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. ### Competing Interest Statement The authors have declared no competing interest. * ACTH : adrenocorticotropic hormone CE : cholesterol ester Cer : ceramide Chol : cholesterol CL : cardiolipin DAG : diacylglycerol DBI : double bond index FADS2 : Fatty Acid Desaturase 2 HexCer : hexosylceramide HFD : high-fat diet LC-MS/MS : liquid chromatography tandem mass spectrometry LI : length index LPA : lyso-phosphatidate LPC : lyso-phosphatidylcholine LPE : lyso-phosphatidylethanolamine LPE O- : ether-linked LPE LPG : lyso-phosphatidylglycerol LPI : lyso-phosphatidylinositol LPS : lyso-phosphatidylserine ND : normal diet PA : phosphatidic acid PC : phosphatidylcholine PC O- : ether-linked PC PCA : principal component analysis PE : phosphatidylethanolamine PE O_ : ether-linked PE PG : phosphatidylglycerol PI : phosphatidylinositol PS : phosphatidylserine PUFA : polyunsaturated fatty acid SM : sphingomyelin TAG : triacylglyceride StAR : Steroidogenic acute regulatory protein Cyp11a1 : Cytochrome P450 Family 11 Subfamily A Member 1 3b-HSD2 : 3b-hydroxysteroid dehydrogenase type 2 Cyp21a1 : Cytochrome P450 Family 21 Subfamily A Member 1 Cyp11b1 : Cytochrome P450 Family 11 Subfamily B Member 1 Cyp11b2 : Cytochrome P450 Family 11 Subfamily B Member 2