Aconitate decarboxylase 1 regulates glucose homeostasis and obesity in mice

Ryan A. Frieler*, Thomas M. Vigil, Jianrui Song, Christy Leung, Daniel R. Goldstein, Carey N. Lumeng, Richard M. Mortensen*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)


Objective: The intersection between immunology and metabolism contributes to the pathogenesis of obesity-associated metabolic diseases as well as molecular control of inflammatory responses. The metabolite itaconate and the cell-permeable derivatives have robust anti-inflammatory effects; therefore, it is hypothesized that cis-aconitate decarboxylase (Acod1)-produced itaconate has a protective, anti-inflammatory effect during diet-induced obesity and metabolic disease. Methods: Wild-type and Acod1−/− mice were subjected to diet-induced obesity. Glucose metabolism was analyzed by glucose tolerance tests, insulin tolerance tests, and indirect calorimetry. Gene expression and transcriptome analysis was performed using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and RNA sequencing. Results: Wild-type and Acod1−/− mice on high-fat diet had equivalent weight gain, but Acod1−/− mice had impaired glucose metabolism. Insulin tolerance tests and glucose tolerance tests after 12 weeks on high-fat diet revealed significantly higher blood glucose levels in Acod1−/− mice. This was associated with significant enrichment of inflammatory gene sets and a reduction in genes related to adipogenesis and fatty acid metabolism. Analysis of naive Acod1−/− mice showed a significant increase in fat deposition at 3 and 6 months of age and obesity and insulin resistance by 12 months. Conclusions: The data show that Acod1 has an important role in the regulation of glucose homeostasis and obesity under normal and high-fat diet conditions.

Original languageEnglish
Pages (from-to)1818-1830
Number of pages13
Issue number9
Publication statusPublished - Sept 2022
Externally publishedYes


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