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    • Albert Einstein College of Medicine: Doctoral Dissertations
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    • Albert Einstein College of Medicine (AECOM)
    • Albert Einstein College of Medicine: Doctoral Dissertations
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    Functional characterization of resistin, a novel adipokine

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    Date
    2005
    Author
    Rajala, Michael William
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    Abstract
    Adiposity is coupled to insulin action via largely unknown mechanisms. Adipocytes are the exclusive or predominant source of several secreted proteins that exert profound effects on systemic carbohydrate and lipid metabolism. The dysregulation of these proteins can partly account for the impaired insulin action associated with obesity in central and peripheral organs.;In a screen to identify new adipocyte specific proteins, I discovered a novel 10 kDa protein, later named resistin, that is upregulated and secreted during adipocyte differentiation. It is a founding member of a novel family of cysteine-rich hormones that includes resistin-like molecules alpha, beta, gamma (RELMs) each of which display specific, yet differential tissue distributions. Our initial characterization of resistin revealed that it is not regulated by pro-inflammatory stimuli, but is highly responsive to nutritional status including acute elevations in serum glucose. Furthermore, resistin has been reported to play a role in insulin sensitivity. Serum resistin is elevated in both genetic and diet-induced mouse models of obesity and its mRNA expression is suppressed by thiazolidinediones (TZD), a class of insulin sensitizing drugs used to treat type 2 diabetics that act primarily on adipose tissue.;To determine whether acute increases in circulating levels of resistin worsen glucose tolerance, either by decreasing glucose uptake, increasing glucose production or both, we combined the pancreatic-insulin clamp technique with infusions of resistin or vehicle in conscious rats. The effects of resistin on in vivo insulin action were completely accounted for by severe hepatic insulin resistance leading to an increase in the rate of glucose production. These results support the notion that resistin can modulate insulin action, and identify the liver as the target organ.;In a collaborative effort, the crystal structure of resistin was solved and reveals a novel disulfide-rich beta-sandwich "head" domain at the C-terminus, and an N-terminal alpha-helical "tail" segment. These helical segments associate to form a three-stranded coiled-coil with a conserved cysteine residue from each helix mediating disulfide linkages to form tail-to-tail hexamers. Analysis of serum samples, as well as conditioned media from cultured adipocytes, reveal that the hexamer is the predominant form and that resistin appears to be secreted and circulates in two forms, likely as hexamers and trimers. (Abstract shortened by UMI.).
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    https://ezproxy.yu.edu/login?url=http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqm&rft_dat=xri:pqdiss:3163146
    https://hdl.handle.net/20.500.12202/752
    Citation
    Source: Dissertation Abstracts International, Volume: 66-02, Section: B, page: 6630.;Advisors: Philipp E. Scherer.
    *This is constructed from limited available data and may be imprecise.
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