Hdl Ldl Vldl

Inhibition of lipolysis

Regulation of insulin sensitivity and fatty acid oxidation Increase of lipogenesis

Stimulation of prostacyclin production by mature fat cells. Interaction with insulin in regulation of adipocyte metabolism Induction of leptin and IGF-I expression. Stimulation of lipolysis Inhibition of lipolysis. Stimulation of glucose transport and oxidation LPL activity inhibition. Induction of lipolysis

Inhibition of lipolysis and stimulation of lipogenesis. Induction of glucose uptake and oxidation.

Stimulation of leptin expression Stimulation of lipolysis. Autocrine regulation of leptin expression Inhibition of lipolysis. Induction of leptin expression

Strong antilypolitic effects (PGE2). Modulation of preadipocyte differentiation (PGF2a and PGI2) Potent inhibition of adipocyte differentiation

Stimulation of lipolysis. Regulation of leptin secretion. Potent inhibition of adipocyte differentiation. Involvement in development of insulin resistance Stimulation of angiogenesis receptors

Inhibition of lipolysis Stimulation of lipolysis

Induction of inositol phosphate production and PKC activation Inhibition of lipolysis. Regulation of preadipocyte growth

Stimulation of lipolysis. Induction of thermogenesis. Reduction of leptin mRNA levels

Control of adipose tissue development (antiadipogenic signals). Modulation of leptin expression Control of adipose tissue development (proadipogenic signals). Modulation of leptin expression Stimulation of adipocyte differentiation

Regulation of fat metabolism. Plays a central role in fatty acid-controlled differentiation of preadipose cells Induction of adipocyte differentiation and insulin sensitivity Regulation of adipocyte differentiation

Stimulation of lipolysis. Regulation of leptin secretion. Induction of adipocyte differentiation. Regulation of insulin effects

Clearance and metabolism of HDL Stimulation of cholesterol uptake

Binding and internalization of VLDL particles. Involvement in lipid accumulation

Abbreviations: ACRP30, adipocyte complement-related protein of 30kDa; apM1, adipose most abundant gene transcript 1; ASP, acylation-stimulating protein; FFA, free fatty acids; GBP28, gelatin-binding protein 28; GH, growth hormone; HDL, high density lipoprotein; IGF, insulin-like growth factor; IL-6, interleukin 6; LDL, low density lipoprotein; LPL, lipoprotein lipase; NO, nitric oxide; NPY-Y1 & -Y5, neuropeptide receptors Y-1 & -5; OB-R, leptin receptor; PAI-1, plasminogen activator inhibitor -1; PGE2, prostaglandin E2; PGF2a, prostaglandin F2a; PGI2, prostacyclin; PPAR, peroxisome proliferator-activated receptor; RAR, retinoic acid receptor; RXR, retinoid x receptor; T3, triiodothyronine; TGF-ß, transforming growth factor-ß; TNF-a, tumor necrosis factor-a; VEGF, vascular endothelial growth factor; VLDL, very low-density lipoprotein; a1- & a2-AR, a1- & a2-adrenergic receptors; ßr, ß2- & ß3-AR, ß-|-, ß2- & ß3 adrenergic receptors.

aspects of WAT physiology relates to the synthesis of products involved in lipid metabolism such as perilipin, adipocyte lipid-binding protein (ALBP, FABP4, or aP2), CETP (cholesteryl ester transfer protein), and retinol binding protein (RBP). Adipose tissue has also been identified as a source of production of factors with immunological properties participating in immunity and stress responses, as is the case for ASP (acylation-simulating protein)

and metallothionein. More recently, the pivotal role of adipocyte-derived factors in cardiovascular function control such as angiotensinogen, adipo-nectin, peroxisome proliferator-activated receptor 7 angiopoietin related protein/fasting-induced adipose factor (PGAR/FIAF), and C-reactive protein (CRP) has been established. A further subsection of proteins produced by adipose tissue concerns other factors with an autocrine-paracrine function like

PPAR-7 (peroxisome proliferator-activated receptor), IGF-1, monobutyrin, and the UCPs.

It is generally assumed that under normal physiological circumstances adult humans are practically devoid of functional brown adipose tissue. As is the case in other larger mammals the functional capacity of brown adipose tissue decreases because of the relatively higher ratio between heat production from basal metabolism and the smaller surface area encountered in adult animals. In addition, clothing and indoor life have reduced the need for adaptive nonshivering thermogenesis. However, it has been recently shown that human WAT can be infiltrated with brown adipocytes expressing UCP-1.

Regulation of Metabolism

The control of fat storage and mobilization has been marked by the identification of a number of regulatory mechanisms in the last few decades. Isotopic tracer studies have clearly shown that lipids are continuously being mobilized and renewed even in individuals in energy balance. Fatty acid esterification and triglyceride hydrolysis take place continuously. The half-life of depot lipids in rodents is about 8 days, meaning that almost 10% of the fatty acid stored in adipose tissue is replaced daily by new fatty acids. The balance between lipid loss and accretion determines the net outcome on energy homeostasis.

The synthesis of triglycerides, also termed lipogen-esis, requires a supply of fatty acids and glycerol. The main sources of fatty acids are the liver and the small intestine. Fatty acids are esterified with gly-cerol phosphate in the liver to produce triglycerides. Since triglycerides are bulky polar molecules that do not cross cell membranes well, they must be hydro-lyzed to fatty acids and glycerol before entering fat cells. Serum very low-density lipoproteins (VLDLs) are the major form in which triacylglycerols are carried from the liver to WAT. Short-chain fatty acids (16 carbons or less) can be absorbed from the gastrointestinal tract and carried in chylomicra directly to the adipocyte. Inside fat cells, glycerol is mainly synthesized from glucose. In WAT, fatty acids can be synthesized from several precursors, such as glucose, lactate, and certain amino acids, with glucose being quantitatively the most important in humans. In the case of glucose, GLUT4, the principal glucose transporter of adipocytes, controls the entry of the substrate into the adipocyte. Insulin is known to stimulate glucose transport by promoting GLUT4 recruitment as well as increasing its activity. Inside the adipocyte, glucose is initially phosphorylated and then metabolized both in the cytosol and in the mitochondria to produce cytosolic acetyl-CoA with the flux being influenced by phos-phofructokinase and pyruvate dehydrogenase. Gly-cerol does not readily enter the adipocyte, but the membrane-permeable fatty acids do. Once inside the fat cells, fatty acids are re-esterified with glycerol phosphate to yield triglycerides. Lipogenesis is favored by insulin, which activates pyruvate kinase, pyruvate dehydrogenase, acetyl-CoA carboxylase, and glycerol phosphate acyltransferase. When excess nutrients are available insulin decreases acetyl-CoA entry into the tricarboxylic acid cycle while directing it towards fat synthesis. This insulin effect is antagonized by growth hormone. The gut hormones glu-cagon-like peptide 1 and gastric inhibitory peptide also increase fatty acid synthesis, while glucagon and catecholamines inactivate acetyl-CoA carboxy-lase, thus decreasing the rate of fatty acid synthesis.

The release of glycerol and free fatty acids by lipolysis plays a critical role in the ability of the organism to provide energy from triglyceride stores. In this sense, the processes of lipolysis and lipogen-esis are crucial for the attainment of body weight control. For this purpose adipocytes are equipped with a well-developed enzymatic machinery, together with a number of nonsecreted proteins and binding factors directly involved in the regulation of lipid metabolism. The hydrolysis of triglycerides from circulating VLDL and chylomicrons is catalyzed by lipoprotein lipase (LPL). This rate-limiting step plays an important role in directing fat partitioning. Although LPL controls fatty acid entry into adipocytes, fat mass has been shown to be preserved by endogenous synthesis. From observations made in patients with total LPL deficiency it can also be concluded that fat deposition can take place in the absence of LPL. A further key enzyme catalyzing a rate-limiting step of lipolysis is HSL (hormome sensitive lipase), which cleaves tria-cylglycerol to yield glycerol and fatty acids. Some fatty acids are re-esterified, so that the fatty acid: glycerol ratio leaving the cell is usually less than the theoretical 3:1. Increased concentrations of cAMP activate HSL as well as promote its movement from the cytosol to the lipid droplet surface. Cate-cholamines and glucagon are known inducers of the lipolytic activity, while the stimulation of lipolysis is attenuated by adenosine and protaglandin E2. Interestingly, HSL deficiency leads to male sterility and adipocyte hypertrophy, but not to obesity, with an unaltered basal lipolytic activity suggesting that other lipases may also play a relevant role in fat mobilization.

The lipid droplets contained in adipocytes are coated by structural proteins, such as perilipin, that stabilize the single fat drops and prevent triglyceride hydrolysis in the basal state. The phosphorylation of perilipin following adrenergic stimulation or other hormonal inputs induces a structural change of the lipid droplet that allows the hydrolysis of triglycerides. After hormonal stimulation, HSL and perilipin are phosphorylated and HSL translocates to the lipid droplet. ALBP, also termed aP2, then binds to the N-terminal region of HSL, preventing fatty acid inhibition of the enzyme's hydrolytic activity.

The function of CETP is to promote the exchange of cholesterol esters of triglycerides between plasma lipoproteins. Fasting, high-cholesterol diets as well as insulin stimulate CETP synthesis and secretion in WAT. In plasma, CETP participates in the modulation of reverse cholesterol transport by facilitating the transfer of cholesterol esters from high-density lipoprotein (HDL) to triglyceride-rich apoB-contain-ing lipoproteins. VLDLs, in particular, are converted to low-density lipoproteins (LDLs), which are subjected to hepatic clearance by the apoB/E receptor system. Adipose tissue probably represents one of the major sources of CETP in humans. Therefore, WAT represents a cholesterol storage organ, whereby peripheral cholesterol is taken up by HDL particles, acting as cholesterol efflux acceptors, and is returned for hepatic excretion. In obesity, the activity and protein mass of circulating CETP is increased showing a negative correlation with HDL concentrations at the same time as a positive correlation with fasting glycemia and insulinemia suggesting a potential link with insulin resistance.

Synthesis and secretion of RBP by adipocytes is induced by retinoic acid and shows that WAT plays an important role in retinoid storage and metabolism. In fact, RBP mRNA is one of the most abundant transcripts present in both rodent and human adipose tissue. Hepatic and renal tissues have been regarded as the main sites of RBP production, while the quantitative and physiological significance of the WAT contribution remains to be fully elucidated.

The processes participating in the control of energy balance, as well as the intermediary lipid and carbohydrate metabolism, are intricately linked by neurohumoral mediators. The coordination of the implicated molecular and biochemical pathways underlies, at least in part, the large number of intracellular and secreted proteins produced by WAT with autocrine, paracrine, and endocrine effects. The finding that WAT secretes a plethora of pleiotropic adipokines at the same time as expressing receptors for a huge range of compounds has led to the development of new insights into the functions of adipose tissue at both the basic and clinical level. At this early juncture in the course of adipose tissue research, much has been discovered. However, a great deal more remains to be learned about its physiology and clinical relevance. Given the adipocyte's versatile and ever-expanding list of secretory proteins, additional and unexpected discoveries are sure to emerge. The growth, cellular composition, and gene expression pattern of adipose tissue is under the regulation of a large selection of central mechanisms and local effectors. The exact nature and control of this complex cross-talk has not been fully elucidated and represents an exciting research topic.

Abbreviations

ACRP30/apM1/

adipocyte complement-related

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