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 ωoxidation. 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 nine 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.

Dicarboxylic acids counteract the metabolic effects of a Western diet by boosting energy expenditure

“…The paradigm of nutrient composition acknowledges only three energy substrates: glucose, amino acids, and fatty acids. In this issue of the JCI, Goetzman et al, ( 2 ) confirmed and magnified the evidence of previous investigations establishing the presence and metabolic importance of a fourth nutrient, DAs. While metabolizable DAs are classified as medium-chain fatty acids, they possess two terminal carboxylic groups that permit the formation of dicarboxylic salts, making them easily soluble in water and promptly available as energy.…”

“…Another important advantage of dietary DC12 over fatty acids that was highlighted in Goetzman et al ( 2 ) is its storage; DC12 was not stored intracellularly and thus it did not promote fat deposition. In other words, DAs are completely oxidized either in mitochondria or in peroxisomes ( Figure 1 ).…”

“…Goetzman et al, ( 2 ) fed mice with diets containing various fat combinations during a nine-week course. Unlike most dietary fats, DAs could not be stored, but, rather, were completely oxidized.…”

“…In an era where obesity has become a pandemic ( 10 ), DAs might represent a way to reduce the obesity burden in association with antiobesity medications and minimally invasive surgery. Moreover, Goetzman and colleagues ( 2 ) demonstrated that DAs, in particular DC12, increased energy expenditure.…”

“…Interestingly, Goetzman et al ( 2 ) proved that excess of succinate formation from DA oxidation increased protein succinylation also in white adipose tissue, promoting a process called “beiging” by binding the adipocyte surface through the succinate receptor GPR91. This is a very interesting observation.…”