Signal leptin

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. 

JAKs and signal transducers and activators of transcription (STATs) are functionally analogous with IRS and PI3K. JAKs are physically associated with a cell surface receptor (e.g. for leptin, erythropoietin (EPO), growth factors or cytokines) STATs are free monomeric proteins within the cytosol but following phosphorylation by a JAK, individual proteins dimerize and then move into the nucleus of the cell where they control gene expression. 

Two tyrosine kinase-based mechanisms have been described the IR and the JAK/ STAT cascades. It should not be assumed that these are either/or mechanisms as there may be parallel transduction (cross-talk) between the two pathways. For example, leptin, an appetite suppressor described more fully in Chapter 9 is a cytokine-like peptide produced by adipose tissue, which signals in the hypothalamus of the brain via JAK2/STAT3, but also influences the IRS/PI3K pathway. 

Leptin signalling is via monomeric receptors in the brain. A short-form of the leptin receptor (Lep-R) is required to transport the hormone across the blood-brain barrier and a long-form Lep-R is located in the hypothalamus. The long-form is functionally linked with a particular type of receptor-associated tyrosine kinase called Janus kinase (JAK, see Section 4.7) whose function is to phosphorylate a STAT (signal transducer and activator of transcription) protein a similar mechanism to that often associated with signalling by inflammatory cytokines. 

The regulation of food intake in humans is complex. In addition to genetic and cultural influences, it involves the action of leptin, insulin, ghrelin, PYY, cholecystokinin, and amylin. Most of these molecules act by signaling to the brain. 

The lipostat theory postulates a mechanism that inhibits eating behavior and increases energy consumption whenever body weight exceeds a certain value (the set point) the inhibition is relieved when body weight drops below the set point (Fig. 23-30). This theory predicts that a feedback signal originating in adipose tissue influences the brain centers that control eating behavior and activity (metabolic and motor). The first such factor, leptin, was discovered in 1994, and several others are now known. 

A second mouse gene, designated DB (diabetic), has also been found to have a role in appetite regulation. Mice with two defective copies (db/db) are obese and diabetic. The DB gene encodes the leptin receptor. When the leptin receptor is defective, the signaling function of leptin is lost. 

Leptin Triggers a Signaling Cascade That Regulates Gene Expression... 

The leptin signal is transduced by a mechanism also used by receptors for interferon and growth factors, the JAIC-STAT system (Fig. 23-34 see Fig. 12-9). The leptin receptor, which has a single transmembrane segment, dimerizes when leptin binds to the extracellular domain of two monomers. Both monomers are phos-phorylated on a Tyr residue of the intracellular domain by a Janus kinase (JAK). The -Tyr residues become docking sites for three proteins that are signal transducers and activators of transcription (STATs 3, 5, and 6, sometimes called fat-STATS). The docked STATs are then phosphorylated on Tyr residues by the... 

Leptin makes the cells of liver and muscle more sensitive to insulin. One hypothesis to explain this effect suggests cross-talk between the protein tyrosine kinases activated by leptin and those activated by insulin (Fig. 23-35) common second messengers in the two signaling pathways allow leptin to trigger some of the same downstream events that are triggered by insulin, through insulin receptor substrate-2 (IRS-2) and phos-phoinositide 3-kinase (PI-3K) (Chapter 12). 

The signal-transduction mechanism for leptin involves phosphorylation of the JAK-STAT system. On phosphorylation by JAK, STATs can bind to regulatory regions in nuclear DNA and alter the expression of genes for the proteins that set the level of metabolic activity and determine feeding behavior. Insulin acts on receptors in the arcuate nucleus, with results similar to those caused by leptin. 

Auwerx, J. Staels, B. (1998) Leptin.Lancet 351, 737-742. Brief overview of the leptin system and JAK-STAT signal transductions. 

Barrett, K., Leptin, M., and Settleman, J. (1997). The Rho GTPase and a putative RhoGEF mediate a signaling pathway for the cell shape changes in Drosophila gastrulation. Cell 91, 905—915. 

Bjorbaek C, Kahn BB. Leptin signaling in the central nervous system and the periphery. Recent Prog Horm Res. 2004 59 305-331. 

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