Feb 26, 2009 - short-chain acylcarnitines derived from amino acid and fatty acid oxidation. ... Shinichi Miyagawa, Yoshihiko Satoh, Ryuma Haraguchi, Kentaro ...
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E N D O C R I N O L O G Y A b s t r a c t s
The following abstracts from Molecular Endocrinology have been selected by the editors of JCEM as being particularly relevant to readers interested in translational science.
Increased Insulin Sensitivity in Mice Lacking Collectrin, a Downstream Target of HNF-1␣ Sandra M. Malakauskas, Wissam M. Kourany, Xiao Yin Zhang, Danhong Lu, Robert D. Stevens, Timothy R. Koves, Hans E. Hohmeier, Deborah M. Muoio, Christopher B. Newgard, and Thu H. Le (Mol Endocrinol, published February 26, 2009, 10.1210/me.2008-0274) ABSTRACT 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⫺/y). 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. Loss- and 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.
J Clin Endocrinol Metab, May 2009, 94(5):1837–1838
jcem.endojournals.org
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Translational Highlights from MOLECULAR ENDOCRINOLOGY
J Clin Endocrinol Metab, May 2009, 94(5):1837–1838
Ghrelin Induces Abdominal Obesity via GHS-R-Dependent Lipid Retention Jeffrey S. Davies, Pia Kotokorpi, Sinan R. Eccles, Sarah K. Barnes, Paweł F. Tokarczuk, Sophie K. Allen, Hilary S. Whitworth, Irina A. Guschina, Bronwen A. J. Evans, Agneta Mode, Jeffrey M. Zigman, and Timothy Wells (Mol Endocrinol, published March 19, 2009, 10.1210/me.2008-0432) ABSTRACT Circulating ghrelin elevates abdominal adiposity by a mechanism independent of its central orexigenic activity. In this study we tested that hypothesis that peripheral ghrelin induces a depot-specific increase in white adipose tissue (WAT) mass in vivo by growth hormone secretagogue receptor (GHS-R1a)-mediated lipolysis. Chronic intravenous infusion of acylated ghrelin increased retroperitoneal and inguinal WAT volume in rats without elevating superficial subcutaneous fat, food intake or circulating lipids and glucose. Increased retroperitoneal WAT mass resulted from adipocyte enlargement probably due to reduced lipid export [ATP-binding cassette transporter (ABCG1) mRNA expression and circulating free fatty acids (FFAs) were halved by ghrelin infusion]. In contrast, ghrelin treatment did not upregulate biomarkers of adipogenesis [peroxisome proliferator-activated receptor (PPAR)␥2 or CCAAT/enhancer binding protein (C/EBP)␣] or substrate uptake (glucose transporter, GLUT4, lipoprotein lipase or CD36) and although ghrelin elevated sterol regulatory element binding protein (SREBP)1c expression, WAT-specific mediators of lipogenesis [liver X receptor (LXR)␣ and fatty acid synthase] were unchanged. Adiposity was unaffected by infusion of unacylated ghrelin, and the effects of acylated ghrelin were abolished by transcriptional blockade of GHS-R1a, but GHS-R1a mRNA expression was similar in responsive and unresponsive WAT. Microarray analysis suggested that depot-specific sensitivity to ghrelin may arise from differential fine-tuning of signal transduction and/or lipid handling mechanisms. Acylated ghrelin also induced hepatic steatosis, increasing lipid droplet number and triacylglycerol content by a GHS-R1a-dependent mechanism. Our data imply that during periods of energy insufficiency exposure to acylated ghrelin may limit energy utilization in specific WAT depots by GHS-R1a-dependent lipid retention.
The DREAM Protein Is Associated to Thyroid Enlargement and Nodular Development Marcos Rivas, Britt Mellstro¨m, Begon˜a Torres, Gaetano Cali, Alfonso M. Ferrara, Daniela Terracciano, Mariastella Zannini, Gabriella Morreale de Escobar and Jose R. Naranjo (Mol Endocrinol, published March 19, 2009, 10.1210/me.2008-0466) ABSTRACT G protein-coupled receptors (GPCR) are involved in the pathophysiology of a wide range of diseases and constitute an attractive therapeutic target. In the thyroid gland, thyroid-stimulating hormone receptor (TSHR), a member of the GPCR family, is a major regulator of thyroid differentiation and function. Alterations in TSHR activity are often involved in the development of pathologies such as thyroid cancer and thyroid enlargement (goiter). Here we show that DREAM (downstream regulatory element antagonist modulator) modulates TSHR activity through a direct protein-protein interaction that promotes coupling between the receptor and G␣s. In transgenic mice, DREAM overexpression provokes a marked enlargement of the thyroid gland. Increased levels of DREAM protein were observed in human multi-nodular goiters, suggesting a novel etiopathogenic mechanism in nodular development in humans. Taken together, these findings identify a mechanism for the control of TSHR activity and provide a new approach for the study and treatment of thyroid pathologies associated with impaired TSHR function.
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