Abstract
Lipid droplets (LDs) are organelles that coordinate lipid storage and mobilization, both processes being especially important in cells specialized in managing fat, the adipocytes. Proteomic analyses of LDs have consistently identified the small GTPase Rab18 as a component of the LD coat. However, the specific contribution of Rab18 to adipocyte function remains to be elucidated. Herein, we have analyzed Rab18 expression, intracellular localization and function in relation to the metabolic status of adipocytes. We show that Rab18 production increases during adipogenic differentiation of 3T3-L1 cells. In addition, our data show that insulin induces, via phosphatidylinositol 3-kinase (PI3K), the recruitment of Rab18 to the surface of LDs. Furthermore, Rab18 overexpression increased basal lipogenesis and Rab18 silencing impaired the lipogenic response to insulin, thereby suggesting that this GTPase promotes fat accumulation in adipocytes. On the other hand, studies of the β-adrenergic receptor agonist isoproterenol confirmed and extended previous evidence for the participation of Rab18 in lipolysis. Together, our data support the view that Rab18 is a common mediator of lipolysis and lipogenesis and suggests that the endoplasmic reticulum (ER) is the link that enables Rab18 action on these two processes. Finally, we describe, for the first time, the presence of Rab18 in human adipose tissue, wherein the expression of this GTPase exhibits sex- and depot-specific differences and is correlated to obesity. Taken together, these findings indicate that Rab18 is involved in insulin-mediated lipogenesis, as well as in β-adrenergic-induced lipolysis, likely facilitating interaction of LDs with ER membranes and the exchange of lipids between these compartments. A role for Rab18 in the regulation of adipocyte biology under both normal and pathological conditions is proposed.
Highlights
White adipose tissue is essential for the maintenance of energy homeostasis, in terms of its role both as an endocrine organ and as the main energy reservoir of the body, responsible for storing energy in the form of triglycerides (TAG) during periods of energy excess and releasing it as free fatty acids (FFAs) to be used as an energy source by other tissues during times of energy deprivation
Studies in differentiating 3T3-L1 cells, the cell line most commonly used to study adipogenesis, revealed that Rab18 mRNA reached a maximal level on day 3 of differentiation, coinciding with the appearance of late differentiation markers, which are responsible for the maintenance of the adipocyte phenotype in 3T3-L1 cells [34,35]
This hormone triggered Rab18 association with lipid droplets (LDs), a process that seems to be mediated by activation of the key upstream regulator of the metabolic actions induced by insulin in adipocytes, phosphatidylinositol 3-kinase (PI3K) [25]
Summary
White adipose tissue is essential for the maintenance of energy homeostasis, in terms of its role both as an endocrine organ and as the main energy reservoir of the body, responsible for storing energy in the form of triglycerides (TAG) during periods of energy excess and releasing it as free fatty acids (FFAs) to be used as an energy source by other tissues during times of energy deprivation. TAG accumulation (i.e., lipogenesis) and hydrolysis (i.e., lipolysis) in adipocytes are primarily controlled by insulin and catecholamines [1,2,3], which, together with other endocrine and paracrine/autocrine factors, ensure correct lipid storage and utilization [4,5,6]. Adjustments in lipid metabolism take place in specialized organelles, the lipid droplets (LDs), in which TAG and other neutral lipids accumulate in a central core that is surrounded by a phospholipid monolayer and a coat of associated proteins [9,10]. PAT (perilipin-adipophilin-Tip47) proteins [14] have been extensively studied in terms of their association with the LD surface and their role in controlling LD function [reviewed by 15]. It is clear that LDs act as integration centers of lipid metabolism in adipocytes and understanding the intracellular mechanisms that control LD biology holds the key to building a unified picture of the (patho)physiological function of adipocytes
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