The role of leptin receptor signaling in feeding and neuroendocrine function

doi:10.1016/j.tem.2003.10.003

Trends in Endocrinology & Metabolism

Volume 14, Issue 10, December 2003, Pages 447-452

https://doi.org/10.1016/j.tem.2003.10.003 Get rights and content

Abstract

The adipose-derived hormone leptin regulates energy balance and neuroendocrine function, and resistance to its appetite-suppressing effects might underlie common forms of obesity. Understanding the intracellular signaling pathways and hypothalamic neural circuitry by which leptin controls satiety and body weight is central to our understanding of leptin resistance and the identification of potential therapeutic targets. Here, we review the mechanisms by which leptin activates intracellular signaling and the roles of two specific leptin-activated signals [phosphatidylinositol 3-kinase and signal transducer and activator of transcription-3 (STAT3)] in the regulation of body weight and neuroendocrine function. The pathway by which leptin activates STAT3 is particularly intriguing because it is crucial for the regulation of feeding but dispensable for the control of reproductive and growth axes.

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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Trends in Endocrinology & Metabolism

The role of leptin receptor signaling in feeding and neuroendocrine function

Abstract

Section snippets

LRs and sites of leptin action

Leptin resistance and obesity

LRb mediates JAK2 activation

Leptin regulation of neural networks and neurophysiology

The IRS–PI 3-kinase pathway in the control of energy balance

Leptin signaling and physiology: the state of the field

Acknowledgements

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Leptin receptor long-form splice-variant protein expression in neuron cell bodies of the brain and co-localization with neuropeptide Y mRNA in the arcuate nucleus

J. Histochem. Cytochem.