Loss of Muscle Carnitine Palmitoyltransferase 2 Prevents Diet-Induced Obesity and Insulin Resistance despite Long-Chain Acylcarnitine Accumulation

Pereyra, Andrea M.; Rajan, Arvind; Ferreira, Christina R.; Ellis, Jessica M.

doi:10.1016/j.celrep.2020.108374

Cited by 33 publications

(28 citation statements)

References 58 publications

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“…Because heart and skeletal muscle had higher oxidation rates for octanoyl-CoA + Carn and octanoylcarnitine, and because the only known mitochondrial acyl-CoA-acylcarnitine exchanger is the carnitine shuttle (CPT1-CACT-CPT2), we decided to determine if carnitine-palmitoyltransferase activity is required for oxidation of octanoylcarnitine. Oxidation rates were determined in skeletal muscle mitochondria from control and skeletal muscle-specific CPT2-deficient mice ( Cpt2 Sk −/− ) ( 24 ). In agreement with our previous findings in Cpt2 M−/− hearts ( 23 ), the oxidation rates of octanoylcarnitine in skeletal muscle mitochondria were not different between control and Cpt2 Sk −/− ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…This biophysical property is important for membrane curvature and protein-membrane interactions. It is possible that the reduction in highly unsaturated phospholipid species in Cpt2 M−/− hearts, and in Cpt2 Sk−/− muscles ( 24 ), is a compensatory mechanism to maintain membrane dynamics because of membrane acylcarnitine integration. Reduced membrane unsaturation is also reported in individuals with genetic defects in mFAO, and these patients are often supplemented with dietary DHA ( 66 ).…”

Section: Discussionmentioning

confidence: 99%

“…006475) or the human alpha-skeletal actin promoter (The Jackson Laboratory; stock no. 006149) as described ( 23 , 24 ). Littermates lacking the Cre transgene were used as controls.…”

Section: Methodsmentioning

confidence: 99%

“…All dietary interventions began between week 3 and 6 of age and lasted 4 weeks. For carnitine studies, powdered l -carnitine (Sigma C0283) was dissolved in the drinking water at 300 mg/kg/day, as described ( 24 , 25 ). Echocardiograms were collected as previously described ( 23 ) from isoflurane-anesthetized mice (1–3% in 1.5 l/min medical-grade air) via high-frequency ultrasound (Vevo2100; FUJIFILM VisualSonics).…”

Section: Methodsmentioning

confidence: 99%

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Octanoate is differentially metabolized in liver and muscle and fails to rescue cardiomyopathy in CPT2 deficiency

Pereyra

Harris

Soepriatna

et al. 2021

Journal of Lipid Research

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Long-chain fatty acid oxidation is frequently impaired in primary and systemic metabolic diseases affecting the heart; thus, therapeutically increasing reliance on normally minor energetic substrates, such as ketones and medium-chain fatty acids, could benefit cardiac health. However, the molecular fundamentals of this therapy are not fully known. Here, we explored the ability of octanoate, an eight-carbon medium-chain fatty acid known as an unregulated mitochondrial energetic substrate, to ameliorate cardiac hypertrophy in long-chain fatty acid oxidation-deficient hearts because of carnitine palmitoyltransferase 2 deletion ( Cpt2 M−/− ). CPT2 converts acylcarnitines to acyl-CoAs in the mitochondrial matrix for oxidative bioenergetic metabolism. In Cpt2 M − / − mice, high octanoate-ketogenic diet failed to alleviate myocardial hypertrophy, dysfunction, and acylcarnitine accumulation suggesting that this alternative substrate is not sufficiently compensatory for energy provision. Aligning this outcome, we identified a major metabolic distinction between muscles and liver, wherein heart and skeletal muscle mitochondria were unable to oxidize free octanoate, but liver was able to oxidize free octanoate. Liver mitochondria, but not heart or muscle, highly expressed medium-chain acyl-CoA synthetases, potentially enabling octanoate activation for oxidation and circumventing acylcarnitine shuttling. Conversely, octanoylcarnitine was oxidized by liver, skeletal muscle, and heart, with rates in heart 4-fold greater than liver and, in muscles, was not dependent upon CPT2. Together, these data suggest that dietary octanoate cannot rescue CPT2-deficient cardiac disease. These data also suggest the existence of tissue-specific mechanisms for octanoate oxidative metabolism, with liver being independent of free carnitine availability, whereas cardiac and skeletal muscles depend on carnitine but not on CPT2.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…006475) or the human alpha-skeletal actin promoter (The Jackson Laboratory; stock no. 006149) as described ( 23 , 24 ). Littermates lacking the Cre transgene were used as controls.…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Octanoate is differentially metabolized in liver and muscle and fails to rescue cardiomyopathy in CPT2 deficiency

Pereyra

Harris

Soepriatna

et al. 2021

Journal of Lipid Research

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show abstract

“…However, our recent work has cast doubt on a causal link between muscle long-chain acylcarnitine accumulation and insulin resistance. 10 Additional alternative mechanisms that may link obesogenic diets and diabetes to mitochondrial function include the obesity-related downregulation of transcription factors that drive nuclear-encoded mitochondrial genes (NEMGs), such as nuclear respiratory factor-1 (NRF-1) and peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α). 11,12 Conversely, exercise is an effector of both oxidative metabolic flux and an activator of transcription factors such as PGC-1α.…”

mentioning

confidence: 99%

A single bout of cycling exercise induces nucleosome repositioning in the skeletal muscle of lean and overweight/obese individuals

Devarshi¹,

Pereyra

Ellis

et al. 2021

Diabetes Obesity Metabolism

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Aim: To compare the molecular and metabolic effects of a single exercise bout in the skeletal muscle between lean and overweight/obese (Ov/Ob) individuals.Materials and Methods: Participants recruited were men, aged 19-30 years, who were either lean (body mass index [BMI] < 25, 18.5À24.1 kg/m 2 ; n = 15) or Ov/Ob (BMI ≥ 25, 25.5À36.9 kg/m 2 ; n = 15). Four hours after a high-carbohydrate breakfast (7 kcal/kg; 60% carbohydrate, 25% fat, 15% protein), participants performed a cycling exercise (50% VO 2 max, expending ~650 kcal). Muscle biopsies and peripheral blood samples were collected 30 minutes before the meal and immediately after exercise. Blood analysis, and muscle acylcarnitine profiles, transcriptomics, and nucleosome mapping by micrococcal nuclease digestion with deep sequencing were performed.Results: A single exercise bout improved blood metabolite profiles in both lean and Ov/Ob individuals. Muscle long-chain acylcarnitines were increased in Ov/Ob compared with lean participants, but were not altered by exercise. A single exercise bout increased the mRNA abundance of genes related to mitochondria and insulin signalling in both lean and Ov/Ob participants. Nucleosome mapping by micrococcal nuclease digestion with deep sequencing revealed that exercise repositioned the -1 nucleosome away from the transcription start site of the PGC1a promoter and of other mitochondrial genes, but did not affect genes related to insulin signalling, in both lean and Ov/Ob participants. Conclusion:These data suggest that a single exercise bout induced epigenetic alterations in skeletal muscle in a BMI-independent manner.

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Effect of vitamin A supplement on the growth performance, antioxidant status, and lipid accumulation of Chinese mitten crab Eriocheir Sinensis fed different lipid levels

et al. 2022

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Loss of Muscle Carnitine Palmitoyltransferase 2 Prevents Diet-Induced Obesity and Insulin Resistance despite Long-Chain Acylcarnitine Accumulation

Cited by 33 publications

References 58 publications

Octanoate is differentially metabolized in liver and muscle and fails to rescue cardiomyopathy in CPT2 deficiency

Octanoate is differentially metabolized in liver and muscle and fails to rescue cardiomyopathy in CPT2 deficiency

A single bout of cycling exercise induces nucleosome repositioning in the skeletal muscle of lean and overweight/obese individuals

Effect of vitamin A supplement on the growth performance, antioxidant status, and lipid accumulation of Chinese mitten crab Eriocheir Sinensis fed different lipid levels

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