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Rebecca L Hull, Joshua R Willard, Matthias D Struck, Breanne M Barrow, Gurkirat S Brar, Sofianos Andrikopoulos and Sakeneh Zraika

Mouse models are widely used for elucidating mechanisms underlying type 2 diabetes. Genetic background profoundly affects metabolic phenotype; therefore, selecting the appropriate model is critical. Although variability in metabolic responses between mouse strains is now well recognized, it also occurs within C57BL/6 mice, of which several substrains exist. This within-strain variability is poorly understood and could emanate from genetic and/or environmental differences. To better define the within-strain variability, we performed the first comprehensive comparison of insulin secretion from C57BL/6 substrains 6J, 6JWehi, 6NJ, 6NHsd, 6NTac and 6NCrl. In vitro, glucose-stimulated insulin secretion correlated with Nnt mutation status, wherein responses were uniformly lower in islets from C57BL/6J vs C57BL/6N mice. In contrast, in vivo insulin responses after 18 weeks of low fat feeding showed no differences among any of the six substrains. When challenged with a high-fat diet for 18 weeks, C57BL/6J substrains responded with a similar increase in insulin release. However, variability was evident among C57BL/6N substrains. Strikingly, 6NJ mice showed no increase in insulin release after high fat feeding, contributing to the ensuing hyperglycemia. The variability in insulin responses among high-fat-fed C57BL/6N mice could not be explained by differences in insulin sensitivity, body weight, food intake or beta-cell area. Rather, as yet unidentified genetic and/or environmental factor(s) are likely contributors. Together, our findings emphasize that caution should be exercised in extrapolating data from in vitro studies to the in vivo situation and inform on selecting the appropriate C57BL/6 substrain for metabolic studies.

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Patricia K Russell, Salvatore Mangiafico, Barbara C Fam, Michele V Clarke, Evelyn S Marin, Sofianos Andrikopoulos, Kristine M Wiren, Jeffrey D Zajac and Rachel A Davey

It is well established that testosterone negatively regulates fat mass in humans and mice; however, the mechanism by which testosterone exerts these effects is poorly understood. We and others have shown that deletion of the androgen receptor (AR) in male mice results in a phenotype that mimics the three key clinical aspects of hypogonadism in human males; increased fat mass and decreased bone and muscle mass. We now show that replacement of the Ar gene specifically in mesenchymal progenitor cells (PCs) residing in the bone marrow of Global-ARKO mice, in the absence of the AR in all other tissues (PC-AR Gene Replacements), completely attenuates their increased fat accumulation. Inguinal subcutaneous white adipose tissue and intra-abdominal retroperitoneal visceral adipose tissue depots in PC-AR Gene Replacement mice were 50–80% lower than wild-type (WT) and 75–90% lower than Global-ARKO controls at 12 weeks of age. The marked decrease in subcutaneous and visceral fat mass in PC-AR Gene Replacements was associated with an increase in the number of small adipocytes and a healthier metabolic profile compared to WT controls, characterised by normal serum leptin and elevated serum adiponectin levels. Euglycaemic/hyperinsulinaemic clamp studies reveal that the PC-AR Gene Replacement mice have improved whole-body insulin sensitivity with higher glucose infusion rates compared to WT mice and increased glucose uptake into subcutaneous and intra-abdominal fat. In conclusion, these data provide the first evidence for an action of androgens via the AR in mesenchymal bone marrow PCs to negatively regulate fat mass and improve metabolic function.