A Gut Microbial Metabolite HYA Ameliorates Adipocyte Hypertrophy by Activating AMP-Activated Protein Kinase

<b>Background/Objectives:</b> Metabolites produced by gut microbiota play an important role in the crosstalk between the gut and other organs. Although HYA (10-hydroxy-<i>cis</i>-12-octadecenoic acid), a linoleic acid metabolite produced by lactic acid bacteria represented by <i>Lactobacillus</i>, has been shown to exert physiological effects such as metabolic improvement and anti-inflammation in the host, its direct action on adipose tissue and the mechanism remains unknown. <b>Methods</b>: The effect of HYA administration on adipocyte size in mice fed a high-fat diet was examined. In 3T3-L1 mature adipocytes treated with HYA, the amount of intracellular lipid droplets was evaluated by Oil red O staining, gene expression by real-time qPCR, phosphorylation of AMP-activated protein kinase (AMPK) by immunoblotting, and intracellular Ca²⁺ concentration with calcium imaging. <b>Results</b>: Administration of HYA, but not linoleic acid, to obese mice fed a high-fat diet significantly reduced adipocyte size. To investigate whether the inhibition of adipocyte hypertrophy by HYA has a direct effect on adipocytes, 3T3-L1 adipocytes were treated with HYA, which significantly decreased the amount of intracellular lipid droplets in these cells. Gene expression analysis by real-time PCR showed decreased expression of genes related to lipogenesis such as FAS and ACC1, and increased expression of CPT1A, which is involved in fatty acid oxidation. Mechanistically, HYA was found to activate AMPK in adipocytes by increasing intracellular Ca²⁺ concentration. <b>Conclusions</b>: HYA suppresses adipocyte hypertrophy by activating AMPK in adipocytes. HYA may be a potential therapeutic for obesity and related metabolic disorders.