Increased Insulin Sensitivity in Mice Lacking Collectrin, a Downstream Target of HNF-1α

Collectrin is a downstream target of the transcription factor hepatocyte nuclear factor-1 (HNF-1 ), which is mutated in maturityonset diabetes of the young subtype 3 (MODY3). Evidence from transgenic mouse models with collectrin overexpression in pancreatic islets suggests divergent roles for collectrin in influencing -cell mass and insulin exocytosis. To clarify the function of collectrin in the pancreas, we used a mouse line with targeted deletion of the gene. We examined pancreas morphology, glucose homeostasis by ip glucose tolerance testing (IPGTT) and insulin tolerance testing (IPITT), and pancreas function by in vivo acutephase insulin response determination and glucose-stimulated insulin secretion from isolated islets. We find no difference in either pancreas morphology or function between wild-type and collectrin-deficient animals (Tmem27 ). However, we note that by 6 months of age, Tmem27 /y mice exhibit increased insulin sensitivity by IPITT and decreased adiposity by dual-energy x-ray absorptiometry scanning compared with wild-type. We have previously reported that Tmem27 /y mice exhibit profound aminoaciduria due to failed renal recovery. We now demonstrate that Tmem27 /y animals also display inappropriate excretion of some short-chain acylcarnitines derived from amino acid and fatty acid oxidation. We provide further evidence for compensatory up-regulation of oxidative metabolism in Tmem27 /y mice, along with enhanced protein turnover associated with preserved lean mass even out to 1.5 yr of age. Our studies suggest that collectrin-deficient mice activate a number of adaptive mechanisms to defend energy homeostasis in the setting of ongoing nutrient losses. Genetic Interactions of the Androgen and Wnt/ -Catenin Pathways for the Masculinization of External Genitalia Shinichi Miyagawa, Yoshihiko Satoh, Ryuma Haraguchi, Kentaro Suzuki, Taisen Iguchi, Makoto M. Taketo, Naomi Nakagata, Takahiro Matsumoto, Ken-ichi Takeyama, Shigeaki Kato, and Gen Yamada (Mol Endocrinol, published March 12, 2009, 10.1210/me.2008-0478) ABSTRACT In most mammals, the sexually dimorphic development of embryos is typically achieved by the differentiation of the external genitalia. Hence, the sexual distinction of mammalian newborns is based on the external genital structure. Although it was shown in the 1940s and 1950s that androgen from the testes establishes the male sexual characteristics, the involvement of nongonadal and locally produced masculine effectors remains totally unknown. It is noteworthy that the disorders of fetal masculinization, including hypospadias, one of the most frequent birth defects, occur at a high frequency. Furthermore, their causative factors remain unclear. In this study, the involvement of the coordinated actions of androgen and the growth factor systems was genetically analyzed for the first time on mammalian reproductive organ formation. The results demonstrated that the Wnt/ catenin pathway is indispensable masculine factor for the external genital development. The bilateral mesenchymal region adjacent to the urethral plate epithelium displayed a sexually dimorphic activity of Wnt/ -catenin signaling. Lossand gain-offunction -catenin mutants displayed altered sexual development of the external genitalia. These results indicate the novel functions of the Wnt/ -catenin pathway as a locally expressed masculine effector. This could be the first genetic study analyzing the roles of the genetic interactions between androgen and locally expressed growth factor signaling during the development of reproductive organs. These results also shed new insight on the reproductive genetics and the causative factors of genital disorders. T R A N S L A T I O N A L H I G H L I G H T S F R O M M O L E C U L A R E N D O C R I N O L O G YIn most mammals, the sexually dimorphic development of embryos is typically achieved by the differentiation of the external genitalia. Hence, the sexual distinction of mammalian newborns is based on the external genital structure. Although it was shown in the 1940s and 1950s that androgen from the testes establishes the male sexual characteristics, the involvement of nongonadal and locally produced masculine effectors remains totally unknown. It is noteworthy that the disorders of fetal masculinization, including hypospadias, one of the most frequent birth defects, occur at a high frequency. Furthermore, their causative factors remain unclear. In this study, the involvement of the coordinated actions of androgen and the growth factor systems was genetically analyzed for the first time on mammalian reproductive organ formation. The results demonstrated that the Wnt/ catenin pathway is indispensable masculine factor for the external genital development. The bilateral mesenchymal region adjacent to the urethral plate epithelium displayed a sexually dimorphic activity of Wnt/ -catenin signaling. Lossand gain-offunction -catenin mutants displayed altered sexual development of the external genitalia. These results indicate the novel functions of the Wnt/ -catenin pathway as a locally expressed masculine effector. This could be the first genetic study analyzing the roles of the genetic interactions between androgen and locally expressed growth factor signaling during the development of reproductive organs. These results also shed new insight on the reproductive genetics and the causative factors of genital disorders. T R A N S L A T I O N A L H I G H L I G H T S F R O M M O L E C U L A R E N D O C R I N O L O G Y