Direct Effect of Glucocorticoids on Lipolysis in Adipocytes

Abstract

Hypercortisolemia and glucocorticoid treatment cause elevated level of circulating free fatty acids (FFAs). The basis of this phenomenon has long been linked to the effect of glucocorticoids permitting and enhancing the adipose lipolysis response to various hormones. In this study, we demonstrate that glucocorticoids directly stimulate lipolysis in rat primary adipocytes in a dose- and time-responsive manner; this lipolytic action was attenuated by treatment with the glucocorticoid antagonist RU486. Dexamethasone down-regulates mRNA and protein levels of cyclic-nucleotide phosphodiesterase 3B, thereby elevating cellular cAMP production and activating protein kinase A (PKA). On inhibition of PKA but not other kinases, the lipolysis response ceases. Furthermore, dexamethasone induces phosphorylation and down-regulation of perilipin, a lipid droplet-associating protein that modulates lipolysis; this effect is restored by RU486 or PKA inhibitor H89. Dexamethasone up-regulates mRNA and protein levels of hormone-sensitive lipase (HSL) and adipose triglyceride lipase; these effects, parallel to increased lipolysis, are attenuated by RU486 or actinomycin D. Phosphorylation at Ser-563 and Ser-660 residues of HSL and activity of cellular lipases are elevated on dexamethasone stimulation but abrogated by the coaddition of H89. However, dexamethasone does not induce HSL translocation to the lipid droplet surface in differentiated adipocytes. We show that elevated FFA concentration in plasma is associated with increased lipase activity and lipolysis in vivo in adipose tissues of dexamethasone-treated rats. Therefore, the lipolytic action of glucocorticoids liberates FFA efflux from adipocytes to the bloodstream, which could be a cellular basis of systemic FFA elevation in response to glucocorticoid challenge.

11β-HSD1 is the major regulator of the tissue-specific effects of circulating glucocorticoid excess

“…This strongly suggests increased intracellular GC availability in adipose tissue, and not the liver, underpins hepatic TAG accumulation in GCtreated WT mice. In support, GCs are well known to directly stimulate lipolysis in adipose tissue, resulting in elevated serum free fatty acid levels (26). However, we have not fully discounted the possibility that increased GC delivery from adipose tissue to the liver via the portal vein underpins these phenotypic observations.…”

Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones

“…The metabolic response of adipose tissue to glucocorticoids also depends on the duration of exposure. There is not an acute lipolytic response to glucocorticoids, yet, chronically elevated glucocorticoids stimulate lipolysis in adipocytes (Xu et al 2009a). This chronic induction of lipolysis is transcriptionally regulated, as glucocorticoids upregulate HSL expression and downregulate phosphodiesterase 3B expression, which increases HSL activity by limiting cAMP degradation (Xu et al 2009a).…”

“…There is not an acute lipolytic response to glucocorticoids, yet, chronically elevated glucocorticoids stimulate lipolysis in adipocytes (Xu et al 2009a). This chronic induction of lipolysis is transcriptionally regulated, as glucocorticoids upregulate HSL expression and downregulate phosphodiesterase 3B expression, which increases HSL activity by limiting cAMP degradation (Xu et al 2009a). Glucocorticoids also increase catecholamine-induced cAMP signaling by enhancing beta-adrenergic receptor expression, resulting in a more robust elevation in adenylyl cyclase and PKA activity (Lamberts et al 1975, Lacasa et al 1988.…”

Effect of Prunus Dulcis Extract against Total Cholesterol Level in Mice that Given Monosodium Glutamate

“…Furthermore, Prunus dulcisis also rich with thiamine, riboflavin, pantothenic acid, niacin and folate. These compounds have a role as enzyme cofactors in the level of cellular metabolism [14]. With the existence of the enzyme cofactor molecules guaranteed to the process of metabolism intracellular nutrients occur in balance without the effect of stress caused by feeding so that there is no weight loss happened in the P2 group mice.…”