Effect of polymethoxyflavones on glucose metabolism in a mouse model of cachexia with mutation in the adenomatous polyposis coli gene

Abstract

Mice carrying a mutation in the adenomatous polyposis coli (APC) gene (APC^min/+) exhibit cachexia symptoms, including abnormalities in hepatic glucose metabolism, which are associated with endoplasmic reticulum (ER) stress. APC^min/+ mice are widely known to be associated with abnormalities in the Wnt/β-catenin pathway and gastrointestinal polyp formation. It is unclear whether abnormalities in the Wnt/β-catenin pathway are associated with cachexia in APC^min/+ mice. In this study, we orally administered polymethoxyflavonoids (PMFs) such as 5,7,3′,4′-tetramethoxyflavone (TMF), 7,8,3′,4′-TMF, or Nobiletin, to APC^min/+ mice, and analyzed their effects on cachexia symptoms. We found that APC^min/+ mice gradually lost weight, which was suppressed in the group that was administered PMFs. Furthermore, administration of these PMFs improved abnormal glucose metabolism in APC^min/+ mice. Our results suggest that the improvement in glucose metabolism observed in APC^min/+ mice orally administered PMFs is mediated by normalization of glycolysis or alleviation of hypoxia-induced ER stress.