Copper-catalyzed diastereo- and enantioselective desymmetrization of cyclopropenes: Synthesis of cyclopropylboronates

This document is the accepted manuscript version of a Published Work that appeared in final form in Journal of American Chemical Society 136.45, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see DOI: 10.1021/ja510419zA novel Cu-catalyzed diastereo- and enantioselective desymmetrization of cyclopropenes to afford nonracemic cyclopropylboronates is described. Trapping the cyclopropylcopper intermediate with electrophilic amines allows for the synthesis of cyclopropylaminoboronic esters and demonstrates the potential of the approach for the synthesis of functionalized cyclopropanesWe thank the European Research Council (ERC-337776) and MINECO (CTQ2012-35957) for financial support. M. T. and A. P. thank MICINN for RyC and JdC contract

Selective inactivation of c-Jun NH2 terminal kinase (JNK) in the adipose tissue is sufficient to protect against diet-induced-obesity and its associated metabolic disorders in mice

Open URL - http://www.endojournals.org/site/abstracts/P1-1_to_P1-729.pdfINTRODUCTION: Obesity caused by feeding a high fat diet is associated with increased activation of c-Jun NH2-terminal kinase (JNK), which has been implicated in the development of obesity-related insulin resistance and type 2 diabetes. However, the relative tissue-specific contribution and the underlying mechanisms remain to be defined. METHOD: In this study, we generated a transgenic mouse model with adipose tissue-specific over-expression of dominant negative (DN) JNK. Their phenotypic changes on a high fat diet were comprehensively characterized. Adipose tissues, liver, muscle and serum were collected for further biochemical and morphological analysis. RESULTS: On the standard chow diet, the transgenic mice showed no significant difference in body weight gain, insulin sensitivity, glucose or lipid profiles, from their wild-type littermates. However, on a high fat diet, the DN-JNK transgenic mice were protected against diet-induced obesity, with reduced weight gain, fat mass and size of adipocytes in the adipose tissues. Significantly, the DN-JNK transgenic mice were resistant to the deleterious impact of high-fat diet on systemic insulin sensitivity and glucose tolerance. They also demonstrated a lower level of hepatic gluconeogenesis in vivo, and greater insulin-induced glucose uptake in skeletal muscles ex vivo. These metabolic changes were accompanied by a markedly decreased macrophage infiltration in the adipose tissue, reduced production of pro-inflammatory adipokines, increased expression of adiponectin and reduced circulating levels of adipocyte fatty acid binding protein. As a secondary effect, the DN-JNK transgenic mice also exhibited a resistance to the hepatosteatosis induced by high fat diet. The DN-JNK mice, when on a high fat diet, had significant increases in 24-hour oxygen consumption and reductions in respiration exchange rates, compared with their wild-type littermates. CONCLUSION: Selective suppression of JNK activation in the adipose tissue alone was sufficient to counteract high fat diet-induced obesity and its associated metabolic dysregulations in mice, in part through an increase in energy expenditure and a decrease in systemic inflammation.The 92nd Annual Meeting & Expo of the Endocrine Society (ENDO 2010), San Diego, CA., 19-22 June 2010. In Endocrine Reviews, 2010, v. 31 n. 3, suppl. 1, p. S481, abstract no. P1-41