Glucagon plays a major role in the regulation of glucose homeostasis during fed and fasting states. However, the mechanisms responsible for the regulation of pancreatic α cell mass and function are not completely understood. In the current study, we identified mTOR complex 1 (mTORC1) as a major regulator of α cell mass and glucagon secretion. Using mice with tissuespecific deletion of the mTORC1 regulator Raptor in α cells (αRaptor KO ), we showed that mTORC1 signaling is dispensable for α cell development, but essential for α cell maturation during the transition from a milk-based diet to a chow-based diet after weaning. Moreover, inhibition of mTORC1 signaling in αRaptor KO mice and in WT animals exposed to chronic rapamycin administration decreased glucagon content and glucagon secretion. In αRaptor KO mice, impaired glucagon secretion occurred in response to different secretagogues and was mediated by alterations in K ATP channel subunit expression and activity. Additionally, our data identify the mTORC1/FoxA2 axis as a link between mTORC1 and transcriptional regulation of key genes responsible for α cell function. Thus, our results reveal a potential function of mTORC1 in nutrient-dependent regulation of glucagon secretion and identify a role for mTORC1 in controlling α cell-mass maintenance.Loss of mTORC1 signaling alters pancreatic α cell mass and impairs glucagon secretion The Journal of Clinical Investigation R E S E A R C H A R T I C L E4 3 8 0 jci.org Volume 127 Number 12 December 2017 transcription of critical α cell genes. This work provides insights into how nutrient-dependent glucagon secretion and α cell mass are regulated and suggest that pharmacologic inhibition of this pathway using immunosuppressant medications, such as everolimus or rapamycin, could alter glucagon levels and glucose homeostasis. ResultsLack of mTORC1 signaling after deletion of Raptor in α cells. α Cell-specific deletion of Raptor was achieved by crossing glucagon-Cre and Raptor fl/fl mice (αRaptor KO ) (18,19). Deletion of flanked exon 6 exclusively in α cells from αRaptor KO mice was demonstrated by nested reverse transcription PCR (RT-PCR) for exon 6 using different tissues and single α cells ( Figure 1A) (19). Loss of mTORC1 signaling was confirmed by lack of phospho-S6 (Ser240) immunofluorescence staining only in glucagon-positive cells in dispersed islets from 1-month-old αRaptor KO mice ( Figure 1B). To validate the reduction in mTORC1 signaling in α cells from αRaptor KO mice, we assessed phospho-S6 (Ser240), glucagon, and insulin staining in dispersed islets by flow cytometry using quantitative mean fluorescence intensity (MFI). Figure 1C shows pS6 MFI levels in α cells (glucagon + cell count) and Figure 1D includes pS6 MFI levels in β cells (insulin + cell count). Phospho-S6 (Ser240) levels were nearly lost in glucagon-positive cells from αRaptor KO mice (red curve) compared with controls (black curve) (Figures 1C). In contrast, the MFI for phospho-S6 (Se240) was similar in insulin-positive cells from αRaptor ...
This article analyzes girl games, a subgenre of casual mobile and online games created and marketed for preteen girls. Through an examination of Barbie Fashionistas, Style Studio: Fashion Designer, and Central Park Wedding Prep, all of which are representative of traditional dress-up and makeover-oriented girl games, I explore how seemingly broad mechanics-based choices available to players within the games reinforce and respond to patriarchal ideologies, and argue that the mechanics of mobile and online girl games serve gendered and neoliberal ends both in game and in the larger context of North American gaming culture. Conducting close readings on and accounting for the mechanics of an understudied genre within the field to advocate for greater study of both game mechanics and girl games, I demonstrate how the availability of choice intrinsic in girl games provides opportunity to explore how players are constructed as neoliberal subjects.
Drawing from social media studies and the literature on American economic decline and conceptualizations of gender and sexuality, this article asks how Twitter's medium-specific features can be understood through an examination of its representational qualities in the context of the promotion of two contemporary superhero films. The accounts @ BatmanvSuperman and @SpiderManMovie provide case studies of film promotion that uses Twitter's particularities as a platform in order to advance distinct narratives about the films being promoted, via original tweets and retweets that, respectively, represent differing approaches to advertisement. Through this study, the article advances the arguments, first, that cultural representations are reflective of Twitter's specificities as a social media platform, and second, that these representations work in conjunction with cultural norms of the contemporary US. One form of idealized White masculinity advanced by the latter is reliant on technology and its merging with the White man's body. As a result, the technologies of superheroes' suits as well as Twitter itself become representative of the present sociopolitical climate and its various aspirations and anxieties.
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