Lipolysis in adipocytes

Abstract

Lipolysis in adipocytes, the hydrolysis of triacylglycerol (TAG) to release fatty acids (FAs) and glycerol for use by other organs, is a unique function of white adipose tissue. Lipolysis in adipocytes occurs at the surface of cytosolic lipid droplets, which have recently gained much attention as dynamic organelles integral to lipid metabolism. Desnutrin/ATGL is now established as a bona fide TAG hydrolase and mutations in human desnutrin/ATGL/PNPLA2, as well as in its activator, comparative gene identification 58, are associated with Neutral Lipid Storage Disease. Furthermore, recent identification of AdPLA as the major adipose phospholipase A(2), has led to the discovery of a dominant autocrine/paracrine regulation of lipolysis through PGE(2). Here, we review emerging concepts in the key players in lipolysis and the regulation of this process. We also examine recent findings in mouse models and humans with alterations/mutations in genes involved in lipolysis and discuss activation of lipolysis in adipocytes as a potential therapeutic target.

Figure 1. Regulation of lipolysis in adipocytes

A) Desnutrin/ATGL initiates lipolysis by hydrolyzing triacylglycerol (TAG) to diacylglycerol (DAG). Hormone-sensitive lipase (HSL) hydrolyzes DAG to monoacylglycerol (MAG), which is subsequently hydrolyzed by MAG lipase to generate glycerol and three fatty acids (FAs). The FAs generated during lipolysis can be released into the circulation for use by other organs or oxidized within adipocytes. During fasting, catecholamines, by binding to Gαs-coupled β-adrenergic receptors (β-AR), activate adenylate cyclase (AC) to increase cAMP and activate protein kinase A (PKA). PKA phosphorylates HSL, resulting in translocation of HSL from the cytosol to the lipid droplet. PKA also phosphorylates the lipid droplet associated protein perilipin. Additionally, during fasting, glucocorticoids increase the expression of desnutrin/ATGL. B) In the fed state, insulin binding to the insulin receptor (IR), results in decreased cAMP levels and decreased lipolysis. Insulin also suppresses expression of desnutrin/ATGL. Recent studies have revealed that lipolysis is dominantly regulated by prostaglandin E₂ (PGE₂) through adipose-specific phospholipase A₂ (AdPLA). AdPLA hydrolyzes the sn-2 position of phospholipids to generate arachidonic acid (AA), which via cyclooxygenase (COX) produces PGE₂, that acts locally by binding to Gαi-coupled EP3 present in adipocytes, resulting in inhibition of AC and decreased lipolysis.

Figure 1. Regulation of lipolysis in adipocytes

A) Desnutrin/ATGL initiates lipolysis by hydrolyzing triacylglycerol (TAG) to diacylglycerol (DAG). Hormone-sensitive lipase (HSL) hydrolyzes DAG to monoacylglycerol (MAG), which is subsequently hydrolyzed by MAG lipase to generate glycerol and three fatty acids (FAs). The FAs generated during lipolysis can be released into the circulation for use by other organs or oxidized within adipocytes. During fasting, catecholamines, by binding to Gαs-coupled β-adrenergic receptors (β-AR), activate adenylate cyclase (AC) to increase cAMP and activate protein kinase A (PKA). PKA phosphorylates HSL, resulting in translocation of HSL from the cytosol to the lipid droplet. PKA also phosphorylates the lipid droplet associated protein perilipin. Additionally, during fasting, glucocorticoids increase the expression of desnutrin/ATGL. B) In the fed state, insulin binding to the insulin receptor (IR), results in decreased cAMP levels and decreased lipolysis. Insulin also suppresses expression of desnutrin/ATGL. Recent studies have revealed that lipolysis is dominantly regulated by prostaglandin E₂ (PGE₂) through adipose-specific phospholipase A₂ (AdPLA). AdPLA hydrolyzes the sn-2 position of phospholipids to generate arachidonic acid (AA), which via cyclooxygenase (COX) produces PGE₂, that acts locally by binding to Gαi-coupled EP3 present in adipocytes, resulting in inhibition of AC and decreased lipolysis.