Leptin receptor

The cytokine leptin is secreted by adipocytes (fat cells) in proportion to the size of the adipose dq>ot and circulates via the bloodstream to the brain, where it ultimately affects feeding behavior, endocrine systems including reproductive function and, at least in rodents, energy expenditure. The major effect of Lqrtin is on the hy-pothalamous, where it suppresses appetite and hence food intake. Leptin exerts its effects via binding to the leptin receptor in the brain (specifically in the hypothalamus), which activates the JAK-STAT 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 leptin story has been augmented by a second mouse genetic defect leading to obesity. These mice are known as db/db they are very similar to ob/ob mice. However, these mice have normal levels of leptin. Scientists at Millennium Pharmaceuticals identified the molecular defect in db/db mice. They lack the normal leptin receptor. Therefore, we have both sides of the coin ob/ob mice cannot make leptin, eat too much, and are therefore obese db/db mice make leptin, cannot respond to it for lack of the leptin receptor, eat too much, and are obese. Administration of leptin to ob/ob mice normalizes their body weight but administration of leptin to db/db mice has... 

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. 

The leptin receptor is expressed primarily in regions of the brain known to regulate feeding behavior— neurons of the arcuate nucleus of the hypothalamus... 

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... 

FIGURE 23-35 A possible mechanism for cross-talk between receptors for insulin and leptin. The insulin receptor has intrinsic Tyr kinase activity (see Fig. 12-6), and the leptin receptor, when occupied by its ligand, is phosphorylated by a soluble Tyr kinase (JAK). One possible explanation for the observed interaction between leptin and insulin is that both may phosphorylate the same substrate—in the case shown here, insulin receptor substrate-2 (IRS-2). When phosphorylated, IRS-2 activates PI-3K, which has downstream consequences that include inhibition of food intake. IRS-2 serves here as an integrator of the input from two receptors. 

Banks, W.A., et al. 2002. Leptin transport across the blood-brain barrier of the Koletsky rat is not mediated by a product of the leptin receptor gene. Brain Res 950 130. 

Vanadium compounds have also been shown to be effective in animal models of insulin resistance and type 2 diabetes. Oral administration of vanadium compounds lowered blood glucose levels to near normal in the ob/ob and db/db mouse and fa/fa rat [149-151], These rodent models are homozygous for the indicated gene and are characterized by obesity, hyperglycemia, and hyperinsulinemia [12]. The ob allele is the gene for leptin, whereas db and fa are the genes for the leptin receptor in the mouse and rat, respectively. Leptin is one of the cytokine hormones that are produced in fat cells and act on receptors in the central nervous system. Its effects involve inhibition of food intake and promotion of energy expenditure [99],... 

Fig. 20.1 Leptin receptor isoforms. Leptin receptor isoforms (Ob-Ra to Ob-Re) are the result of alternative gene splicing. Ob-Rb is considered to be the active isoform for carrying out downstream signaling. The extracellular region of the receptor is comprised of two CK (cytokine receptor domain) and three F3 (fibronectin domain) domains. The extracellular domain is followed by the transmembrane domain. The intracellular region consists of B1 (box 1) and B2 (box 2) for JAK2 binding and STAT (signal transducers and activators of transcription) binding domain.

In addition to cardiac tissue, leptin receptors have also been identified in both cerebral and coronary vessels (Bjorbaek et al. 1997 Knudson et al. 2005). With respect to the latter it was proposed that OBR-mediated leptin-induced vasodilation occurs through an NO-dependent process and which was abolished by hyperleptinemia. This finding emphasizes the potential dual role of leptin on vascular tissue, a direct NO-dependent vasodilation and vasoconstriction occurring secondarily to central stimulation of the sympathetic nervous system. These effects will be discussed below in greater detail. 

Fig. 20.2 A general schematic representation of leptin signaling. Stimulation of the long form of the leptin receptor (OBRb) can result in the activation of various cell signaling components many of which are dependent on the activation of the JAK/STAT. This results in a multiplicity of cell signaling responses many of which subsequently target the nucleus resulting in transcriptional changes. See text for further discussion.

Modulation of Leptin Receptor Expression in the Cardiovascular System... 

Bjorbaek, C., Uotani, S., da Silva, B., and Flier, J. S. 1997. Divergent signaling capacities of the long and short isoforms of the leptin receptor. J. Biol. Chem. 272 32686-32695. 

Ge, H., Huang, L., Pourbahrami, T., and Li, C. 2002. Generation of soluble leptin receptor by ectodomain shedding of membrane-spanning receptors in vitro and in vivo. J. Biol. Chem. 277 45898 15903. 

Knudson, J. D., Dincer, U. D., Zhang, C., Swafford, A. N., Jr., Koshida, R., Picchi, A., Focardi, M., Dick, G. M., and Tune, J. D. 2005. Leptin receptors are expressed in coronary arteries, and hyperleptinemia causes significant coronary endothelial dysfunction. Am. J. Physiol. Heart Circ. Physiol. 289 H48-H56. 

Lollmann, B., Gruninger, S., Stricker-Krongrad, A., and Chiesi, M. 1997. Detection and quantification of the leptin receptor splice variants Ob-Ra, b, and, e in different mouse tissues. Biochem. Biophys. Res. Commun. 238 648-652. 

Generation of human soluble leptin receptor by proteolytic cleavage of membrane-anchored receptors. Endocrinology 142 4389-4393. 

Matsui, H., Motooka, M., Koike, H., Inoue, M., Iwasaki, T., Suzuki, T., Kurabayashi, M., and Yokoyama, T. 2007. Ischemia/reperfusion in rat heart induces leptin and leptin receptor gene expression. Life Sci. 80 672-680. 

Interleukin-8 (= IL-8-R)] (8 kDa protein) Leptin receptor (LEP-R) Animal [Immunomodulatory, chemotactic chemokine (G-X-G family)] 8.3L... 

A major site of leptin receptors is in the hypothalamus (the arcuate nucleus). 

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