Obesity-associated lipidomic remodeling of the adrenal gland indicates an important role of the FADS2-arachidonic acid axis in adrenocortical hormone production

Objective Adrenocortical hormone levels increase in obesity, potentially contributing to development of obesity-associated pathologies. Here we explored whether lipidomic remodeling of the adrenal gland could mediate altered adrenocortical steroidogenesis during obesity. Methods Lipidomic analysis was performed in adrenal glands using shotgun mass spectrometry (MS), and steroid profiling of sera by liquid chromatography tandem mass spectrometry (LC-MS/MS) from lean and obese mice. Gene expression analysis was performed in adrenal glands and adrenocortical cell populations. The role of Fatty Acid Desaturase 2 (FADS2) and arachidonic acid on steroid hormone production was studied in primary adrenal gland cell cultures. Results Adrenal glands of obese mice displayed a distinct lipidomic profile, encompassing longer and more unsaturated storage lipids and phospholipids compared to adrenal glands of lean mice. Arachidonoyl acyl chains were abundant in the adrenal gland phospholipidome and increased upon obesity. This was accompanied by increased Fads2 expression, the rate-limiting enzyme of arachidonic acid synthesis, and enhanced plasma adrenocortical hormone levels. Inhibition of FADS2 in primary adrenal gland cell cultures abolished steroidogenesis, which was restored by arachidonic acid supplementation. Conclusions Our data suggest that the FADS2 – arachidonic acid axis regulates adrenocortical hormone synthesis, while alterations in the content of arachidonoyl chains in the adrenal gland phopsholipidome could account for disturbed adrenocortical hormone production. Highlights The adrenal gland lipidome is remodeled in obesity. Arachidonoyl groups are abundant in the adrenal gland phospholipidome and increase in obesity. FADS2 is highly expressed in the adrenal gland and its expression is further increased in obesity. FADS2 inhibition blunts adrenocortical steroidogenesis in primary adrenal gland cell cultures, while arachidonic acid supplementation restores it.