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 3

Dietary DC12 is excreted only in trace amounts and is not stored intracellularly.

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Dietary DC12 is excreted only in trace amounts and is not stored intrace...
(A) Male 129S1 mice (n = 3) were adapted to either a HFD or an isocaloric DC12 diet for 5 weeks, and nighttime urine was collected for mass spectrometry to detect DCAs. (B) Male 129S1 mice (n = 4) were adapted to the DC12 diet over a 5 day period, with 24-hr urine samples collected on days 0, 1, 3, and 5 for mass spectrometry to detect DCAs. (C) Similarly, fecal pellets were collected from n = 3–4 male 129S1 mice on days 0 and 7 of DC12 adaptation for mass spectrometry. (D and E) Primary hepatocytes (D) or white adipose explants (E) were incubated with 14C-labeled palmitate (C16) or DC12 for 3 hr, washed, and extracted for lipids and FAO products (n = 5).The amount of stored versus oxidized are expressed as a percentage of the total radiolabel signal detected. (F) WAT (n = 3) blotted for the mitochondrial marker Hsp60 and Ucp1; bar graphs show densitometric analysis normalized to ponceau stain. All graphs represent means and SDs. In panel B, *P < 0.05, DC6 versus Day 0; #P < 0.05, DC8 versus Day 0. In remaining panels: **P < 0.01, ***P < 0.001, ****P < 0.0001. All were analyzed with 2-sided Student’s t test.