Dietary dicarboxylic acids provide a nonstorable alternative fat source that protects mice against obesity
Eric S. Goetzman, … , Steven F. Dobrowolski, Birgit Schilling
Eric S. Goetzman, … , Steven F. Dobrowolski, Birgit Schilling
Published April 30, 2024
Citation Information: J Clin Invest. 2024;134(12):e174186. https://doi.org/10.1172/JCI174186.
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Dietary dicarboxylic acids provide a nonstorable alternative fat source that protects mice against obesity

Abstract

Dicarboxylic fatty acids are generated in the liver and kidney in a minor pathway called fatty acid ω-oxidation. The effects of consuming dicarboxylic fatty acids as an alternative source of dietary fat have not been explored. Here, we fed dodecanedioic acid, a 12-carbon dicarboxylic (DC12), to mice at 20% of daily caloric intake for 9 weeks. DC12 increased metabolic rate, reduced body fat, reduced liver fat, and improved glucose tolerance. We observed DC12-specific breakdown products in liver, kidney, muscle, heart, and brain, indicating that oral DC12 escaped first-pass liver metabolism and was utilized 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 to the TCA cycle intermediate succinyl-CoA. In tissues with low peroxisomal fatty acid oxidation capacity, DC12 was oxidized by mitochondria. In vitro, DC12 was catabolized even by adipose tissue and was not stored intracellularly. We conclude that DC12 and other dicarboxylic acids may be useful for combatting obesity and for treating metabolic disorders.

Authors

Eric S. Goetzman, Bob B. Zhang, Yuxun Zhang, Sivakama S. Bharathi, Joanna Bons, Jacob Rose, Samah Shah, Keaton J. Solo, Alexandra V. Schmidt, Adam C. Richert, Steven J. Mullett, Stacy L. Gelhaus, Krithika S. Rao, Sruti S. Shiva, Katherine E. Pfister, Anne Silva Barbosa, Sunder Sims-Lucas, Steven F. Dobrowolski, Birgit Schilling

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Figure 1

A HFD substituted with DC12 increases metabolic rate and prevents obesity.

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A HFD substituted with DC12 increases metabolic rate and prevents obesit...
(A and B) Male 129S1 mice (n = 6) were transitioned to a HFD or the isocaloric DC12 diet at age 8 weeks. Food pellets were weighed every 2–3 days for 5 weeks to determine intake, and body weights were recorded every 2–3 days. (C and D) EchoMRI was used to assess total fat mass and lean mass after 5 weeks or 9 weeks of the special diets (n = 10). (E) Epididymal WAT (eWAT) was excised and weighed after 9 weeks on the diets. (F–I) HFD, DC12, and chow-fed control mice (n = 7–8) were subjected to indirect calorimetry after 7 days on the diets. Body weight was equal at the start of indirect calorimetry (F). Whole-body respiration was measured every 30 min over a 48 hr period (G). Panels H and I are the RER and energy expenditure calculated from the data in panel G, with each separated into night versus day cycles for statistical analysis. All graphs depict means and SDs. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001, by Student’s 2-sided t tests.