PPARγ Activation Mitigates Glucocorticoid Receptor-Induced Excessive Lipolysis in Adipocytes via Homeostatic Crosstalk†
| Autor: | Arif Ul Hasan, Hiroyuki Kobori, Kazuyo Kamitori, Asadur Rahman, Masaaki Tokuda, Koji Ohmori, Takeshi Hashimoto, Fuminori Yamaguchi |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Glycerol kinase medicine.medical_specialty Lipolysis Peroxisome proliferator-activated receptor 030209 endocrinology & metabolism Hormone-sensitive lipase Biochemistry Article Dexamethasone 03 medical and health sciences Mice 0302 clinical medicine Glucocorticoid receptor Receptors Glucocorticoid Internal medicine 3T3-L1 Cells medicine Adipocytes Animals Molecular Biology chemistry.chemical_classification Pioglitazone Chemistry Lipid metabolism Cell Biology PPAR gamma 030104 developmental biology Endocrinology Adipose triglyceride lipase Perilipin |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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