Adipocytes

The pathways for liberation of fatty acids from triacylglycerols, either from adipose cells or from the diet, are shown in Figures 24.2 and 24.3. Fatty acids are mobilized from adipocytes in response to hormone messengers such as adren-... 

Fibroblasts, which are undifferentiated pre-adipo-cytes, can be stimulated and converted into adipocytes. 

The term adipokine refers to any protein secreted from adipocytes [1]. Collectively, the various adipokines form the adipokinome which together with the lipid moieties secreted from fat cells (e.g. fatty acids, cholesterol, retinol) constitute what can be referred to as the secretome of adipocytes. Most adipokines are also secreted from other cell types in other organs, but one in particular - adiponectin - is considered to be exclusive to adipocytes. 

A number of adipokines are linked to inflammation and immunity (Fig. 1). This includes both leptin and adiponectin, and also a number of other key inflammatory proteins, particularly cytokines and chemokines [1]. The cytokines and chemokines encompass interleukin-1(3 (EL-1 (3), IL-6, DL-10, TNFa, monocyte chemoattractant protein-1 (MCP-1), and macrophage migration inhibitory factor (MIF). Other major inflammation-related adipokines include nerve growth factor (NGF), and acute phase proteins such as serum amyloid A and haptoglobin. In addition, adipocytes secrete plasminogen activator inhibitor-1 (PAI-1), which is an important thrombotic factor as well as an acute phase protein. 

The wide range of inflammation-related factors that adipocytes secrete is linked to the inflammatory response that the tissue exhibits in obesity [1]. Obesity in general, like an increasing number of other diseases, is characterised by a state of mild chronic inflammation, and adipose tissue plays a central role in this. The production of most inflammation-related adipokines increases markedly in obesity and there is an elevated circulating level of a number of these factors as well as of other inflammatory markers such as C-reactive protein (CRP). The increased production of inflammatory adipokines (and decreased production of adiponectin with its anti-inflammatory action) in the obese is considered to play a critical role in the development of the obesity-associated pathologies, particularly type 2 diabetes and the metabolic syndrome [1]. 

An important component of the inflammatory state in adipose tissue in obesity comes from the infiltration of the tissue by macrophages. These are likely to be attracted through the secretion by adipocytes of MCP-1 and MEF. The macrophages in turn secrete factors which both directly add to the total production of inflammatory agents by adipose tissue and also catalyse the production of such agents from adipocytes - and perhaps preadipocytes as well. 

The wide range of inflammatory and immune factors secreted by adipocytes has led to the view that there are many similarities between these cells and cells of the immune system. 

Rosen ED, Spiegelman BM (2006) Adipocytes as regulators of energy balance and glucose homeostasis. Nature 444 847-853... 

A major adipokine, molecular weight 28,000 Da (monomeric form), that is secreted only from adipocytes. It exists at high levels in the plasma and has a number of fimctions, including an important role in insulin sensitivity, inflammation (anti-anti-inflammato-ry action) and atherogenesis. Unlike most adipokines, the plasma levels fall in obesity. 

AMPK is also regulated by a number of cytokines, including adipokines secreted from adipocytes that... 

Lipolysis 1 Hormone sensitive lipase (HSL) l Adrenergic stimulation of lipolysis Adipocytes... 

The thiazolidinediones have also been reported to act as inhibitors of the respiratory chain at high concentrations, and this appears to account for their ability to activate AMGPK in cultured cells. However, the primary target of the thiazolidinediones appears to be the peroxisome proliferator-activated receptor-y ( PPAR-y), a member of the nuclear receptor superfamily expressed in adipocytes. One of the major effects of stimulation of PPAR-y in adipocytes is the release ofthe... 

PPARy is strongly expressed in adipocytes, and stimulation by TZDs promotes adipogenesis, predominantly in preadipocytes from subcutaneous depots. Increased transcription of transporters and enzymes involved in fatty acid uptake and lipogenesis increases the deposition of lipid in these adipocytes (Table 2). This appears to facilitate a reduction in hyperglycaemia by reducing circulating concentrations of non-esterified... 

Gene activated Lipoprotein lipase fatty acid transporter protein adipocyte fatty acid binding protein acyl-CoA synthetase malic enzyme GLUT-4 glucose transporter phosphoenolpyruvate carboxykinase... 

Biological actions Adipocyte differentiation fatty acid uptake lipogenesis glucose uptake other effects on nutrient metabolism which lower hepatic glucose production... 

Leptin is a cytokine produced and secreted by adipose tissue in proportion to the body fat content [3]. Mice and humans lacking leptin or its receptor develop a severe hyperphagia and a dramatic degree of obesity which is considerably more pronounced than that of the NDRKO mouse. Thus, leptin is the key adiposity signal in rodents and humans. Leptin secretion appears to reflect the metabolic status of the adipocyte rather than the sheer size of triglyceride deposits, and leptin levels may transiently be dissociated from total body fat. Nonetheless, over the course of a day with unrestricted food supply, plasma leptin levels reliably reflect the amount of total body fat. Local administration of leptin into the brain results in reduced food intake. The vast majority of patients with obesity have elevated serum levels of leptin. Thus, it is believed that the polygenic obesity is due to leptin resistance rather than to inadequate leptin secretion, or to a reduced blood/brain transport of the cytokine. 

AQP7 is expressed in the proximal tubule of the kidney, testis, gastrointestinal tract, immature dendritic cells and ear. This glycerol channel is also highly expressed in adipocytes where it is thought to control the release of triglycerides. 

Obesity and hyperglycemia 2. 2-AG levels are elevated in mouse adipocytes and epididymal of mice with DIO. AEA and 2-AG levels are elevated in rat insulinoma p-cells, in pancreas of mice with DIO, and in obese women. Patients with obesity or hyperglycaemia caused by type 2 diabetes exhibit elevated levels of 2-AG or of both endocannabinoids in visceral fat or blood, respectively. AEA levels are elevated in the liver of DIO mice 2. CB1 antagonists... 

Fatty Acid Transporters. Figure 2 Quencher-based real-time fatty acid uptake assay with a fluorescently labeled FFA analogue (C1-Bodipy-C12). Predominantly protein-mediated fatty acid uptake by 3T3-L1 adipocytes (diamonds) was compared with diffusion-driven uptake by fibroblasts (squares) using the QBT Fatty Acid Uptake reagent (Molecular Devices Corp., CA, USA), which contains C1-Bodipy-C12 as substrate in conjunction with a cell impermeable quencher. Uptake kinetics was recorded using a Gemini fluorescence plate reader. Error bars indicate the standard deviations from 12 independent wells. RFU relative fluorescence units. 

In vitro and ex vivo studies have shown that FATPs transport LCFAs and very long-chain fatty acids (VLCFAs) but no medium-chain fatty acids, fatty acid esters, or lipid-soluble vitamins [4]. LCFA transport is inhibited by prior protease treatment. Synthetic substrates for FATPs include 14C-labeled fatty acids and the fluorescently labeled fatty acid analogue C1 -BODEP Y-Cl 2. Using the latter substrate, differences in fatty acid uptake kinetics between FATP expressing 3T3 LI adipocytes and 3T3 LI fibroblasts, which are devoid of FATPs, can be readily appreciated (Fig. 2). 

The insulin receptor is a transmembrane receptor tyrosine kinase located in the plasma membrane of insulin-sensitive cells (e.g., adipocytes, myocytes, hepatocytes). It mediates the effect of insulin on specific cellular responses (e.g., glucose transport, glycogen synthesis, lipid synthesis, protein synthesis). 

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