Leptin function

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. 

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. 

Adipocytes have an important secretory function. Numerous factors (collectively termed adipokines or adipocytokines), mostly peptides but also eicosanoids are produced by preadipocytes and mature adipocytes (Table 9.3). Some of these factors act in an autocrine or paracrine fashion to regulate adipogenesis, that is differentiation and maturation of adipocytes themselves, whilst others, notably, leptin, adiponectin and some cytokines act in truly endocrine way, having effects on the brain, endothelial cells, liver and skeletal muscle. Disturbance in secretion from adipocytes is associated with eating disorders and metabolic syndrome. 

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. 

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. 

Although the adipocyte s primary role is to store fat, it also function as an endocrine cell that releases numerous regulatory molecifes such as leptin, adiponectin, and resistin. 

In 30 patients with lipodystrophy associated with HAART rosiglitazone 8 mg/day for 24 weeks had no effect on body weight, subcutaneous or intra-abdominal fat, total body fat, anthropometry, or serum leptin concentrations (84). However, it reduced percentage liver fat and serum insulin concentrations and normalized liver function tests. During the first 12 weeks serum triglycerides rose from 3.5 to 6.5 mmol/1 and serum cholesterol from 6.0 to 7.8 mmol/1. The results on insulin resistance and lipid profiles were opposite to those found in a comparable study with pioglitazone (83). 

Leptin is a peptide hormone secreted by adipocytes. Recombinant human leptin has been investigated for its potential as an antiobesity agent [105,106]. Women with hypothalamic amenorrhea display reduced levels of leptin. Leptin administration to these women improves reproductive and neuroendocrine function [107], Nasal administration of leptin to rats in the presence of either TDM (1) or LPC [108] caused a significant increase in serum leptin levels. Increased serum leptin levels were associated with reduced food consumption [108], The development of an effective nasal formulation of leptin containing an absorption enhancer may allow more frequent dosing with leptin and thereby overcome the limited efficacy observed following subcutaneous injections of large doses of this hormone. 

Finally, peptides such as galanin, leptin, neuropeptide Y, vasoactive intestinal polypeptide (VIP), and pituitary adenylate cyclase-activating polypeptide (PACAP) have been identified in various areas of the CNS. These and other peptides may affect various CNS functions, either by acting directly as neurotransmitters or by acting as cotransmitters moderating the effects of other neurotransmitters.7 24,27,34... 

Cardiovascular Actions of Leptin Effect on Cardiomyocyte Function... 

Gonzalez, A. A., Kumar, R., Mulligan, J. D., Davis, A. J., Weindruch, R., and Saupe, K. W. 2004. Metabolic adaptations to fasting and chronic caloric restriction in heart, muscle, and liver do not include changes in AMPK activity. Am. J. Physiol. Endocrinol. Metab. 287 E1032-E1037. Grassi, G. 2004. Leptin, sympathetic nervous system, and baroreflex function. Curr. Hypertens. Rep. 6 236-240. 

Seufert, J. 2004. Leptin effects on pancreatic beta-cell gene expression and function. Diabetes. 53 Suppl 1 S152—S158. 

Uotani, S., Bjorbaek, C., Tomoe, J., and Flier, J. S. 1999. Functional properties of leptin receptor isoforms internalization and degradation of leptin and ligand-induced receptor downregulation. Diabetes 48 279-286. 

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