Trends in Endocrinology & Metabolism
The role of leptin receptor signaling in feeding and neuroendocrine function
Section snippets
LRs and sites of leptin action
There are multiple LR isoforms, which result from alternative mRNA splicing of the transcript of the lepr gene and/or from proteolytic processing of the subsequent protein products 8, 9. The lepr gene contains 17 common exons and several alternatively spliced exons. In mice, the five distinct LR isoforms that have been identified are designated LRa–LRe. In all species, LR isoforms can be divided into three classes: secreted, short and long. The secreted forms are either alternative splice
Leptin resistance and obesity
Over 25% of adults in the U.S.A. are obese and the incidence of obesity continues to rise in industrialized nations. Obesity is a major risk factor for type 2 diabetes mellitus, cardiovascular disease and some forms of cancer [22]. Because administration of leptin to rodents decreases food intake and increases energy expenditure, which results in loss of fat mass, leptin was initially hailed as a potential cure for obesity 1, 2, 8, 13, 16. However, with the exception of humans with a rare
LRb mediates JAK2 activation
The LR belongs to the interleukin 6 receptor family of class 1 cytokine receptors. These contain an extracellular ligand-binding domain, a transmembrane domain and a cytoplasmic signaling domain 8, 24. Cytokine receptors have no intrinsic enzymatic activity, but signal via a noncovalently associated member of the Janus kinase (JAK) family of tyrosine kinases 25, 26. Four members of the JAK family have been identified (JAK1–3 and Tyk2). JAK1, JAK 2 and Tyk2 are widely distributed, whereas JAK3
Leptin regulation of neural networks and neurophysiology
LRb is present in several tissues, with the highest levels in neurons of the nuclei of the basomedial hypothalamus, including the arcuate (ARC), dorsomedial hypothalamic (DMH) and ventromedial hypothalamic (VMH) nuclei 14, 15. Chemical and physical ablation of these nuclei results in increased feeding and neuroendocrine abnormalities that are similar to the phenotypes of db/db and ob/ob mice. This indicates that these hypothalamic nuclei, which make up the so-called ‘satiety center’, are
The IRS–PI 3-kinase pathway in the control of energy balance
To date, two LRb signaling pathways have been implicated in leptin action. These are STAT3 (see below) and the IRS–PI 3-kinase pathway. First described as insulin-receptor substrates, IRS proteins (IRS-1–4), are members of a class of intracellular signaling molecules, termed docking proteins, that are phosphorylated by several tyrosine kinases, including insulin receptors and some cytokine receptors [44]. Docking proteins, including the IRS proteins, are devoid of enzymatic activity, but are
Leptin signaling and physiology: the state of the field
Leptin binding to LRb activates intracellular signaling pathways via phosphorylation of several tyrosine residues on JAK2 and of Tyr985 and Tyr1138 on the intracellular tail of LRb. The JAK2–IRS–PI 3-kinase signal is important for the regulation of membrane potential in LRb-containing neurons in the hypothalamus and is crucial for the control of appetite and sympathetic nervous system function by leptin. However, the function of this pathway in most other aspects of neuroendocrine function is
Acknowledgements
The authors were supported by NIH DK56731 and DK 57768 and grants from the American Diabetes Association (MGM) and an American Diabetes Association/European Association for the Study of Diabetes Transatlantic Fellowship (SHB).
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