Leptin is a four‐helix bundle: secondary structure by NMR

Kline, Allen D.; Becker, Gerald W.; Churgay, Lisa M.; Landen, Bryan E.; Martin, D; Muth, William L.; Rathnachalam, Radhakrishnan; Richardson, John M.; Schoner, Brigitte E.; Ulmer, Maverick; Hale, John E.

doi:10.1016/s0014-5793(97)00353-0

Cited by 49 publications

(27 citation statements)

References 37 publications

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“…This lack of ready reversibility reflects the delicate balance of distinct intracellular and extracellular redox environments required for successful cytokine-mediated signal transduction. The extracellular environment must be oxidizing to maintain the structural integrity of cytokines, such as IL-3 (46,47), which exist in a structure composed of a core four-helical bundle constrained by interhelical disulfide bridges (48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62). Further, inducible trans-receptor disulfide bridges are crucial to the biological responsiveness of several cytokine receptors, such as the receptors for IL-3 (63), IL-6, leukemia inhibitory factor, and ciliary neurotrophic factor (64).…”

Section: Discussionmentioning

confidence: 99%

Nitric oxide and thiol redox regulation of Janus kinase activity

Duhé

Evans

Erwin

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

141

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The activation of Janus kinases (JAKs) is crucial for propagation of the proliferative response initiated by many cytokines. The proliferation of various cell lines, particularly those of hematopoietic origin, is also modulated by mediators of oxidative stress such as nitric oxide and thiol redox reagents. Herein we demonstrate that nitric oxide and other thiol oxidants can inhibit the autokinase activity of rat JAK2 in vitro, presumably through oxidation of crucial dithiols to disulfides within JAK2. The reduced form of JAK2 is the most active form, and the oxidized JAK2 form is inactive. Nitric oxide pretreatment of quiescent Ba͞F3 cells also inhibits the interleukin 3-triggered in vivo activation of JAK2, a phenomenon that correlates with inhibited proliferation. Furthermore, we observed that the autokinase activity of JAK3 responds in a similar fashion to thiol redox reagents in vitro and to nitric oxide donors in vivo. We suggest that the thiol redox regulation of JAKs may partially explain the generally immunosuppressive effects of nitric oxide and of other thiol oxidants.

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Section: Discussionmentioning

confidence: 99%

Nitric oxide and thiol redox regulation of Janus kinase activity

Duhé

Evans

Erwin

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

141

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“…Leptin (Kline et al, 1997) concentrations in plasma were determined by use of a commercially available enzyme-linked immunosorbent assay kit (Rat Leptin TiterZyme EIA; Assay Designs, Ann Arbor, MI). Two experimental samples were selected as "quality control standards" to assess experimental variations between different runs.…”

Section: Leptin Analysismentioning

confidence: 99%

Mechanism-Based Modeling of Nutritional and Leptin Influences on Growth in Normal and Type 2 Diabetic Rats

Landersdorfer¹,

DuBois²,

Almon³

et al. 2008

J Pharmacol Exp Ther

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Influences of genetic and nutritional factors on body weight, fat mass, and leptin production and effects of leptin were assessed in normal [Wistar-Kyoto (WKY)] and diabetic [GotoKakizaki (GK)] rats by mechanism-based modeling. The study included 60 WKY and 60 GK rats; half received high-fat diet (HF), and the others received normal rat chow (N). Body weights and food consumption were measured twice weekly. Six rats per group were sacrificed at 4, 8, 12, 16, and 20 weeks. Abdominal fat was weighed, and plasma leptin was measured by enzyme-linked immunosorbent assay. All data were comodeled using NONMEM version VI level 1.1 (first-order conditional estimation with interaction) (Beal SL, Boeckmann AJ, Sheiner LB, and NONMEM Project Group, NONMEM Users Guides, University of California, San Francisco, CA, 2007). Weight gain was modeled as differences between energy intake and metabolic rate based on allometrically scaled lean body mass (LBM).The GK had higher metabolic rates (1.15 kcal/day/g LBM 0.75 ) than WKY-N (0.92) and WKY-HF (1.02) rats and higher efficiency in transforming energy into body weight. Leptin effect was modeled as inhibition of food consumption. Total body fat was estimated from abdominal fat. Leptin production from fat was 4.7-fold higher for GK (3.03 ng/ml/day/g) than WKY (0.66 ng/ml/day/g). Leptin production rate from LBM was 0.53 ng/ ml/day/g for all groups. The IC 50 for inhibition of food intake by leptin was approximately 3-fold higher in GK versus WKY, indicating leptin resistance for the effect on food consumption in GK. The GK had similar intake of kilocalories but lower body weights and fat mass than WKY, possibly because of higher metabolic rates. Our mechanism-based model explains intrinsic reasons for differences in growth, food intake, and leptin concentrations among these two strains of rats.Type 2 diabetes (T2DM) is a major health risk in many countries and the number of diabetic patients and associated costs for health systems are increasing. More than 180 million people are diabetic worldwide, and this number was estimated to more than double by 2030 (Centers for Disease Control and Prevention, http://www.cdc.gov/diabetes/pubs/ factsheets.htm). In 2005, an estimated 1.1 million people died from diabetes, and such deaths were predicted to increase by more than 50% over the next 10 years (Centers for Disease Control and Prevention, http://www.cdc.gov/ diabetes/pubs/factsheets.htm).

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Section: Citationmentioning

confidence: 99%

“…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), with four α-helices (helices A-D) and a distorted segment E in the CD loop [9,[26][27][28] (Figure 1).Generally, leptin appears to be highly conserved due to its functional importance [12,[29][30][31][32]. However, episodes of rapid sequence evolution and positive selection have been…”

mentioning

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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Leptin is a four‐helix bundle: secondary structure by NMR

Cited by 49 publications

References 37 publications

Nitric oxide and thiol redox regulation of Janus kinase activity

Nitric oxide and thiol redox regulation of Janus kinase activity

Mechanism-Based Modeling of Nutritional and Leptin Influences on Growth in Normal and Type 2 Diabetic Rats

Natural selection and adaptive evolution of leptin

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