Aconitate decarboxylase 1 regulates glucose homeostasis and obesity in mice

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.

Automated summary

The study suggests that Acod1 plays an important role in regulating glucose homeostasis and obesity. Acod1(-/-) mice showed impaired glucose metabolism and higher blood glucose levels on a high-fat diet. The absence of Acod1 also led to an increase in fat deposition and insulin resistance.