scholarly journals Alteration of cardiolipin-dependent mitochondrial coupling in muscle protects against obesity

2019 ◽  
Author(s):  
Alexandre Prola ◽  
Jordan Blondelle ◽  
Aymeline Vandestienne ◽  
Jérôme Piquereau ◽  
Raphaël GP Denis ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid Biosynthesis ◽  
Coupling Efficiency ◽  
Inner Mitochondrial Membrane ◽  
Long Chain Fatty Acid ◽  
Diet Induced Obesity ◽  
Composition Structure ◽  
Basal Energy Expenditure ◽  
Strong Curvature

SummaryThe tubular shape of mitochondrial cristae depends upon a specific composition of the inner mitochondrial membrane, including cardiolipin that allows strong curvature and promotes optimal organization of ATP synthase. Here we identify Hacd1, which encodes an enzyme involved in very long chain fatty acid biosynthesis, as a key regulator of composition, structure and functional properties of mitochondrial membranes in muscle. In Hacd1-deficient mice, the reduced cardiolipin content was associated with dilation of cristae and caused defective phosphorylating respiration, characterized by absence of proton leak and oxidative stress.The skeletal muscle-specific mitochondrial coupling defect produced a global elevation in basal energy expenditure with increased carbohydrate and lipid catabolism, despite decreased muscle mass and locomotor capacities. Mice were protected against diet-induced obesity despite reduced muscle activity, providing an in vivo proof of concept that reducing mitochondrial coupling efficiency in skeletal muscle might be an actionable mechanism in metabolic disease conditions.

scholarly journals CTRP9 transgenic mice are protected from diet-induced obesity and metabolic dysfunction

2013 ◽  
Vol 305 (5) ◽  
pp. R522-R533 ◽  
Author(s):  
Jonathan M. Peterson ◽  
Zhikui Wei ◽  
Marcus M. Seldin ◽  
Mardi S. Byerly ◽  
Susan Aja ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Transgenic Mice ◽  
High Fat Diet ◽  
Fat Oxidation ◽  
Acid Oxidation ◽  
Ampk Activation ◽  
High Fat ◽  
Diet Induced Obesity

CTRP9 is a secreted multimeric protein of the C1q family and the closest paralog of the insulin-sensitizing adipokine, adiponectin. The metabolic function of this adipose tissue-derived plasma protein remains largely unknown. Here, we show that the circulating levels of CTRP9 are downregulated in diet-induced obese mice and upregulated upon refeeding. Overexpressing CTRP9 resulted in lean mice that dramatically resisted weight gain induced by a high-fat diet, largely through decreased food intake and increased basal metabolism. Enhanced fat oxidation in CTRP9 transgenic mice resulted from increases in skeletal muscle mitochondrial content, expression of enzymes involved in fatty acid oxidation (LCAD and MCAD), and chronic AMPK activation. Hepatic and skeletal muscle triglyceride levels were substantially decreased in transgenic mice. Consequently, CTRP9 transgenic mice had a greatly improved metabolic profile with markedly reduced fasting insulin and glucose levels. The high-fat diet-induced obesity, insulin resistance, and hepatic steatosis observed in wild-type mice were prevented in transgenic mice. Consistent with the in vivo data, recombinant protein significantly enhanced fat oxidation in L6 myotubes via AMPK activation and reduced lipid accumulation in H4IIE hepatocytes. Collectively, these data establish CTRP9 as a novel metabolic regulator and a new component of the metabolic network that links adipose tissue to lipid metabolism in skeletal muscle and liver.

scholarly journals Cold Exposure Affects Lipid Metabolism, Fatty Acids Composition and Transcription in Pig Skeletal Muscle

2021 ◽  
Vol 12 ◽  
Author(s):  
Ziye Xu ◽  
Wentao Chen ◽  
Liyi Wang ◽  
Yanbing Zhou ◽  
Qiuyun Nong ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acids ◽  
Fatty Acid ◽  
Lipid Metabolism ◽  
Meat Quality ◽  
Cold Exposure ◽  
Fatty Acid Biosynthesis ◽  
Total Content ◽  
Fatty Acids Composition

Cold exposure promotes glucose oxidation and modulates the lipid metabolism in adipose tissue, but it is still not fully clear whether cold exposure could affect meat quality and fatty acid metabolism in skeletal muscle of pig in vivo. Here, we kept finishing pigs under cold or room temperature overnight and determined the effects of cold exposure on meat quality, fatty acids composition and transcriptional changes in skeletal muscle of pigs. We found that cold exposure significantly reduced the meat colour24 h and pH24 h, without affecting carcass characteristics and other meat quality traits. Considerable changes were found in the proportions of individual fatty acids and the total content of saturated fatty acid, polyunsaturated fatty acids, monounsaturated fatty acid and n3-fatty acids. RNA-seq results showed upregulated fatty acid biosynthesis genes and downregulated mitochondrial beta-oxidation genes. The lipid metabolism in cold-treated longissimus dorsi muscle might be regulated by functions of the lipoprotein particle, the extracellular matrix, and the PPAR signaling pathways. Our study revealed the potential of cold exposure to regulate the lipid metabolism and fatty acid composition in skeletal muscle of farmed animals.

scholarly journals Evolution and Functional Characteristics of the Novel Elovl8 That Play Pivotal Roles in Fatty Acid Biosynthesis

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1287
Author(s):  
Shouxiang Sun ◽  
Yumei Wang ◽  
Pei-Tian Goh ◽  
Mónica Lopes-Marques ◽  
L. Filipe C. Castro ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Biosynthesis ◽  
The Novel ◽  
Acid Biosynthesis ◽  
Long Chain Fatty Acid ◽  
Rate Limiting Step ◽  
Gene Expression Quantification ◽  
Rate Limiting ◽  
Zebrafish Liver

Elongation of very long-chain fatty acid (Elovl) proteins are key enzymes that catalyze the rate-limiting step in the fatty acid elongation pathway. The most recently discovered member of the Elovl family, Elovl8, has been proposed to be a fish-specific elongase with two gene paralogs described in teleosts. However, the biological functions of Elovl8 are still to be elucidated. In this study, we showed that in contrast to previous findings, elovl8 is not unique to teleosts, but displays a rather unique and ample phylogenetic distribution. For functional determination, we generated elovl8a (elovl8a−/−) and elovl8b (elovl8b−/−) zebrafish using CRISPR/Cas9 technology. Fatty acid composition in vivo and zebrafish liver cell experiments suggest that the substrate preference of Elovl8 overlapped with other existing Elovl enzymes. Zebrafish Elovl8a could elongate the polyunsaturated fatty acids (PUFAs) C18:2n-6 and C18:3n-3 to C20:2n-6 and C20:3n-3, respectively. Along with PUFA, zebrafish Elovl8b also showed the capacity to elongate C18:0 and C20:1. Gene expression quantification suggests that Elovl8a and Elovl8b may play a potentially important role in fatty acid biosynthesis. Overall, our results provide novel insights into the function of Elovl8a and Elovl8b, representing additional fatty acid elongases not previously described in chordates.

scholarly journals FATP1 Is an Insulin-Sensitive Fatty Acid Transporter Involved in Diet-Induced Obesity

2006 ◽  
Vol 26 (9) ◽  
pp. 3455-3467 ◽  
Author(s):  
Qiwei Wu ◽  
Angelica M. Ortegon ◽  
Bernice Tsang ◽  
Holger Doege ◽  
Kenneth R. Feingold ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Fatty Acid Uptake ◽  
Dietary Lipids ◽  
Fatty Acid Transport ◽  
Acid Uptake ◽  
Diet Induced Obesity ◽  
Fatty Acid Transporter ◽  
Knockout Animals

ABSTRACT Fatty acid transport protein 1 (FATP1), a member of the FATP/Slc27 protein family, enhances the cellular uptake of long-chain fatty acids (LCFAs) and is expressed in several insulin-sensitive tissues. In adipocytes and skeletal muscle, FATP1 translocates from an intracellular compartment to the plasma membrane in response to insulin. Here we show that insulin-stimulated fatty acid uptake is completely abolished in FATP1-null adipocytes and greatly reduced in skeletal muscle of FATP1-knockout animals while basal LCFA uptake by both tissues was unaffected. Moreover, loss of FATP1 function altered regulation of postprandial serum LCFA, causing a redistribution of lipids from adipocyte tissue and muscle to the liver, and led to a complete protection from diet-induced obesity and insulin desensitization. This is the first in vivo evidence that insulin can regulate the uptake of LCFA by tissues via FATP1 activation and that FATPs determine the tissue distribution of dietary lipids. The strong protection against diet-induced obesity and insulin desensitization observed in FATP1-null animals suggests FATP1 as a novel antidiabetic target.

scholarly journals Reciprocity between Skeletal Muscle AMPK Deletion and Insulin Action in Diet-Induced Obese Mice

2020 ◽  
Author(s):  
Ada Admin ◽  
Louise Lantier ◽  
Ashley S. Williams ◽  
Ian M.Williams ◽  
Amanda Guerin ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Insulin Signaling ◽  
Insulin Action ◽  
Energy State ◽  
Energy Charge ◽  
Ampk Signaling ◽  
Diet Induced Obesity ◽  
Energy Sensor ◽  
Amp Activated Protein Kinase

Insulin resistance due to overnutrition places a burden on energy-producing pathways in skeletal muscle (SkM). Nevertheless, energy state is not compromised. The hypothesis that the energy sensor AMP-activated protein kinase (AMPK) is necessary to offset the metabolic burden of overnutrition was tested using chow-fed and high fat (HF)-fed SkM-specific AMPKa1a2 knockout (mdKO) mice and AMPKa1a2lox/lox littermates (WT). Lean mdKO and WT mice were phenotypically similar. HF-fed mice were equally obese and maintained lean mass regardless of genotype. Results did not support the hypothesis that AMPK is protective during overnutrition. Paradoxically, mdKO mice were more insulin sensitive. Insulin-stimulated SkM glucose uptake was ~two-fold greater in mdKO mice in vivo. Furthermore, insulin signaling, SkM GLUT4 translocation, hexokinase activity, and glycolysis were increased. AMPK and insulin signaling intersect at mTOR, a critical node for cell proliferation and survival. Basal mTOR activation was reduced by 50% in HF-fed mdKO mice, but was normalized by insulin-stimulation. Mitochondrial function was impaired in mdKO mice, but energy charge was preserved by AMP deamination. Results show a surprising reciprocity between SkM AMPK signaling and insulin action that manifests with diet-induced obesity, as insulin action is preserved to protect fundamental energetic processes in the muscle.

scholarly journals Endogenous omega-3 long-chain fatty acid biosynthesis from alpha-linolenic acid is affected by substrate levels, gene expression, and product inhibition

RSC Advances ◽  
2017 ◽  
Vol 7 (65) ◽  
pp. 40946-40951 ◽  
Author(s):  
Shun-he Wang ◽  
Yong Pan ◽  
Jing Li ◽  
Hai-qin Chen ◽  
Hao Zhang ◽  
...  
Keyword(s):  
Linolenic Acid ◽  
Fatty Acid Biosynthesis ◽  
Product Inhibition ◽  
Chain Fatty Acid ◽  
Omega 3 ◽  
Alpha Linolenic Acid ◽  
Acid Biosynthesis ◽  
Long Chain Fatty Acid ◽  
Long Chain

Previous studies have suggested that dietary alpha-linolenic acid (ALA) increases the levels of omega-3 long-chain polyunsaturated fatty acids (ω-3 LC-PUFAs)in vivo, but the conversion procedure and the genes involved remain poorly understood.

Selective PPARδ agonist treatment increases skeletal muscle lipid metabolism without altering mitochondrial energy coupling: an in vivo magnetic resonance spectroscopy study

2007 ◽  
Vol 293 (5) ◽  
pp. E1256-E1264 ◽  
Author(s):  
Beat M. Jucker ◽  
Dewen Yang ◽  
Warren M. Casey ◽  
Alan R. Olzinski ◽  
Carolyn Williams ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Lipid Metabolism ◽  
Uncoupling Protein ◽  
Coupling Efficiency ◽  
Atp Synthesis ◽  
Energy Coupling ◽  
Resonance Spectroscopy ◽  
High Dose ◽  
Muscle Lipid

Peroxisome proliferator-activated receptor-δ (PPARδ) activation results in upregulation of genes associated with skeletal muscle fatty acid oxidation and mitochondrial uncoupling. However, direct, noninvasive assessment of lipid metabolism and mitochondrial energy coupling in skeletal muscle following PPARδ stimulation has not been examined. Therefore, in this study we examined the response of a selective PPARδ agonist (GW610742X at 5 or 100 mg·kg−1·day−1 for 8 days) on skeletal-muscle lipid metabolism and mitochondrial coupling efficiency in rats by using in vivo magnetic resonance spectroscopy (MRS). There was a decrease in the intramyocellular lipid-to-total creatine ratio as assessed by in vivo 1H-MRS in soleus and tibialis anterior muscles by day 7 (reduced by 49 and 46%, respectively; P < 0.01) at the high dose. Following the 1H-MRS experiment ( day 8), [1-13C]glucose was administered to conscious rats to assess metabolism in the soleus muscle. The relative fat-vs.-carbohydrate oxidation rate increased in a dose-dependent manner (increased by 52 and 93% in the 5 and 100 mg·kg−1·day−1 groups, respectively; P < 0.05). In separate experiments where mitochondrial coupling was assessed in vivo ( day 7), 31P-MRS was used to measure hindlimb ATP synthesis and 13C-MRS was used to measure the hindlimb tricarboxylic acid cycle flux (Vtca). There was no alteration, at either dose, in mitochondrial coupling efficiency measured as the ratio of unidirectional ATP synthesis flux to Vtca. Soleus muscle GLUT4 expression was decreased by twofold, whereas pyruvate dehydrogenase kinase 4, carnitine palmitoyl transferase 1a, and uncoupling protein 2 and 3 expression was increased by two- to threefold at the high dose ( P < 0.05). In summary, these are the first noninvasive measurements illustrating a selective PPARδ-mediated decrease in muscle lipid content that was consistent with a shift in metabolic substrate utilization from carbohydrate to lipid. However, the mitochondrial-energy coupling efficiency was not altered in the presence of increased uncoupling protein expression.

scholarly journals Reciprocity between Skeletal Muscle AMPK Deletion and Insulin Action in Diet-Induced Obese Mice

2020 ◽  
Author(s):  
Ada Admin ◽  
Louise Lantier ◽  
Ashley S. Williams ◽  
Ian M.Williams ◽  
Amanda Guerin ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Insulin Signaling ◽  
Insulin Action ◽  
Energy State ◽  
Energy Charge ◽  
Ampk Signaling ◽  
Diet Induced Obesity ◽  
Energy Sensor ◽  
Amp Activated Protein Kinase

Insulin resistance due to overnutrition places a burden on energy-producing pathways in skeletal muscle (SkM). Nevertheless, energy state is not compromised. The hypothesis that the energy sensor AMP-activated protein kinase (AMPK) is necessary to offset the metabolic burden of overnutrition was tested using chow-fed and high fat (HF)-fed SkM-specific AMPKa1a2 knockout (mdKO) mice and AMPKa1a2lox/lox littermates (WT). Lean mdKO and WT mice were phenotypically similar. HF-fed mice were equally obese and maintained lean mass regardless of genotype. Results did not support the hypothesis that AMPK is protective during overnutrition. Paradoxically, mdKO mice were more insulin sensitive. Insulin-stimulated SkM glucose uptake was ~two-fold greater in mdKO mice in vivo. Furthermore, insulin signaling, SkM GLUT4 translocation, hexokinase activity, and glycolysis were increased. AMPK and insulin signaling intersect at mTOR, a critical node for cell proliferation and survival. Basal mTOR activation was reduced by 50% in HF-fed mdKO mice, but was normalized by insulin-stimulation. Mitochondrial function was impaired in mdKO mice, but energy charge was preserved by AMP deamination. Results show a surprising reciprocity between SkM AMPK signaling and insulin action that manifests with diet-induced obesity, as insulin action is preserved to protect fundamental energetic processes in the muscle.

scholarly journals Cardiolipin content controls mitochondrial coupling and energetic efficiency in muscle

2021 ◽  
Vol 7 (1) ◽  
pp. eabd6322
Author(s):  
Alexandre Prola ◽  
Jordan Blondelle ◽  
Aymeline Vandestienne ◽  
Jérôme Piquereau ◽  
Raphaël G. P. Denis ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Energy Expenditure ◽  
Coupling Efficiency ◽  
Chain Fatty Acid ◽  
Health Concern ◽  
Whole Body ◽  
Energetic Efficiency ◽  
Long Chain Fatty Acid ◽  
Basal Energy Expenditure ◽  
Long Chain

Unbalanced energy partitioning participates in the rise of obesity, a major public health concern in many countries. Increasing basal energy expenditure has been proposed as a strategy to fight obesity yet raises efficiency and safety concerns. Here, we show that mice deficient for a muscle-specific enzyme of very-long-chain fatty acid synthesis display increased basal energy expenditure and protection against high-fat diet–induced obesity. Mechanistically, muscle-specific modulation of the very-long-chain fatty acid pathway was associated with a reduced content of the inner mitochondrial membrane phospholipid cardiolipin and a blunted coupling efficiency between the respiratory chain and adenosine 5′-triphosphate (ATP) synthase, which was restored by cardiolipin enrichment. Our study reveals that selective increase of lipid oxidative capacities in skeletal muscle, through the cardiolipin-dependent lowering of mitochondrial ATP production, provides an effective option against obesity at the whole-body level.

2056-P: In Vivo Human Islet Compensation and Dysfunction to Diet-Induced Obesity: A Phase 0 Preclinical Model

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 2056-P
Author(s):  
JULIE A. KERR-CONTE ◽  
JULIEN THEVENET ◽  
GIANNI PASQUETTI ◽  
PAULINE PETIT ◽  
CLARA CLABAUT ◽  
...  
Keyword(s):  
Human Islet ◽  
Preclinical Model ◽  
Diet Induced Obesity ◽  
Phase 0
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