ESPE Yearbook of Paediatric Endocrinology

Brief Summary: This study demonstrates that FADS2 is a major regulator of steroidogenesis in the adrenal gland due to its key role in shaping the lipidomic landscape of adrenocortical cells.

Comment: The corticosteroids aldosterone and cortisol are produced in the zona glomerulosa and zona fasciculata of the adrenal cortex, respectively (1, 2). Excess production of aldosterone in primary hyperaldosteronism results in resistant hypertension and cardiovascular disease (1), while hypercortisolism leads to several comorbidities, including central obesity, impaired glucose tolerance and Type 2 diabetes (T2D), dyslipidemia and hypertension (3). Obesity is associated with moderately increased glucocorticoid production, which exacerbates central obesity, hyperlipidemia, hypertension and cardiovascular disease risk (4–8). However, the mechanisms underlying increased corticoid production in obesity are not fully understood.

Corticosteroid synthesis in the adrenal cortex requires the release of cholesterol from lipid droplets, where it is stored in the form of cholesterol esters (CE), and its translocation into mitochondria via the steroidogenic acute regulatory (StAR) protein, which is the rate-limiting step of steroidogenesis. Once inside the mitochondria, cholesterol is used for steroidogenesis through a series of enzymatic steps.

This study investigated the impact of mitochondrial membrane lipids on steroidogenesis in adrenocortical cells, and in particular to which extent the lipidomic landscape of the adrenal gland affects its steroidogenic function. It analyzed the adrenal lipidome of lean and obese mice and found that a high content of phospholipids in longer and more unsaturated lipids is associated with increased steroidogenesis in obese mice. Arachidonic acid (ARA) is a particularly abundant acyl chain in adrenal phospholipids and is increased with obesity. Inhibition of fatty acid desaturase 2 (FADS2), the rate-limiting enzyme of polyunsaturated fatty acid (PUFA) synthesis, transformed the mitochondrial lipidome, inhibited cholesterol import, and diminished steroidogenesis. FADS2 is highly expressed in the adrenal gland compared to other tissues and is increased in the adrenal gland of obese animals. FADS2 deficiency in mice impaired mitochondrial structure in adrenocortical cells and reduced corticosterone and aldosterone production. Conversely, FADS2 expression was up-regulated in the adrenal glands of obese mice and in aldosterone-producing adenomas compared to non-active adenomas (producing low amounts of aldosterone) and non-tumorous adrenocortical tissue of patients, while FADS2 inhibition reduced corticoid concentrations in obese mice.

These data collectively identify FADS2 as a major regulator of adrenal gland steroidogenesis due to its key role in shaping the lipidomic landscape of adrenocortical cells. Moreover, the adrenal lipidome can be modulated by icosapent ethyl dietary supplementation, which consequently influences corticoid production. This finding endorses the evaluation of icosapent ethyl dietary supplementation as a means to regulate cortisol and aldosterone concentrations in obesity. Ethyl eicosapentaenoic acid (E-EPA, icosapent ethyl) is made from the omega-3 fatty acid eicosapentaenoic acid (EPA) and is often used to treat dyslipidemia and hypertriglyceridemia. Finally, these data indicate a clear correlation between FADS2 expression and steroidogenic capacity in the human adrenal gland. The role of FADS2–mediated lipidomic changes in adrenocortical tumorigenesis should be further investigation.

References: 1. Feldman RD. Aldosterone and blood pressure regulation: recent milestones on the long and winding road from electrocortin to KCNJ5 GPER, and beyond. Hypertension. 2014; 63(1): 19-21.2. Lightman SL, Birnie MT, Conway-Campbell BL. Dynamics of ACTH and Cortisol Secretion and Implications for Disease. Endocr Rev. 2020; 41(3): bnaa002.3. Koch CA. Cushing syndrome and glucocorticoid excess, in Disorders of Blood Pressure Regulation: Phenotypes, mechanisms, therapeutic options, A. Berbari, G. Mancia, Eds, (Springer, 2018), pp. 481–512.4. Calhoun DA, Sharma K. The role of aldosteronism in causing obesity-related cardiovascular risk. Cardiol Clin. 2010; 28(3): 517-27.5. Swierczynska MM, Mateska I, Peitzsch M, Bornstein SR, Chavakis T, Eisenhofer G, Lamounier-Zepter V, Eaton S. Changes in morphology and function of adrenal cortex in mice fed a high-fat diet. Int J Obes (Lond). 2015; 39(2): 321-30.6. Hofmann A, Peitzsch M, Brunssen C, Mittag J, Jannasch A, Frenzel A, Brown N, Weldon SM, Eisenhofer G, Bornstein SR, Morawietz H. Elevated Steroid Hormone Production in the db/db Mouse Model of Obesity and Type 2 Diabetes. Horm Metab Res. 2017; 49(1): 43-49.7. Galitzky J, Bouloumié A. Human visceral-fat-specific glucocorticoid tuning of adipogenesis. Cell Metab. 2013; 18(1): 3-5.8. Roberge C, Carpentier AC, Langlois MF, Baillargeon JP, Ardilouze JL, Maheux P, Gallo-Payet N. Adrenocortical dysregulation as a major player in insulin resistance and onset of obesity. Am J Physiol Endocrinol Metab. 2007; 293(6): E1465-78.