Obesity and the Regulation of Body Mass:- 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 JAK-STAT system (Fig. 1). The leptin receptor, which has a single transmembrane seg ment, dimerizes when leptin binds to the extracellular domain of two monomers. Both monomers are phosphorylated on a Tyr residue of the intracellular domain by a Janus kinase (JAK). The P–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 same JAK. After phosphorylation, the STATs dimerize then move to the nucleus, where they bind to specific DNA sequences and stimulate the expression of target genes, including the gene for POMC, from which α-MSH is produced.
The increased catabolism and thermogenesis triggered by leptin are due in part to increased synthesis of the mitochondrial uncoupling protein UCP in adipocytes. Leptin stimulates the synthesis of this un coupling protein by altering synaptic transmissions from neurons in the arcuate nucleus to adipose and other tis sues. In these tissues, leptin causes increased release of norepinephrine, which acts through β3-adrenergic receptors to stimulate transcription of the gene for UCP. The resulting uncoupling of electron transfer from ox idative phosphorylation consumes fat and is thermo genic .
Might human obesity be the result of insufficient leptin production, and therefore treatable by the injection of leptin? Blood levels of leptin are in fact usually much higher in obese animals (including humans) than in animals of normal body mass (except, of course, in ob/ob animals, which cannot make leptin). Some downstream element in the leptin response system must be defective in obese individuals, and the elevation in leptin is the result of an (unsuccessful) attempt to overcome the leptin resistance. In those very rare humans with extreme obesity who have a defective leptin gene (OB), leptin injection does result in dramatic weight loss. In the vast majority of obese individuals, however, the OB gene is intact. In clinical trials, the injection of leptin did not have the weight-reducing effect observed in obese ob/ob mice. Clearly, most cases of human obesity involve one or more factors in addition to leptin.
FIGURE 1 The JAK-STAT mechanism of leptin signal transduction in the hypothalamus. Leptin binding induces dimerization of the leptin receptor, followed by phosphorylation of Tyr residues of the receptor, catalyzed by Janus kinase (JAK). STATs bound to the phosphorylated leptin receptor through their SH2 domains are now phosphorylated on Tyr residues by a separate activity of JAK. The STATs dimerize, binding each other’s P–Tyr residues, and enter the nucleus. Here, they bind specific regulatory regions in the DNA and alter the expression of certain genes. The products of these genes ultimately in fluence the organism’s feeding behavior and energy expenditure.
