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Extensive metabolic remodeling after limiting mitochondrial lipid burden is consistent with an improved metabolic health profile

Published on Aug 16, 2019in Journal of Biological Chemistry
路 DOI :10.1074/jbc.RA118.006074
Sujoy Ghosh30
Estimated H-index: 30
(Pennington Biomedical Research Center),
Shawna E. Wicks8
Estimated H-index: 8
(Pennington Biomedical Research Center)
+ 7 AuthorsRobert C. Noland19
Estimated H-index: 19
(Pennington Biomedical Research Center)
Abstract
  • References (47)
  • Citations (2)
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References47
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#1Jaycob D. Warfel (LSU: Louisiana State University)H-Index: 4
#2Bolormaa Vandanmagsar (LSU: Louisiana State University)H-Index: 10
Last. Randall L. Mynatt (LSU: Louisiana State University)H-Index: 30
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Inhibiting fatty acid oxidation is one approach to lowering glucose levels in diabetes. Skeletal muscle specific Carnitine Palmitoyltransferase 1b knockout mice (Cpt1bm-/-) comprise a model of impaired fat oxidation; and have decreased fat mass and enhanced glucose disposal and muscle oxidative capacity compared to controls. However, unfavorable effects occur relative to controls when Cpt1bm-/- mice are fed a 25% fat diet, including decreased activity and fat free mass and increased intramuscula...
4 CitationsSource
#1Monkol Lek (Broad Institute)H-Index: 35
#2Konrad J. Karczewski (Broad Institute)H-Index: 35
Last. Daniel G. MacArthur (Broad Institute)H-Index: 57
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Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Here we describe the aggregation and analysis of high-quality exome (protein-coding region) DNA sequence data for 60,706 individuals of diverse ancestries generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence fo...
4,484 CitationsSource
#1Bolormaa Vandanmagsar (LSU: Louisiana State University)H-Index: 10
#2Jaycob D. Warfel (LSU: Louisiana State University)H-Index: 4
Last. Randall L. Mynatt (LSU: Louisiana State University)H-Index: 30
view all 11 authors...
Summary Fatty acids are the primary fuel source for skeletal muscle during most of our daily activities, and impaired fatty acid oxidation (FAO) is associated with insulin resistance. We have developed a mouse model of impaired FAO by deleting carnitine palmitoyltransferase-1b specifically in skeletal muscle聽( Cpt1b m鈭/鈭 ). Cpt1b m鈭/鈭 mice have increased glucose utilization and are resistant to diet-induced obesity. Here, we show that inhibition of mitochondrial FAO induces FGF21 expression spec...
30 CitationsSource
#1Michael N. Davies (Duke University)H-Index: 3
#2Lilja Kjalarsdottir (Duke University)H-Index: 1
Last. Deborah M. Muoio (Duke University)H-Index: 50
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Lysine acetylation (AcK), a posttranslational modification wherein a two-carbon acetyl group binds covalently to a lysine residue, occurs prominently on mitochondrial proteins and has been linked to metabolic dysfunction. An emergent theory suggests mitochondrial AcK occurs via mass action rather than targeted catalysis. To test this hypothesis, we performed mass spectrometry-based acetylproteomic analyses of quadriceps muscles from mice with skeletal muscle-specific deficiency of carnitine acet...
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#1J. Michael SalbaumH-Index: 16
#2Claudia KrugerH-Index: 10
Last. Claudia KappenH-Index: 16
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Failure to close the neural tube results in birth defects, with severity ranging from spina bifida to lethal anencephaly. Few genetic risk factors for neural tube defects are known in humans, highlighting the critical role of environmental risk factors, such as maternal diabetes. Yet, it is not well understood how altered maternal metabolism interferes with embryonic development, and with neurulation in particular. We present evidence from two independent mouse models of diabetic pregnancy that ...
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#1Arthur Liberzon (Broad Institute)H-Index: 14
#2Chet Birger (Broad Institute)H-Index: 6
Last. Pablo Tamayo (UCSD: University of California, San Diego)H-Index: 58
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Summary The Molecular Signatures Database (MSigDB) is one of the most widely used and comprehensive databases of gene sets for performing gene set enrichment analysis. Since its creation, MSigDB has grown beyond its roots in metabolic disease and cancer to include >10,000 gene sets. These better represent a wider range of biological processes and diseases, but the utility of the database is reduced by increased redundancy across, and heterogeneity within, gene sets. To address this challenge, he...
874 CitationsSource
#1Shawna E. Wicks (Pennington Biomedical Research Center)H-Index: 8
#2Bolormaa Vandanmagsar (Pennington Biomedical Research Center)H-Index: 10
Last. Randall L. Mynatt (Pennington Biomedical Research Center)H-Index: 30
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The correlations between intramyocellular lipid (IMCL), decreased fatty acid oxidation (FAO), and insulin resistance have led to the hypothesis that impaired FAO causes accumulation of lipotoxic intermediates that inhibit muscle insulin signaling. Using a skeletal muscle-specific carnitine palmitoyltransferase-1 KO model, we show that prolonged and severe mitochondrial FAO inhibition results in increased carbohydrate utilization, along with reduced physical activity; increased circulating nonest...
42 CitationsSource
The increased prevalence of hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, and fatty liver disease has provided increasingly negative connotations toward lipids. However, it is important to remember that lipids are essential components supporting life. Lipids are a class of molecules defined by their inherent insolubility in water. In biological systems, lipids are either hydrophobic (containing only polar groups) or amphipathic (possess polar and nonpolar groups). These characteris...
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#1Hideo Matsumura (Shinshu University)H-Index: 31
#2Detlev H. Kr眉ger (Charit茅)H-Index: 42
Last. Ryohei TerauchiH-Index: 50
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#1Michael I. Love (MPG: Max Planck Society)H-Index: 21
#2Wolfgang HuberH-Index: 76
Last. Simon AndersH-Index: 25
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In comparative high-throughput sequencing assays, a fundamental task is the analysis of count data, such as read counts per gene in RNA-seq, for evidence of systematic changes across experimental conditions. Small replicate numbers, discreteness, large dynamic range and the presence of outliers require a suitable statistical approach. We present DESeq2, a method for differential analysis of count data, using shrinkage estimation for dispersions and fold changes to improve stability and interpret...
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#1Nadia Ml Amorim (UNSW: University of New South Wales)
#2Anthony J. Kee (UNSW: University of New South Wales)H-Index: 21
Last. David Simar (UNSW: University of New South Wales)H-Index: 20
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Abstract Background Metabolic complications are highly prevalent in cancer survivors treated with irradiation but the underlying mechanisms remain unknown. Methods Chow or high fat-fed C57Bl/6鈥疛 mice were irradiated (6Gy) before investigating the impact on whole-body or skeletal muscle metabolism and profiling their lipidomic signature. Using a transgenic mouse model (Tg:Pax7-nGFP), we isolated muscle progenitor cells (satellite cells) and characterised their metabolic functions. We recruited ch...
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Fatty acids and glucose are the main bioenergetic substrates in mammals. Impairment of mitochondrial fatty acid oxidation causes mitochondrial myopathy leading to decreased physical performance. Here, we report that haploinsufficiency of ADCK2, a member of the aarF domain-containing mitochondrial protein kinase family, in human is associated with liver dysfunction and severe mitochondrial myopathy with lipid droplets in skeletal muscle. In order to better understand the etiology of this rare dis...
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#1P. Darrell Neufer (ECU: East Carolina University)H-Index: 40
Competing theories have held opposite views on the role of flux through 尾-oxidation in causing insulin resistance. New transcriptomics, proteomics, and metabolomics data of skeletal muscle from mice in which lipid oxidation is limited by restricting entry of fat into mitochondria reveal extensive remodeling of metabolic pathways, consistent with an overall reduction in metabolic efficiency and improved metabolic health. These findings point to a potential new therapeutic approach for treating in...
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