Augmenting muscle diacylglycerol and triacylglycerol content by blocking fatty acid oxidation does not impede insulin sensitivity

Timmers, Silvie; Nabben, Miranda; Bosma, Madeleen; Bree, Bianca van; Lenaers, Ellen; Beurden, Denis van; Schaart, Gert; Westerterp-Plantenga, Margriet S.; Langhans, Wolfgang; Hesselink, Matthijs K. C.; Schrauwen‐Hinderling, Vera B.; Schrauwen, Patrick

doi:10.1073/pnas.1206868109

Cited by 72 publications

(72 citation statements)

References 38 publications

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“…Using the muscleselective Cpt1b inhibitor, oxfenicine, Keung et al (23) showed decreased diacylglycerol (DAG) and ceramide levels following short-term treatment of obese mice. In contrast, Timmers et al (21) showed increased IMCL and DAG accumulation following 8 d of treatment with the nonselective global Cpt1 inhibitor, etomoxir. These studies revealed short-term benefits in Significance Many theories regarding the causes of insulin resistance in skeletal muscle center on the ability of muscle to oxidize fat, with evidence supporting either decreased or increased fatty acid oxidation (FAO) as causal to insulin resistance.…”

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confidence: 94%

“…There have been a handful of studies that have used pharmacological inhibition of Cpt1 to target insulin resistance. The results are inconsistent and, in some cases, completely contradictory due to species/model differences and methods of assessing insulin sensitivity (17)(18)(19)(20)(21)(22)(23). These studies also lack tissue specificity and are generally of short duration and/or initiated after development of insulin resistance/diabetes.…”

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confidence: 99%

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Impaired mitochondrial fat oxidation induces adaptive remodeling of muscle metabolism

Wicks

Vandanmagsar

Haynie

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

107

134

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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 nonesterified fatty acids; and increased IMCLs, diacylglycerols, and ceramides. Perhaps more importantly, inhibition of mitochondrial FAO also initiates a local, adaptive response in muscle that invokes mitochondrial biogenesis, compensatory peroxisomal fat oxidation, and amino acid catabolism. Loss of its major fuel source (lipid) induces an energy deprivation response in muscle coordinated by signaling through AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) to maintain energy supply for locomotion and survival. At the whole-body level, these adaptations result in resistance to obesity.carnitine palmitoyltransferase | muscle | fatty acid | lipid | carbohydrate C onsiderable evidence suggests that when oversupply of dietary fat exceeds the storage capacity of adipose tissue, ectopic lipids accumulate in skeletal muscle, leading to "metabolic stress" that induces insulin resistance. One prevailing theory is that impaired skeletal muscle fatty acid oxidation (FAO) (1-4) leads to cytosolic accumulation of lipotoxic intermediates that are directly linked to defects in insulin signaling (5-11). Recent findings counter this premise because they have shown that models of insulin resistance consistently exhibit enhanced (not reduced) FAO, as demonstrated by elevated incomplete β-oxidation and accumulation of excess lipid-derived acylcarnitines (12, 13). Supporting evidence was obtained using a whole-body genetic approach to elevate levels of the endogenous carnitine palmitoyltransferase-1 (Cpt1) inhibitor, malonyl-CoA (12). These studies have led to the contrasting theory that lipid overload and incomplete FAO within the mitochondria accelerate the progression of insulin resistance (14). Faced with a plethora of studies supporting both hypotheses, a crucial question remains: "Is inhibition of mitochondrial FAO in skeletal muscle sufficient to initiate development of insulin resistance?" Cpt1 is essential for long-chain acyl-CoA transport into the mitochondria, and lies at the nexus of both the lipotoxicity and the mitochondrial overload hypotheses. If decreased FAO is a root cause of lipotoxicity, then muscle-specific ablation of Cpt1b activity should lead to impaired FAO, intramyocellular lipid (IMCL) accumulation, and insulin resistance. In stark contrast, the mitochondrial overload hypothesis suggests that decreased Cpt1b activity would preserve insulin sensitivity by preventing unbalanced overfueling of β-oxidation. Characterization of the rare genetic disorders o...

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confidence: 94%

mentioning

confidence: 99%

Impaired mitochondrial fat oxidation induces adaptive remodeling of muscle metabolism

Wicks

Vandanmagsar

Haynie

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

107

134

View full text Add to dashboard Cite

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“…If humans, animals or in vitro preparations of muscle are exposed to an increased availability of FAs in the presence of glucose, the oxidation of FAs increases and the oxidation and uptake of glucose decrease (Boden et al 1994, Vaag et al 1994. On the other hand, reduction of the availability of FAs by inhibiting lipolysis (Vaag et al 1991, Lim et al 2011 and blocking FA entry into the mitochondria reduces FA oxidation and increases glucose uptake and oxidation (Oakes et al 1997, Timmers et al 2012, Keung et al 2013, although there are some reports that prolonged inhibition of FA oxidation can lead to reduced glucose uptake (Dobbins et al 2001). Although the initial observations of Randle and colleagues on the reciprocal relationship between glucose and FA metabolism were made 50 years ago, the idea that increasing or reducing FA availability will reciprocally affect glucose utilisation is no less valid today.…”

Section: Substrate Competition and Reduced Insulin Actionmentioning

confidence: 99%

Fatty acid metabolism, energy expenditure and insulin resistance in muscle

Turner¹,

Cooney²,

Kraegen³

et al. 2013

Journal of Endocrinology

167

120

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Fatty acids (FAs) are essential elements of all cells and have significant roles as energy substrates, components of cellular structure and signalling molecules. The storage of excess energy intake as fat in adipose tissue is an evolutionary advantage aimed at protecting against starvation, but in much of today's world, humans are faced with an unlimited availability of food, and the excessive accumulation of fat is now a major risk for human health, especially the development of type 2 diabetes (T2D). Since the first recognition of the association between fat accumulation, reduced insulin action and increased risk of T2D, several mechanisms have been proposed to link excess FA availability to reduced insulin action, with some of them being competing or contradictory. This review summarises the evidence for these mechanisms in the context of excess dietary FAs generating insulin resistance in muscle, the major tissue involved in insulin-stimulated disposal of blood glucose. It also outlines potential problems with models and measurements that may hinder as well as help improve our understanding of the links between FAs and insulin action. (C:18:0), oleic acid (C18:1n-9), linoleic acid (C18:2n-6) and, particularly in smaller mammals, arachidonic acid (20:4n-6) and docosahexaenoic acid (22:6n-3). These FAs are the major components of storage triglycerides and cellular membranes, and although C16-C18 FAs are also components of some of the FA-derived signalling molecules (diacylglycerols (DAGs) and ceramides), many of the major lipid signalling molecules (prostaglandins and leukotrienes) are synthesised from very-long-chain, unsaturated FAs (e.g. arachidonic and docosahexaenoic acids) ( Kruger et al. 2010).In the context of the links between excessive lipid storage (obesity) and reduced insulin action (insulin Journal of EndocrinologyThematic Review N TURNER and others Fatty acids and insulin action 220:2 T61-T79

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“…shRNA-hBRCA1-or scrambled-shRNA-treated human myotubes were incubated in 30 M BSA-conjugated palmitate/oleate mixture in DMEM for 4 h as previously described ( 34 ). Myotubes were then stained with BODIPY (Molecular Probes, Carlsbad CA) as previously described ( 35 ).…”

Section: Human Myotube Palmitate/oleate Incubation and Bodipy Imagingmentioning

confidence: 99%

“…Myotubes were then stained with BODIPY (Molecular Probes, Carlsbad CA) as previously described ( 35 ). Myotubes were imaged with a Zeiss Axiovision 4 (Zeiss, Oberkochen, Germany) as previously described ( 34,36 ).…”

Section: Human Myotube Palmitate/oleate Incubation and Bodipy Imagingmentioning

confidence: 99%

BRCA1 is a novel regulator of metabolic function in skeletal muscle

Jackson

Gidlund

Norrbom

et al. 2014

Journal of Lipid Research

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This article is available online at http://www.jlr.org breast cancer and/or tumorigenesis in reproductive tissues ( 3 ). The BRCA1 gene produces either a full-length breast cancer type 1 susceptibility protein (BRCA1) or through alternatively splicing two documented variants, BRCA1 ⌬ 11 or BRCA1 ⌬ 11b, both of which lack a nuclear localization signal ( 4 ). Recently, BRCA1 was identifi ed as a regulator of lipid metabolism in human breast cancer cells (MCF7) as a result of direct interaction with the phosphorylated form of acetylCoA carboxylase (ACC-p) at the BRCA1 C-terminal (BRCT) domains ( 5, 6 ). The interaction encourages the maintenance of the phosphorylated state of ACC thereby altering lipid metabolism in the cancer cell line ( 5, 6 ).ACC has two isoforms, ACC1 or ACC2, with ACC2 containing an extra 146 amino acids in the NH 2 -terminal region. ACC activity is negatively regulated by phosphorylation of residue Ser 79 on ACC1 and Ser 221 on ACC2 ( 7,8 ). In the active form (i.e., dephosphorylated), ACC catalyzes the carboxylation of acetyl-CoA into malonyl-CoA (MaCoA). Changes in cellular MaCoA content alter intracellular lipid dynamics in two specifi c manners ( 9, 10 ). MaCoA directly contributes to de novo synthesis of palmitate via FAS and MaCoA also allosterically inhibits carnitine palmitoyltransferase-1 (CPT-1), a mitochondrial long chain fatty acid transporter ( 11 ). Thus, in mammary tissue the ability of BRCA1 to affect ACC activity alters cellular lipid concentrations by indirectly regulating rates of fatty acid synthesis and/or the fl ux of fatty acids into the mitochondria.Abstract Breast cancer type 1 (BRCA1) susceptibility protein is expressed across multiple tissues including skeletal muscle. The overall objective of this investigation was to defi ne a functional role for BRCA1 in skeletal muscle using a translational approach. For the fi rst time in both mice and humans, we identifi ed the presence of multiple isoforms of BRCA1 in skeletal muscle. In response to an acute bout of exercise, we found increases in the interaction between the native forms of BRCA1 and the phosphorylated form of acetyl-CoA carboxylase. Decreasing BRCA1 content using a shRNA approach in cultured primary human myotubes resulted in decreased oxygen consumption by the mitochondria and increased reactive oxygen species production. The decreased BRCA1 content also resulted in increased storage of intracellular lipid and reduced insulin signaling. These results indicate that BRCA1 plays a critical role in the regulation of metabolic function in skeletal muscle. Collectively, these data reveal BRCA1 as a novel target to consider in our understanding of metabolic function and risk for development of metabolic-based diseases. -Jackson, K. C., E-K. Gidlund, J. Abbreviations: ACC, acetyl-CoA carboxylase; ACC-p, phosphorylated form of acetyl-CoA carboxylase; AICAR, 5-amino-1-β-D-ribofuranosylimidazole-4-carboxamide; AMPK, AMP-activated protein kinase; BRCA1, Breast Cancer 1, early onset; BRCA1 MG KO, mammary gland tissue fr...

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Augmenting muscle diacylglycerol and triacylglycerol content by blocking fatty acid oxidation does not impede insulin sensitivity

Cited by 72 publications

References 38 publications

Impaired mitochondrial fat oxidation induces adaptive remodeling of muscle metabolism

Impaired mitochondrial fat oxidation induces adaptive remodeling of muscle metabolism

Fatty acid metabolism, energy expenditure and insulin resistance in muscle

BRCA1 is a novel regulator of metabolic function in skeletal muscle

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