The skinny on fat: lipolysis and fatty acid utilization in adipocytes

Abstract

Lipolysis for the provision of fatty acids (FA) for other organs during times of energy demand occurs uniquely in white adipose tissue (WAT). Recent findings have identified a bona fide TAG hydrolase and the major adipose phospholipase A(2), AdPLA. By controlling PGE(2) levels, AdPLA dominantly regulates lipolysis in an autocrine/paracrine manner. Moreover, recent findings demonstrate that, surprisingly, increasing lipolysis in adipose tissue does not necessarily increase serum FA levels, which are usually correlated with insulin resistance. Rather, increasing lipolysis in adipose tissue causes a shift within adipocytes towards increased FA utilization and energy expenditure and thus protects against obesity. Here, we discuss the regulation of lipolysis and its effects on FA utilization within WAT and on insulin resistance.

Figure 1. Regulation of lipolysis in adipocytes

(i) Desnutrin/ATGL performs the initial step of TAG hydrolysis, resulting in diacylglycerol (DAG). (ii) DAG is hydrolyzed by hormone-sensitive lipase (HSL) to monoacylglycerol (MAG), which is subsequently hydrolyzed by (iii) monoglyceride lipase (MGL) to generate glycerol and three fatty acids (FA). (iv) The FAs generated during lipolysis can be released into the circulation for use by other organs or re-esterified to TAG. Glycerol 3-phosphate (G-3-P) can be used as a backbone for TAG synthesis. FA released from lipolysis can also be oxidized within the adipocyte. Lipolysis is under tight endocrine regulation. (v) During fasting, catecholamines by binding to Gαs-coupled β-adernergic receptors (β-AR), activate adenylate cyclase (AC) to increase cAMP and thus activate protein kinase A (PKA). PKA phosphorylates hormone sensitive lipase (HSL), resulting in translocation of HSL from the cytosol to the lipid droplet and increased lipolysis. PKA also phosphorylates the lipid droplet associated protein perilipin. (vi) Additionally, during fasting, glucocorticoids increase the expression of desnutrin/ATGL. (vii) In the fed state, insulin binding to the insulin receptor (IR) results in decreased cAMP levels and decreased lipolysis. Recent findings revealed that lipolysis is dominantly regulated by prostaglandin E₂ (PGE₂) through adipose-specific phospholipase A2 (AdPLA). (viii) AdPLA hydrolyzes the sn-2 position of phospholipids to generated arachidonic acid (AA), which via cylcooxygenase (COX) produces PGE₂. (ix) PGE₂ secreted by adipocytes can act locally by binding to the Gαi-coupled EP3 present in adipocytes, resulting in inhibition of AC and decreased lipolysis.