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      • Record: found
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      Is Open Access

      Targeting both sides of the GDF15-GFRAL-RET receptor complex: A new approach to achieve body weight homeostasis

      a , , b , c

      Genes & Diseases

      Chongqing Medical University

      Anorexia, Brain, GDF15, GFRAL, MIC-1, Obesity, RET

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Obesity is a chronic, complex disease, which is associated with several comorbidities, including diabetes mellitus, hypertension, and cardiovascular diseases. It is estimated that the prevalence of obesity among both adults and children nearly tripled between 1975 and 2016, highlighting a huge unmet treatment need. However, the currently available anti-obesity drugs have serious side effects, which limit their long-term use. The finding that the newly-identified brain GDF15-GFRAL-RET receptor signaling complex is involved in stress/disease-induced anorexia will certainly impact our knowledge of body weight homeostasis under healthy and disease conditions. Based on this breakthrough, a new class of GFRAL/RET-based drugs is highly anticipated for the treatment of obesity, as well as cancer-induced cachexia.

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          Most cited references 10

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          Tumor-induced anorexia and weight loss are mediated by the TGF-beta superfamily cytokine MIC-1.

          Anorexia and weight loss are part of the wasting syndrome of late-stage cancer, are a major cause of morbidity and mortality in cancer, and are thought to be cytokine mediated. Macrophage inhibitory cytokine-1 (MIC-1) is produced by many cancers. Examination of sera from individuals with advanced prostate cancer showed a direct relationship between MIC-1 abundance and cancer-associated weight loss. In mice with xenografted prostate tumors, elevated MIC-1 levels were also associated with marked weight, fat and lean tissue loss that was mediated by decreased food intake and was reversed by administration of antibody to MIC-1. Additionally, normal mice given systemic MIC-1 and transgenic mice overexpressing MIC-1 showed hypophagia and reduced body weight. MIC-1 mediates its effects by central mechanisms that implicate the hypothalamic transforming growth factor-beta receptor II, extracellular signal-regulated kinases 1 and 2, signal transducer and activator of transcription-3, neuropeptide Y and pro-opiomelanocortin. Thus, MIC-1 is a newly defined central regulator of appetite and a potential target for the treatment of both cancer anorexia and weight loss, as well as of obesity.
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            Long-term follow-up after bariatric surgery: a systematic review.

            Bariatric surgery is an accepted treatment for obesity. Despite extensive literature, few studies report long-term follow-up in cohorts with adequate retention rates.
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              GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates

              GDF15 has potent anti-obesity effects, but its receptor was unknown. GFRAL has now been identified as the receptor and mediates GDF15's effects through central actions in the hindbrain.
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                Author and article information

                Contributors
                Journal
                Genes Dis
                Genes Dis
                Genes & Diseases
                Chongqing Medical University
                2352-4820
                2352-3042
                21 November 2017
                December 2017
                21 November 2017
                : 4
                : 4
                : 183-184
                Affiliations
                [a ]The Editorial Office of Genes & Diseases, Chongqing Medical University, Chongqing, China
                [b ]John Moorhead Research Laboratory, Centre for Nephrology, University College London, London, UK
                [c ]Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Boston, MA, United States
                Author notes
                []Corresponding author. fei@ 123456genesndiseases.org
                Article
                S2352-3042(17)30085-5
                10.1016/j.gendis.2017.11.004
                6146208
                © 2017 Chongqing Medical University. Production and hosting by Elsevier B.V.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                Categories
                Article

                ret, obesity, mic-1, gfral, gdf15, brain, anorexia

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