One of the basic functions of insulin in the body is to inhibit lipolysis in adipocytes. Recently, we have found that insulin inhibits lipolysis and promotes triglyceride storage by decreasing transcription of adipose triglyceride lipase via the mTORC1-mediated pathway (P. Chakrabarti et al., Diabetes 59:775-781, 2010), although the mechanism of this effect remained unknown. Here, we used a genetic screen in Saccharomyces cerevisiae in order to identify a transcription factor that mediates the effect of Tor1 on the expression of the ATGL ortholog in yeast. This factor, Msn4p, has homologues in mammalian cells that form a family of early growth response transcription factors. One member of the family, Egr1, is induced by insulin and nutrients and directly inhibits activity of the ATGL promoter in vitro and expression of ATGL in cultured adipocytes. Feeding animals a high-fat diet increases the activity of mTORC1 and the expression of Egr1 while decreasing ATGL levels in epididymal fat. We suggest that the evolutionarily conserved mTORC1-Egr1-ATGL regulatory pathway represents an important component of the antilipolytic effect of insulin in the mammalian organism. C urrent epidemics of metabolic diseases, such as type 2 diabetes, cardiac dysfunction, hypertension, hepatic steatosis, etc., are largely caused by widespread obesity. Although obesity can affect human health via several different mechanisms, the bestestablished connection between obesity and metabolic disease is elevated and/or dysregulated levels of circulating free fatty acids (FFA). In addition to their direct pathological effects, superfluous FFA accumulate in the form of lipids, and their metabolic products in nonadipose peripheral tissues, such as liver, skeletal muscle, heart, and pancreas and cause detrimental effects on human health via mechanisms that are currently under intense investigation (1-5).The levels of circulating FFA depend primarily on the rates of lipolysis in the adipose tissue. One of the key physiological functions of insulin as the major anabolic hormone in the body is to restrain lipolysis and to promote fat storage in adipose tissue in the postprandial state. The failure of insulin to suppress lipolysis in adipocytes has been long considered as a very serious metabolic defect and one of the most important if not the most important causative factor of insulin resistance and diabetes mellitus (6, 7).Complete hydrolysis of triglycerides to glycerol and fatty acids is performed jointly by tri-, di-, and monoacylglyceride lipases (8-11). The recently discovered enzyme, adipose triglyceride lipase (ATGL; also known as desnutrin, PNPLA2, TTS2.2, and iPLA 2 ) (12-14), is responsible for the bulk of triacylglycerol hydrolase activity in various cells and represents the rate-limiting lipolytic enzyme. In every experimental model tested thus far, elevated ATGL expression increases, while attenuated ATGL expression decreases, both basal and cAMP-stimulated lipolysis (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). At the same time, ATGL h...

Sortilin is involved in the anterograde traffic of lysosomal enzymes and substrates. It also transports Glut4 in the opposite, retrograde, direction in a retromer-dependent fashion.

Insulin-dependent translocation of Glut4 to the plasma membrane of fat and skeletal muscle cells plays the key role in postprandial clearance of blood glucose. In undifferentiated cells, insulin responsiveness of Glut4 depends on the presence of sortilin, whereas sortilin responds to insulin regardless of Glut4 expression.

Background: FSP27 is a lipid droplet-associated protein.Results: Expression of FSP27 in human adipocytes reversely correlates with ATGL levels. Mechanistically, FSP27 increases the inhibitory effect of Egr1 on the ATGL promoter. Conclusion: FSP27 controls lipolysis by regulating ATGL transcription. Significance: Our study provides a new model of regulation of lipolysis in adipocytes. Current epidemics of metabolic diseases, such as type 2 diabetes, cardiac dysfunction, hypertension, hepatic steatosis, etc., are largely caused by widespread obesity. Although obesity can affect human health via several different mechanisms (1), the best established connection between obesity and metabolic disease is abnormal levels of circulating fatty acids (FA). 3 FA play important physiological roles in energy production and the synthesis of most lipids; nonetheless, their oversupply is highly detrimental as it leads to insulin resistance, oxidative stress, and other pathophysiological effects via mechanisms that are currently under intense investigation (1-5). Lipolysis in fat tissueNormally, dietary FA are partitioned into adipose tissue, converted into triglycerides, and stored in lipid droplets (LDs) that represent dynamic intracellular organelles consisting of a core of triglycerides and cholesterol esters, surrounded by a monolayer of phospholipids. Several proteins are associated with this monolayer, notably the PAT family proteins, PLIN 1-5 (6, 7), and fat-specific protein 27 (FSP27, also known as CIDEC) (8 -10). The latter protein plays an essential role in the regulation of LD morphology. Depletion of FSP27 in adipocytes leads to fragmentation of LDs (11,12), whereas overexpression of FSP27 increases the size of LDs while decreasing their number (8, 9, 12) by promoting LD fusion (13) and exchanging lipids from one droplet to another (14).It has also been demonstrated by us and others that FSP27 has anti-lipolytic activity (8,9,12,(15)(16)(17)(18). Lipolysis in adipose tissue is the major source of circulating . Correspondingly, unrestricted lipolysis in adipose tissue represents a serious metabolic defect and a causative factor of insulin resistance, diabetes mellitus, and other metabolic diseases (3,(25)(26)(27). As the mechanism of the anti-lipolytic activity of FSP27 is not completely clear, we decided to focus on this problem.Our recent study showed that FSP27 directly interacts with ATGL and regulates its lipase activity (18). Another study predicted that FSP27-mediated fusion of LDs might limit the access of intracellular lipases to the LD surface due to decreased surface area of larger LDs (17). As ATGL represents a major lipolytic enzyme (28), reducing its contact with LDs may suppress lipolysis.Here, we report another mechanism of the anti-lipolytic action of FSP27 in human adipocytes. We have found that FSP27 inhibits expression of ATGL at the level of transcription by stimulating the effect of its transcriptional repressor Egr1. EXPERIMENTAL PROCEDURESCell Culture-Human preadipocytes were procured from the ...

Osteoactivin (OA) protein was discovered in bone cells a decade ago. Recent literature suggests that osteoactivin is crucial for the differentiation and functioning of different cell types, including bone-forming osteoblasts and bone-resorbing osteoclast cells. Here, we review the literature to date on various regulatory functions of osteoactivin, as well as its discovery, structure, expression, and function in different tissues and cells. The transcriptional regulation of osteoactivin and its mechanism of action in normal and diseased conditions with special emphasis on bone are also covered in this review. In addition, we touch on the therapeutic potential of osteoactivin in cancer and bone diseases.