyperinsulinemia induced the ability of fAd to elicit fatty acid uptake and enhanced fatty acid oxidation in response to fAd. In summary, our results suggest that both hyperglycemia and hyperinsulinemia cause gAd resistance in rat skeletal muscle cells. However, hyperinsulinemia induces a switch toward increased fAd sensitivity in these cells.

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