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Resistance to high-fat diet-induced obesity and insulin resistance in mice with very long-chain acyl-CoA dehydrogenase deficiency.

ABSTRACT: Mitochondrial fatty acid oxidation provides an important energy source for cellular metabolism, and decreased mitochondrial fatty acid oxidation has been implicated in the pathogenesis of type 2 diabetes. Paradoxically, mice with an inherited deficiency of the mitochondrial fatty acid oxidation enzyme, very long-chain acyl-CoA dehydrogenase (VLCAD), were protected from high-fat diet-induced obesity and liver and muscle insulin resistance. This was associated with reduced intracellular diacylglycerol content and decreased activity of liver protein kinase Cvarepsilon and muscle protein kinase Ctheta. The increased insulin sensitivity in the VLCAD(-/-) mice were protected from diet-induced obesity and insulin resistance due to chronic activation of AMPK and PPARalpha, resulting in increased fatty acid oxidation and decreased intramyocellular and hepatocellular diacylglycerol content.

SUBMITTER: Zhang D

PROVIDER: S-EPMC3146169 | biostudies-other | 2010 May

REPOSITORIES: biostudies-other

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Resistance to high-fat diet-induced obesity and insulin resistance in mice with very long-chain acyl-CoA dehydrogenase deficiency.

Zhang Dongyan D Christianson Jennifer J Liu Zhen-Xiang ZX Tian Liqun L Choi Cheol Soo CS Neschen Susanne S Dong Jianying J Wood Philip A PA Shulman Gerald I GI

Cell metabolism 20100501 5

Mitochondrial fatty acid oxidation provides an important energy source for cellular metabolism, and decreased mitochondrial fatty acid oxidation has been implicated in the pathogenesis of type 2 diabetes. Paradoxically, mice with an inherited deficiency of the mitochondrial fatty acid oxidation enzyme, very long-chain acyl-CoA dehydrogenase (VLCAD), were protected from high-fat diet-induced obesity and liver and muscle insulin resistance. This was associated with reduced intracellular diacylglyc ...[more]

PMID: 20444420

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Project description:BackgroundVery-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (VLCADD) is diagnosed in the US through newborn screening (NBS). NBS often unequivocally identifies affected individuals, but a growing number of variant patterns can represent mild disease or heterozygous carriers.AimsTo evaluate the validity of standard diagnostic procedures for VLCADD by using functional in vitro tools.MethodsWe retrospectively investigated 13 patient samples referred to our laboratory because of a suspicion of VLCADD but with some uncertainty to the diagnosis. All 13 patients were suspected of having VLCADD either because of abnormal NBS or suggestive clinical findings. ACADVL genomic DNA sequencing data were available for twelve of them. Ten of the patients had an abnormal NBS suggestive of VLCADD, with three samples showing equivocal results. Three exhibited suggestive clinical findings and blood acylcarnitine profile (two of them had a normal NBS and the third one was unscreened). Assay of VLCAD activity and immunoblotting or immunohistologic staining for VLCAD were performed on fibroblasts. Prokaryotic mutagenesis and expression studies were performed for nine uncharacterized ACADVL missense mutations.ResultsVLCAD activity was abnormal in fibroblast cells from 9 patients (8 identified through abnormal NBS, 1 through clinical symptoms). For these 9 patients, immunoblotting/staining showed the variable presence of VLCAD; all but one had two mutated alleles. Two patients with equivocal NBS results (and a heterozygous genotype) and the two patients with normal NBS exhibited normal VLCAD activity and normal VLCAD protein on immunoblotting/staining thus ruling out VLCAD deficiency. Nine pathogenic missense mutations were characterized with prokaryotic expression studies and showed a decrease in enzyme activity and variable stability of VLCAD antigen.ConclusionsThese results emphasize the importance of functional investigation of abnormal NBS or clinical testing suggestive but not diagnostic of VLCADD. A larger prospective study is necessary to better define the clinical and metabolic ramifications of the defects identified in such patients.

Project description:Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a rare disorder of mitochondrial fatty acid β-oxidation characterized by a spectrum of clinical manifestations. Patients with the adult-onset form can present with muscle pain, rhabdomyolysis and myoglobinuria after physiological stress, such as fasting and exercise. We report on a 23-year-old female patient with a history of recurrent rhabdomyolysis. The patient completed a 6-month supervised combined (high-intensity interval training [HIIT] + resistance training) program, with the addition of a medium chain triglyceride + carbohydrate supplement provided 60 min before each session. The HIIT consisted of 6 sets of 70-80 s performed at maximum intensity with a minimum cadence of 100 rpm. Resistance training consisted of a circuit of basic exercises with dumbbells and elastic bands, with sets of 4-7 repetitions. The patient was evaluated at months 0, 3 and 6 using an incremental discontinuous step protocol, with steps of 1 min of exercise/1 min of passive recovery, at a high pedal cadence. The test started at 10 W, with a load increase of 10 W/step. Blood creatine kinase (CK) concentration was measured before each evaluation. There was a training-induced increment of 90.2% in peak oxygen uptake (VO2peak), 71.4% in peak power output and 24.7% in peak heart rate. The patient reported no muscle pain, contractures, rhabdomyolysis (basal CK concentration was always <200 U/L) or hospital admissions during the training period. After completion of 6-month program, the patient remained active, doing similar but non-supervised training for 1.5 years (to date). During this period, the patient has not reported myalgias, contractures, rhabdomyolysis or hospital admissions. Our preliminary data suggest that it is possible to carry out a combined (HIIT + strength) training program in patients with VLCADD, safely (without muscle contractures or rhabdomyolysis) and obtaining high values of VO2peak and cycling power output.

Dataset Information

Resistance to high-fat diet-induced obesity and insulin resistance in mice with very long-chain acyl-CoA dehydrogenase deficiency.

Publications

Resistance to high-fat diet-induced obesity and insulin resistance in mice with very long-chain acyl-CoA dehydrogenase deficiency.

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