کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
3001292 1180576 2016 9 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Adipocyte-specific blockade of gamma-secretase, but not inhibition of Notch activity, reduces adipose insulin sensitivity
ترجمه فارسی عنوان
مسدود سازی اختصاصی آديپوسيتي گاما رادياز، اما مهار فعاليت Notch، حساسيت انسولين چربی را کاهش مي دهد
کلمات کلیدی
نکته مجتمع γ-secretase؛ مقاومت به انسولین 2DOG، 2-Deoxy-glycosis؛ DBZ، دیابینازاپین؛ GSI، مهاركننده γ-مخدر NICD، Notch سلول درون سلولی؛ Rbp-Jκ، پروتئین اتصال دهنده سیگنال JK؛ T2D، دیابت نوع 2
موضوعات مرتبط
علوم زیستی و بیوفناوری علم عصب شناسی سیستم های درون ریز و اتونومیک
چکیده انگلیسی


• γ-secretase inhibitors (GSIs) are non-specific inhibitors of Notch signaling.
• GSI-treatment of obese mice increases hepatic, but lowers adipose insulin sensitivity.
• Adipocyte-specific Notch inhibition does not affect adipose mass or glucose homeostasis.
• Adipocyte-specific γ-secretase blockade reduces adipose insulin sensitivity.
• Specific Notch inhibitors may be preferable to GSIs for treatment of Type 2 Diabetes.

ObjectiveAs the obesity pandemic continues to expand, novel molecular targets to reduce obesity-related insulin resistance and Type 2 Diabetes (T2D) continue to be needed. We have recently shown that obesity is associated with reactivated liver Notch signaling, which, in turn, increases hepatic insulin resistance, opening up therapeutic avenues for Notch inhibitors to be repurposed for T2D. Herein, we tested the systemic effects of γ-secretase inhibitors (GSIs), which prevent endogenous Notch activation, and confirmed these effects through creation and characterization of two different adipocyte-specific Notch loss-of-function mouse models through genetic ablation of the Notch transcriptional effector Rbp-Jk (A-Rbpj) and the obligate γ-secretase component Nicastrin (A-Nicastrin).MethodsGlucose homeostasis and both local adipose and systemic insulin sensitivity were examined in GSI-treated, A-Rbpj and A-Nicastrin mice, as well as vehicle-treated or control littermates, with complementary in vitro studies in primary hepatocytes and 3T3-L1 adipocytes.ResultsGSI-treatment increases hepatic insulin sensitivity in obese mice but leads to reciprocal lowering of adipose glucose disposal. While A-Rbpj mice show normal body weight, adipose development and mass and unchanged adipose insulin sensitivity as control littermates, A-Nicastrin mice are relatively insulin-resistant, mirroring the GSI effect on adipose insulin action.ConclusionsNotch signaling is dispensable for normal adipocyte function, but adipocyte-specific γ-secretase blockade reduces adipose insulin sensitivity, suggesting that specific Notch inhibitors would be preferable to GSIs for application in T2D.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Molecular Metabolism - Volume 5, Issue 2, February 2016, Pages 113–121
نویسندگان
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