Reduced metabolic capacity is a hallmark of numerous rare genetic diseases as well as more common disease states such as obesity, diabetes, heart disease, and neurological disorders. However, therapies that stimulate energy metabolism are lacking. Here, we show that substituting ~2/3 of the lipid in a high-fat rodent diet with dodecanedioc acid, a 12-carbon dicarboxylic fatty acid (DC12), increases metabolic rate, reduces body fat, reduces liver fat, and improves glucose tolerance. We observed DC12-specific breakdown products in liver, kidney, muscle, heart, and brain, indicating that oral DC12 escapes first-pass liver metabolism and is metabolized by many tissues. In tissues expressing the a isoform of acyl-CoA oxidase-1 (ACOX1), a key peroxisomal fatty acid oxidation enzyme, DC12 was chain shortened as far as the TCA cycle intermediate succinyl-CoA, which may partially explain the increased metabolic rate. In tissues with low peroxisomal fatty acid oxidation capacity, DC12 was oxidized by mitochondria. DC12 was catabolized even by adipose tissue and cannot be stored intracellularly like other fat sources. Finally, we demonstrate that dicarboxylic acids are a useful alternative energy source to improve metabolic function in a mouse model of long-chain fatty acid oxidation disorders.
[doi:10.25345/C5JW86X8X]
[dataset license: CC0 1.0 Universal (CC0 1.0)]
Keywords: Dodecanedioc acid ; Succinate pro-drug ; Succinylation ; Quantitative proteomics ; Data-independent acquisition (DIA) ; Acyl-CoA oxidase-1 (ACOX1) ; Parallel reaction monitoring (PRM)
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Birgit Schilling, Buck Institute, USA |
Submitting User: | JoannaBons |
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