Adipose tissue lipid metabolism: lipolysis

Abstract

White adipose tissue stores fatty acid (FA) as triglyceride in the lipid droplet organelle of highly specialized cells known as fat cells or adipocytes. Depending on the nutritional state and energy demand, hormonal and biochemical signals converge on activating an elegant and fundamental process known as lipolysis, which involves triglyceride hydrolysis to FAs. Almost six decades of work have vastly expanded our knowledge of lipolysis from enzymatic processes to complex protein assembly, disassembly, and post-translational modification. Research in recent decades ushered in the discovery of new lipolytic enzymes and coregulators and the characterization of numerous factors and signaling pathways that regulate lipid hydrolysis on transcriptional and post-transcriptional levels. This review will discuss recent developments with particular emphasis on the past two years in enzymatic lipolytic pathways and transcriptional regulation of lipolysis. We will summarize the positive and negative regulators of lipolysis, the adipose tissue microenvironment in lipolysis, and the systemic effects of lipolysis. The dynamic nature of adipocyte lipolysis is emerging as an essential regulator of metabolism and energy balance, and we will discuss recent developments in this area.

Figure 1

Generation of FA and glycerol from stored TAG involves a series of highly coordinated enzymatic actions of ATGL, HSL, and MGL at the LD. Enzymatic activity of ATGL is enhanced by CGI-58.

Figure 2

Major pathways involved in positive and negative regulation of lipolysis. β-adrenergic receptors (β-AR) are coupled to Gs, leading to the activation of adenylyl cyclase, increasing the levels of cAMP as a second messenger, and PKA activation, mediating the actions of noradrenaline. PKA then phosphorylates PLIN1, releasing CGI-58 to activate ATGL and phosphorylating HSL to promote its transfer from the cytosol to LDs. CGI-58 interacts with FABP4 to increase ATGL activity. HSL then interacts with PLIN1 to increase its hydrolase activity for DAGs. HSL and PLIN1 are also phosphorylated by ERK1/2 and protein kinase G (PKG) through GHR and NP receptor (NPR) signals. PNPLA3 can compete with ATGL for binding to CGI-58, thereby sequestering CGI-58 away from ATGL. G0S2 and HILPDA interaction inhibits AGTL activity. The binding of natriuretic peptides (NP) to the NPR also activates PKG via GC-derived Guanosine 3’,5’-cyclic monophosphate (cGMP). Insulin and IGF-1 activate PI3K and IRS1/2 that subsequently activate PKB and PDE3B, resulting in the hydrolysis of cAMP, blocking HSL and ATGL activation. Insulin binding blocks FOXO1 transcriptional function and also induces stabilization of PDE3B with ABHD15, which promotes cAMP degradation. Activation of ALK7 inhibits the expression of β-AR and causes phosphorylation of Suppressor of Mothers Against Decapentaplegic (SMAD) proteins to block transcription of Lipe. Ghrelin is recognized as having antilipolytic effects as it activates the PI3K pathway. Additionally, adiponectin can also hinder lipolysis by suppressing PKA by decreasing its regulatory subunit RIIα. FGF1 suppresses lipolysis through FGFR1 by inhibiting the cAMP/PKA axis via activation of PDE4D, which results in cAMP degradation. Activation of Gi-protein-coupled α2-ARs and A1-R inhibits AC and thereby reduces cAMP-dependent signaling to lipolysis.

Figure 3

Recent developments in the local and systemic tissue crosstalk mediated by lipolysis to regulate energy and lipid homeostasis. FA released by adipocytes during fasting and b-adrenergic stimulation can function as PPARα ligands in the liver to upregulate a transcriptional program involved in increasing FA oxidation, FGF21, and ketone bodies, and BAT thermogenic activity. FA released by adipocytes during fasting and β-adrenergic stimulation also leads to insulin secretion from the pancreas that stimulates the uptake of FA-induced TRL from the liver in BAT for optimal thermogenesis. The heart and skeletal muscle use both glucose- and adipocyte- derived FA as an energy substrate for normal function. Linoleic acid from adipocyte lipolysis acts on a pool of CD81+ beige APC for proliferation and conversion into beige adipocytes for optimal thermogenesis. Lipolytic signal also enhances the transcription of Gpr3, a gene encoding GPR3. GPR3 is a constitutively active GPCR that activates the cAMP/PKA pathway to increase thermogenesis in beige and brown adipocytes. FA from adipocyte lipolysis also increases EC proliferation.