The Molecular Brakes of Adipose Tissue Lipolysis

Abstract

Adaptation to changes in energy availability is pivotal for the survival of animals. Adipose tissue, the body’s largest reservoir of energy and a major source of metabolic fuel, exerts a buffering function for fluctuations in nutrient availability. This functional plasticity ranges from energy storage in the form of triglycerides during periods of excess energy intake to energy mobilization via lipolysis in the form of free fatty acids for other organs during states of energy demands. The subtle balance between energy storage and mobilization is important for whole-body energy homeostasis; its disruption has been implicated as contributing to the development of insulin resistance, type 2 diabetes and cancer cachexia. As a result, adipocyte lipolysis is tightly regulated by complex regulatory mechanisms involving lipases and hormonal and biochemical signals that have opposing effects. In thermogenic brown and brite adipocytes, lipolysis stimulation is the canonical way for the activation of non-shivering thermogenesis. Lipolysis proceeds in an orderly and delicately regulated manner, with stimulation through cell-surface receptors via neurotransmitters, hormones, and autocrine/paracrine factors that activate various intracellular signal transduction pathways and increase kinase activity. The subsequent phosphorylation of perilipins, lipases, and cofactors initiates the translocation of key lipases from the cytoplasm to lipid droplets and enables protein-protein interactions to assemble the lipolytic machinery on the scaffolding perilipins at the surface of lipid droplets. Although activation of lipolysis has been well studied, the feedback fine-tuning is less well appreciated. This review focuses on the molecular brakes of lipolysis and discusses some of the divergent fine-tuning strategies in the negative feedback regulation of lipolysis, including delicate negative feedback loops, intermediary lipid metabolites-mediated allosteric regulation and dynamic protein–protein interactions. As aberrant adipocyte lipolysis is involved in various metabolic diseases and releasing the brakes on lipolysis in thermogenic adipocytes may activate thermogenesis, targeting adipocyte lipolysis is thus of therapeutic interest.

Loss of UCP1 function augments recruitment of futile lipid cycling for thermogenesis in murine brown fat

“…Taken together, we demonstrate that brown adipocytes recruit a futile cycle of lipolysis and FA re-esterification to generate heat in the absence of UCP1. Our findings prove that activating the adrenergic receptor-cAMP-PKA-signalling cascade causes lipid turnover to immediately increase [ 62 ]. The main steps defining this futile substrate cycle include ATGL mediated hydrolysis of TGs, activation of FAs by long-chain acyl-CoA synthetase under the consumption of ATP, and esterification of FAs onto diglycerides catalyzed by DGAT1.…”

Uncoupling Protein 1 Does Not Produce Heat without Activation

“…Consequently, lipolysis is inhibited and thermogenesis is terminated. Within this concept, ligands of Gi-coupled receptors are important autocrine/paracrine molecular brakes of brown fat activation and are able to fine-tune heat production to the thermogenic demand (for a review, see [ 10 ] and [ 102 ]).…”

“…Of note, stimulation with the β-adrenergic agonist isoproterenol results in both increased cAMP synthesis and increased cAMP degradation through phosphorylation of PDEs in adipocytes, mostly PDE3B and PDE4 [ 103 ]. Consistent with a feedback regulatory mechanism, this is believed to contribute to the fine-tuning of cAMP levels and PKA activity and thereby control of lipolysis and thermogenesis [ 102 ].…”

“…Ultimately, cessation of lipolysis depends on the dephosphorylation of PKA targets, such as HSL and perilipin, by protein phosphatases; therefore, cAMP degradation and PKA inactivation do not per se terminate the lipolytic cascade and thermogenesis [ 102 ]. Through protein phosphatase (PP)-mediated dephosphorylation of phosphoproteins, protein kinase activity is counteracted to reach a delicate balance, thus ensuring high signal fidelity.…”

Anti-adipogenic and Pro-lipolytic Effects on 3T3-L1 Preadipocytes by CX-4945, an Inhibitor of Casein Kinase 2

“…It is mainly characterized by abnormal lipid accumulation as a result of adipocyte hyperplasia (significant rise in fat cell number) and hypertrophy (in fat cell size) [3]. A wealth of information illustrates that excessive preadipocyte differentiation causes abnormal accumulation and storage of high fat, mainly in triglyceride (TG), in mature adipocytes, which leads to the irregular development of the adipose tissue and the burgeoning of obesity [4]. Evidence also strongly indicates that numerous factors such as environmental and nutritional values and genetic and endocrine abnormalities are closely linked to the induction of obesity [5][6][7].…”