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mTOR signaling coordinates glucose and lipid metabolisms in liver
Author(s) -
Li Ziru
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1249.6
Subject(s) - lipogenesis , medicine , endocrinology , lipid metabolism , gluconeogenesis , pi3k/akt/mtor pathway , biology , fatty acid synthase , oil red o , carbohydrate metabolism , chemistry , metabolism , biochemistry , signal transduction , adipose tissue , adipogenesis
Objective Although aberrant mTOR activity has been linked to the development of obesity and diabetes, its role in hepatic glucose and lipid metabolisms remains largely unknown. We aimed to explore the effects of hepatic mTOR activity on the glucose and lipid homeostatsis. Methods TSC1 flox/flox mice and mTOR flox/flox mice were injected with Cre adenovirus to activate or inhibit mTOR signaling respectively. By breeding albumin‐Cre mice with TSC1 flox/flox mice (AT) or mTOR flox/flox mice (Am), liver‐specific mTOR signaling was activated or suppressed. OGTT and glucose metabolism related genes were evaluated. Oil‐red O staining and lipid metabolism related genes were assessed as well. Results TSC1 flox/flox mice with tail vein injection of Ad‐Cre demonstrated an improvement in glucose tolerance relative to wildtype littermates. Levels of genes related to gluconeogenesis, such as PEP carboxykinase ( pepck ) and pyruvate carboxylase ( pc ) were significantly decreased. Oil‐red staining demonstrated a significant decrease of hepatic lipid accumulation. Hepatic lipogenesis related genes such as pparγ2, srebp1c, acaca, gpat and dgat were markedly decreased. Interestingly, levels of chREBP mRNA were significantly decreased. This alteration was associated with a decrement in L‐type pyruvate kinase ( lpk ) and fatty acid synthase ( fasn ) mRNAs. Inversely, mTOR flox/flox mice with tail vein injection of Ad‐Cre showed deteriorated glucose tolerance compared with wildtype littermates. Genes related to gluconeogenesis were significantly increased. Lipids deposition and lipogenesis related genes were increased as well. Similar results were observed in animal models with genetic interference of mTOR signaling including hepatic deletion of TSC1 (AT) and mTOR (Am ). Activation of mTOR signaling in AT mice demonstrated a decrease in hepatic lipid deposit and triglyceride contents. On the other hand, suppression of hepatic mTOR activity in Am mice increased lipid contents in liver. Conclusion Our studies indicated that hepatic mTOR signaling plays an important role in glucose and lipid metabolisms. Targeting hepatic mTOR signaling may provide a promising therapeutic approach for hepatic steatosis. Support or Funding Information This research was supported by grants from American Diabetes Association grant #1‐13‐BS‐225 .