PPARγ activation mitigates glucocorticoid receptor‐induced excessive lipolysis in adipocytes via homeostatic crosstalk

Proper balance between lipolysis and lipogenesis in adipocytes determines the release of free fatty acids (FFA) and glycerol, which is crucial for whole body lipid homeostasis. Although, dysregulation of lipid homeostasis contributes to various metabolic complications such as insulin resistance, the regulatory mechanism remains elusive. This study clarified the individual and combined roles for glucocorticoid receptor (GCR) and peroxisome proliferator‐activated receptor (PPAR)γ pathways in lipid metabolism of adipocytes. In mature 3T3‐L1 adipocytes, GCR activation using dexamethasone upregulated adipose triglyceride lipase (ATGL) and downregulated phosphoenolpyruvate carboxykinase (PEPCK), resulting in enhanced glycerol release into the medium. In contrast, PPARγ ligand pioglitazone modestly upregulated ATGL and hormone sensitive lipase (HSL), but markedly enhanced PEPCK and glycerol kinase (GK), thereby suppressed glycerol release. Dexamethasone showed permissive like effect on PPARγ target genes including perilipin A and aP2, therefore co‐administration of dexamethasone and pioglitazone demonstrated synergistic upregulation of these enzymes excepting PEPCK, of which downregulation by dexamethasone was abolished by pioglitazone to the level above control. Thus, the excessive glycerol release was prevented as the net outcome of the co‐administration. Consistently, the bodipy stain demonstrated that dexamethasone reduced the amount of cytosolic lipid, which was preserved in co‐treated adipocytes. Moreover, silencing of PPARγ suppressed the synergistic effects of co‐treatment on the lipolytic and lipogenic genes, and therefore the GCR pathway indeed involves PPARγ. In conclusion, crosstalk between GCR and PPARγ is largely synergistic but counter‐regulatory in lipogenic genes, of which enhancement prevents excessive glycerol and possibly FFA release by glucocorticoids into the circulation. (i) Glucocorticoid receptor (GCR) activation enhances lipolysis in adipocytes; (ii) a crosstalk exists between peroxisome proliferator‐activated receptor (PPAR)γ and GCR; (iii) PPARγ can mitigate the deleterious lipolytic effect of GCR; and (iv) interestingly, permissive effect of GCR enables PPARγ to produce this beneficial effect.