Regulation of adipocyte lipolysis

Abstract

In adipocytes the hydrolysis of TAG to produce fatty acids and glycerol under fasting conditions or times of elevated energy demands is tightly regulated by neuroendocrine signals, resulting in the activation of lipolytic enzymes. Among the classic regulators of lipolysis, adrenergic stimulation and the insulin-mediated control of lipid mobilisation are the best known. Initially, hormone-sensitive lipase (HSL) was thought to be the rate-limiting enzyme of the first lipolytic step, while we now know that adipocyte TAG lipase is the key enzyme for lipolysis initiation. Pivotal, previously unsuspected components have also been identified at the protective interface of the lipid droplet surface and in the signalling pathways that control lipolysis. Perilipin, comparative gene identification-58 (CGI-58) and other proteins of the lipid droplet surface are currently known to be key regulators of the lipolytic machinery, protecting or exposing the TAG core of the droplet to lipases. The neuroendocrine control of lipolysis is prototypically exerted by catecholaminergic stimulation and insulin-induced suppression, both of which affect cyclic AMP levels and hence the protein kinase A-mediated phosphorylation of HSL and perilipin. Interestingly, in recent decades adipose tissue has been shown to secrete a large number of adipokines, which exert direct effects on lipolysis, while adipocytes reportedly express a wide range of receptors for signals involved in lipid mobilisation. Recently recognised mediators of lipolysis include some adipokines, structural membrane proteins, atrial natriuretic peptides, AMP-activated protein kinase and mitogen-activated protein kinase. Lipolysis needs to be reanalysed from the broader perspective of its specific physiological or pathological context since basal or stimulated lipolytic rates occur under diverse conditions and by different mechanisms.

AMPK Phosphorylates Desnutrin/ATGL and Hormone-Sensitive Lipase To Regulate Lipolysis and Fatty Acid Oxidation within Adipose Tissue

“…We and others have identified desnutrin/ATGL (also called patatin-like phospholipase domaincontaining protein 2) as the TAG hydrolase highly expressed in adipose tissue. Desnutrin/ATGL has been well accepted to execute the first step in TAG hydrolysis by converting TAG to DAG (8)(9)(10)(11)(12). Adipose-tissue-specific desnutrin/ATGL-overexpressing mice are leaner, with a smaller adipocyte size and decreased adipose-tissue TAG content (13).…”

The Role of PDE3B Phosphorylation in the Inhibition of Lipolysis by Insulin

“…Almost 30 years ago, Londos and colleagues carefully examined the effects of insulin on lipolysis and PKA activity, concluding that, depending on the degree of adrenergic simulation, the suppression of lipolysis by insulin could not always be fully accounted for by the decrease in PKA activity (13,41). Nonetheless, although these data questioned the relationship between changes in cAMP and insulin-dependent antilipolysis, a generally accepted model has emerged in which Akt, whose activity is elevated by insulin, phosphorylates and stimulates PDE3B, thus reducing cAMP levels and PKA activity (9)(10)(11)42). Considerable data support this hypothesis, which is made all the more compelling by analogy to the wellestablished mediation of insulin-regulated glucose metabolism by Akt, as well as the absence of the antilipolytic effects of insulin in Pde3b-KO adipocytes (12).…”

“…Akt, the major node of insulin action, promotes the translocation of the facilitated glucose transporter GLUT4 to the membrane, where it catalyzes increased glucose uptake (8). Akt is also believed to mediate the antilipolytic effect of insulin via phosphorylation of phosphodiesterase 3B (PDE3B), resulting in enhanced hydrolysis of its substrate, cAMP (9)(10)(11). The reduction in cAMP levels in the adipocyte allows phosphatases to return lipolytic signaling to the basal state.…”

NR4A1 retards adipocyte differentiation or maturation via enhancing GATA2 and p53 expression

“…HSL is a multifunctional enzyme that is capable of hydrolysing a variety of acylesters including TAG, DAG and monoacylglycerol (MAG). LPL is the rate‐limiting enzyme for the hydrolysis of the triglyceride and very low‐density lipoproteins 12, 13, 14. The fate of obesity formation depends on the balance between the processes of adipogenesis or lipid accumulation and lipolysis.…”