Hypothalamus leptin

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. 

Neuropeptides play key roles in appetite regulation and obesity. Many genes for neuropeptides and neuropeptide receptors have been implicated in obesity and cachexia, anorexia and bulimia [34]. For example,NPY administration into the CNS causes overeating and obesity. A second peptide involved in obesity is leptin, a product of adipocytes and the stomach. The leptin gene is defective in the ob/ob mouse but in normal mice leptin binds to its receptor in the hypothalamus, causing a decrease in the synthesis and release of hypothalamic NPY. 

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. 

One of the classical obesity mntations in mice is termed ob, for obesity. Mice that are homozygous for the ob mutation (ob/ob mice) are grossly obese. Jeffrey Friedman at the Rockefeller University elucidated the defect in ob/ob mice in 1992. Specifically, the ob gene encodes a protein termed leptin.Leptin is prodnced in fat tissue and acts on the central nervous system at the hypothalamus. Basically, it reports nutritional information to this control center. 

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

Although it has been known for several years that leptin can activate AMPK, recently this pathway has come into focus as it was demonstrated to be of utmost importance in regulating food intake in the hypothalamus (Minokoshi et al. 2002, 2004). AMPK plays a particularly important role in the regulation of fatty acid oxidation. Fatty acids which are not oxidized are stored in cytoplasm as triglycerides. Malonyl CoA is an important fatty acid in maintaining a balance between storage of fatty acids and transport into the mitochondria for oxidation. Elevated malonyl CoA results in impaired transport into the mitochondria and consequently... 

NPY, a 36-residue, highly conserved peptide that is widely distributed throughout the vertebrate nervous system. NPY delivers a powerful orexigenic (appetite-promoting) signal within the hypothalamus, which activates a neural pathway leading to the nucleus of the solitary tract. NPY is over-produced in leptin-deficient mice and may mediate the overfeeding observed in leptin-deflcient animals. 

---