Restoration of metabolic inflammation-related ghrelin resistance by weight loss

    1. Masamitsu Nakazato1,3
    1. 1Division of Neurology, Respirology, Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
    2. 2Department of Sports and Fitness, Faculty of Wellness, Shigakkan University, Obu, Japan
    3. 3Agency for Medical Research and Development-Core Research for Evolutional Medical Science and Technology (AMED-CREST), Japan Agency for Medical Research and Development, Tokyo, Japan
    1. Correspondence should be addressed to M Nakazato: nakazato{at}


    High-fat diet (HFD)-induced metabolic inflammation in the central and peripheral organs contributes to the pathogenesis of obesity. Long-term HFD blunts signaling by ghrelin, a gastric-derived orexigenic peptide, in the vagal afferent nerve via a mechanism involving in situ activation of inflammation. This study was undertaken to investigate whether ghrelin resistance is associated with progressive development of metabolic inflammation. In mice, ghrelin’s orexigenic activity was abolished 2–4 weeks after the commencement of HFD (60% of energy from fat), consistent with the timing of accumulation and activation of macrophages and microglia in the nodose ganglion and hypothalamus. Calorie-restricted weight loss after 12-week HFD feeding restored ghrelin responsiveness and alleviated the upregulation of macrophage/microglia activation markers and inflammatory cytokines. HSP72, a chaperone protein, was upregulated in the hypothalamus of HFD-fed mice, potentially contributing to prevention of irreversible neuron damage. These results demonstrate that ghrelin resistance is reversible following reversal of the HFD-induced inflammation and obesity phenotypes.

    • Received 1 December 2017
    • Accepted 12 December 2017
    • Made available online as an Accepted Preprint 12 December 2017

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    1. J Mol Endocrinol 60 109-118
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