FIGURE 4 | TNF decreases triglyceride deposition and increases lipolysis in adipose cells.

a | In small adipocytes (lean condition), insulin promotes free fatty acid (FFA) esterification into triglycerides (TG, schematically represented as the three-carbon glycerol backbone with three acyl fatty acid chains (wavy lines)) through stimulation of glucose transporter type-4 (GLUT4)-mediated glucose uptake. Glucose can be converted to -glycerol phosphate, the main source of the glycerol backbone of TG. Peroxisome proliferator-activated receptor- (PPAR) activates lipoprotein lipase (LPL) expression and the TG biosynthetic pathway. Secreted LPL hydrolyses TG from circulating very low-density lipoprotein (VLDL), releasing FFAs to be re-esterified. Several thiazolidinediones (TZDs) can activate PPAR. Insulin signalling also downregulates TG lipolysis through hormone-sensitive lipase (HSL). Insulin stimulation of the phosphatidylinositol 3-kinase (PI3K)–AKT/protein kinase B (PKB) pathway leads to activation of the enzyme phosphodiesterase-3 (PDE3). This enzyme catalyses the breakdown of cyclic AMP (cAMP) which in turn reduces activation of HSL. b | In enlarged adipocytes from inflamed fat tissue, high levels of tumour necrosis factor- (TNF) result in decreased fatty acid esterification and enhanced lipolysis. GLUT4, LPL and PPAR protein levels are attenuated by TNF, resulting in decreased glucose transport and fatty acid esterification. TNF also has a stimulatory effect on lipolysis by increasing the levels of cAMP and activation (plus signal) of HSL, combined with the downregulation of perilipin through activation of the mitogen-activated protein kinase (MAPK) pathway.

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