We have previously identified prohibitin (PHB) and annexin A2 (ANX2) as

We have previously identified prohibitin (PHB) and annexin A2 (ANX2) as proteins interacting on the surface of vascular endothelial cells in white adipose tissue (WAT) of humans and mice. Human obesity, a medical condition associated with a number of life-threatening diseases, is causing escalating interpersonal concern (1). Obesity results from excessive growth of white adipose tissue (WAT). Hypertrophy of mature adipocytes differentiating from proliferative progenitor cells in the process of adipogenesis is usually ultimately responsible for obesity and metabolic syndrome, along with its pathological effects (2). WAT remodeling leading to obesity is usually mediated by NVP-TAE 226 adipocyte interactions with stromal and Rabbit Polyclonal to PLCB3 (phospho-Ser1105). vascular endothelial cells and is controlled by concerted actions of a number of extracellular signals that together form a highly integrated network designed to maintain energy balance (3). Lipid accumulation in the adipocyte is a result of de novo lipogenesis, as well as the uptake of circulating nutrients that are converted into triglycerides packaged into cytosolic lipid droplets (4). Glucose and fatty acids (FAs) are the major energy sources assimilated by adipocytes (5). Glucose uptake by adipocytes is usually regulated by integral membrane carrier GLUT4 (6). Uptake of FAs by adipocytes depends on a high-affinity, low-capacity carrierCfacilitated transport system (7, 8). The FA transport protein (FATP) and the membrane FA-binding protein (FABPpm) families (9), as well as caveolins (10), participate in the multiple actions of FA trafficking. The receptor stimulating FA entry into the cell is the FA translocase (Excess fat), also known as CD36 (11, 12). The CD36-dependent FA transporter operates in the context of lipid rafts, the highly ordered lipid microdomains distinguished by specific conversation between sterols and sphingolipids (13, 14). Despite the progress in NVP-TAE 226 characterization of FA uptake by cells of the liver and skeletal muscle mass, many questions remain regarding the molecular control of FA transport in WAT (11, 15). While defined unique GLUT transporters control glucose uptake in different organs (16), the molecular machinery regulating FA uptake by WAT endothelium and NVP-TAE 226 their transfer into adipocytes is usually incompletely comprehended. Like adipocytes, WAT vascular endothelial cells display highly active endocytosis, which regulates internalization of macromolecules and particles into transport vesicles derived from the plasma membrane (17). However, it is not clear whether the molecular uptake by adipose endothelium depends on the same transport machinery as those operating in adipocytes, and it is also unclear which transporters regulate nutrient transfer between adipose endothelial cells and adipocytes. We have previously proposed that WAT endothelium could be used as a target of obesity treatment aimed at cutting off the supply of nutrients and oxygen essential for adipocyte survival (18). NVP-TAE 226 In a screen of a combinatorial library for peptides that bind to cell surface receptors expressed in a tissue-specific manner (19C21), we previously recognized a peptide (sequence KGGRAKD) that homes to WAT vasculature (22). Further, we exhibited that KGGRAKD binds to prohibitin-1 (PHB), a protein present on the surface of endothelial cells selectively in WAT. Based on the capacity of KGGRAKD to undergo PHB-mediated endocytosis, we used this peptide to direct an apoptosis-inducing moiety D(KLAKLAK)2 to mouse WAT in an experimental approach to obesity reversal (22). Preclinically, the WAT vascular-targeting capacity of the KGGRAKD-GG-D(KLAKLAK)2 peptide (now known as adipotide) has been validated in mouse, rat, and nonhuman primate models of obesity and has shown to have antidiabetic effects (23C25). Prohibitins display similarity to several proteins (SPFH, stomatin, flotillin, and HflK/C) made up of a conserved transmembrane domain name (26). PHB is usually a multifunctional protein found in numerous cellular compartments and is also secreted (27). It has been reported to serve as a cell surface receptor for infectious microorganisms (28). Identification of PHB as a component of lipid rafts in association with other integral.

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