Functional Analysis of Leptin Receptor Activation Using a Janus Kinase/Signal Transducer and Activator of Transcription Complementation Assay

Zabeau, Lennart; Defeau, Delphine; Heyden, José Van der; Iserentant, Hannes; Vandekerckhove, Joël; Tavernier, Jan

doi:10.1210/me.2003-0078

Cited by 93 publications

(97 citation statements)

References 66 publications

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“…Based on the previous observation that the receptors become activated upon higher order (i.e. more than two) clustering (16), it is tempting to believe that two leptin molecules cluster two such LR dimers. Leptin site II interacts with the LR CRH2, whereas residues of site III interact with the LR Ig-like domain (20).…”

Section: Discussionmentioning

confidence: 99%

“…Vectors-Murine leptin receptor (mLR) deletion variants mLR ⌬CRH1 and mLR ⌬CRH1, ⌬Ig have been constructed using a mutagenesis strategy (16). In brief, a XhoI site was introduced immediately following the signal-peptide encoding sequence.…”

Section: Methodsmentioning

confidence: 99%

“…The CRH2 domain is necessary and sufficient for leptin binding (15). Despite the lack of any binding affinity for the ligand, the two FNIII and the Ig domains are needed for receptor activation (15,16). Because of alternative splicing and ectodomain shedding, the LR can exist as six isoforms: a LR long form (LRlo or LRb), four short forms (LRa, LRc, LRd, and LRf), and a soluble isoform (LRe).…”

mentioning

confidence: 99%

“…We recently used a JAK/STAT (Janus kinase/signal transducer and activator of transcription) complementation strategy to demonstrate that the LR becomes activated upon higher order clustering, i.e. more than two receptors per activated complex (16). In this approach, two signaling-deficient receptors, one unable to activate the JAKs and the other lacking a functional STAT3 recruitment site, are only able to signal when they are coexpressed.…”

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confidence: 99%

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Leptin Receptor Activation Depends on Critical Cysteine Residues in Its Fibronectin Type III Subdomains

Zabeau

Defeau

Iserentant

et al. 2005

Journal of Biological Chemistry

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The leptin receptor (LR) complex is composed of a single subunit belonging to the class I cytokine receptor family and exists as a preformed complex. The extracellular portion contains two cytokine receptor homology (CRH) domains, separated by an Ig-like domain and followed by two membrane-proximal fibronectin type III (FNIII) domains. The mechanisms underlying ligandinduced receptor activation are still poorly understood. LRs can exist as disulfide-linked dimers at the cell surface, even in the absence of leptin. We evaluated the role of the two unpaired cysteine residues (Cys-672 and Cys-751) in the FNIII domains in receptor clustering, leptin binding, and biological activity. Although mutation of cysteine on position 751 to serine has hardly any effect on ligand binding and receptor activation, the C672S mutant exhibits a marked reduction in STAT3-dependent signaling. The double mutant was completely devoid of biological activity, although leptin binding remained unaffected. Mutation of both residues resulted in complete loss of disulfide bridge formation of FNIII domains in solution. In contrast, no difference was observed in ligand-independent oligomerization of the membranebound receptor, suggesting a role for cysteines in the CRH2 domain in formation of the preformed LR complex. We propose a model wherein leptin-induced clustering of two preformed dimers forms the activated LR complex. Disulfide bridge formation involving Cys-672 and Cys-751 may be necessary for JAK activation and hence signaling.The 16-kDa cytokine-like hormone leptin has been identified as one of the key players in the control of body weight. The product of the ob gene is produced and secreted mainly by adipocytes (1, 2), and plasma protein levels positively correlate with body fat energy stores. Leptin reduces food intake and stimulates energy expenditure by activating its receptor in specific hypothalamic nuclei (3-5). Spontaneous mutations that lead to a functional defect in either leptin (6) or its receptor (7-9) result in a complex syndrome that includes morbid obesity, hypothermia, infertility, hyperglycemia, decreased insulin sensitivity, and hyperlipidemia. Besides serving a weight-regulating function, leptin also plays a role in other processes including metabolism, reproduction, hematopoiesis, and immunity (10 -13).The leptin receptor (LR), 1 the product of the db gene (14), is a member of the class I cytokine receptor family. The extracellular (EC) domain is composed of two so-called cytokine receptor homology (CRH) domains, a membrane distal CRH1 and a membrane proximal CRH2. Both domains are separated by an immunoglobulin-like (Ig) domain and are followed by two fibronectin type III (FNIII) domains proximal to the membrane. The CRH2 domain is necessary and sufficient for leptin binding (15). Despite the lack of any binding affinity for the ligand, the two FNIII and the Ig domains are needed for receptor activation (15, 16). Because of alternative splicing and ectodomain shedding, the LR can exist as six isoforms: a LR long ...

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Leptin Receptor Activation Depends on Critical Cysteine Residues in Its Fibronectin Type III Subdomains

Zabeau

Defeau

Iserentant

et al. 2005

Journal of Biological Chemistry

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“…cytokine receptor homology domain 1 (CRH1) and cytokine receptor homology domain 2 (CRH2) [9,110,115,116]. Based on previously studies, the CRH2 domain is essential for the interaction of leptin and its receptor [9,115,117,118], and it bind to the site II in leptin [9,110,[115][116][117][118].…”

Section: Leptin and Leptin Receptor Co-evolutionmentioning

confidence: 99%

Natural selection and adaptive evolution of leptin

Guo

Zhang

2013

Chin. Sci. Bull.

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Leptin is an adiposity-secreted hormone that is pivotal in regulating feeding behavior, energy metabolism and body mass. The study of leptin has been of crucial importance for public health and pharmaceutical intervention given its role in obesity. Generally, leptin is highly conserved due to its functional importance. However, episodes of rapid sequence evolution and positive selection have been observed in some mammalian species, indicating that the leptin functions in these animals may have undergone adaptive modification to their environments. In this article, we review the adaptive evolution of leptin and its potential functional consequences. This review is expected to guide future research of molecular evolution and functional assays of this gene, and also to provide a theoretical foundation for the use of leptin in therapeutic applications. natural selection, adaptive evolution, leptin, leptin receptor Citation:Zou G, Zhang Y P, Yu L. Natural selection and adaptive evolution of leptin. Chin Sci Bull, 2013Bull, , 58: 21042112, doi: 10.1007 The relationship between the adaptations of an organism to different ecological niches with genetic changes (e.g. the change of genes) has been one of the essential subjects in the study of life sciences. Accordingly, the mechanism underlying how organisms adapt to different living environments at molecular level has fascinated evolutionary biologists [1][2][3][4][5][6][7][8][9]. Metabolism is a series of biochemical reactions, allowing organisms to exchange materials and energy with the environment. These processes control growth, reproduction and behavior of organisms. Although the mechanisms of increased energy utilization are likely to be complex, one important component involves the activation of adipose tissue [10].Leptin, encoded by the obese gene, is a hormone that mainly secreted by adipose tissue. It is important in regulating feeding behavior, energy metabolism and body mass [11][12][13][14][15][16]. The level of plasma leptin is generally regarded as a signal to direct the central nervous system (CNS) to regulate food intake and energy expenditure, which is an important pathway of metabolism to maintain constancy of the adipose mass [12,14,17,18]. The mutation of ob gene results in a myriad of disturbance of metabolism [12,19]. Mice that are homozygous (ob/ob mouse) for mutations in this gene exhibit a profound obesity resulting from defects in energy expenditure, food intake and nutrient partitioning [12,20,21]. In humans, mutation of this gene results in a profound obesity and type II diabetes [12,[20][21][22][23]. Therefore, due to its critical role in obesity, the study of leptin will shed insight into molecular mechanism of energy homeostasis, future pharmaceutical intervention and public health [9,10,24].The leptin gene, spanning over 4.5-kb, consists of three exons and two introns [9,25]. The coding exons (exons 2 and 3) are 501 bp in length in total. Leptin contains an amino-terminal signal peptide (21 residues) and a mature peptide (146 residues),...

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Food Intake, Circuitry, and Energy Metabolism

Yeo

2016

Molecular Neuroendocrinology

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Functional Analysis of Leptin Receptor Activation Using a Janus Kinase/Signal Transducer and Activator of Transcription Complementation Assay

Cited by 93 publications

References 66 publications

Leptin Receptor Activation Depends on Critical Cysteine Residues in Its Fibronectin Type III Subdomains

Leptin Receptor Activation Depends on Critical Cysteine Residues in Its Fibronectin Type III Subdomains

Natural selection and adaptive evolution of leptin

Food Intake, Circuitry, and Energy Metabolism

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