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Here, we use a genetic mouse model to determine myonectin's requirement for metabolic homeostasis. Female myonectin\u2010deficient mice had larger gonadal fat pads and developed mild insulin resistance when fed a high\u2010fat diet (HFD) and had reduced food intake during refeeding after an unfed period but were otherwise indistinguishable from wild\u2010type littermates. Male mice lacking myonectin, however, had reduced physical activity when fed\n                    <jats:italic>ad libitum<\/jats:italic>\n                    and in the postprandial state but not during the unfed period. When stressed with an HFD, myonectin\u2010knockout male mice had significantly elevated VLDL\u2010triglyceride (TG) and strikingly impaired lipid clearance from circulation following an oral lipid load. Fat distribution between adipose and liver was also altered in myonectin\u2010deficient male mice fed an HFD. Greater fat storage resulted in significantly enlarged adipocytes and was associated with increased postprandial lipoprotein lipase activity in adipose tissue. Parallel to this was a striking reduction in liver steatosis due to significantly reduced TG accumulation. Liver metabolite profiling revealed additional significant changes in bile acids and 1\u2010carbon metabolism pathways. Combined, our data affirm the physiologic importance of myonectin in regulating local and systemic lipid metabolism.\u2014Little, H. C., Rodriguez, S., Lei, X., Tan, S. Y., Stewart, A. N., Sahagun, A., Sarver, D. C., Wong, G. W. Myonectindeletion promotes adipose fat storage and reduces liver steatosis. FASEB J. 33, 8666\u20138687 (2019).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.201900520r","type":"journal-article","created":{"date-parts":[[2019,4,19]],"date-time":"2019-04-19T15:56:13Z","timestamp":1555689373000},"page":"8666-8687","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":77,"title":["Myonectin deletion promotes adipose fat storage and reduces liver steatosis"],"prefix":"10.1096","volume":"33","author":[{"given":"Hannah C.","family":"Little","sequence":"first","affiliation":[{"name":"Department of Physiology Johns Hopkins University School of Medicine  Baltimore Maryland USA"},{"name":"Center for Metabolism and Obesity Research Johns Hopkins University School of Medicine  Baltimore Maryland 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