title: Adipocyte-specific blockade of gamma-secretase, but not inhibition of Notch activity, reduces adipose insulin sensitivity.
abstract: OBJECTIVE
  As 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).
  
  
  METHODS
  Glucose 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.
  
  
  RESULTS
  GSI-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.
  
  
  CONCLUSIONS
  Notch 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.
authors.affiliation: Departments of Pediatrics, Columbia University, New York, NY 10032, USA.
authors.forename: David P
authors.initials: DP
authors.lastname: Sparling
authors.affiliation: Department of Medicine, Columbia University, New York, NY 10032, USA.
authors.forename: Junjie
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Medicine, Columbia University, New York, NY 10032, USA.
authors.forename: KyeongJin
authors.initials: K
authors.lastname: Kim
authors.affiliation: Department of Medicine, Columbia University, New York, NY 10032, USA.
authors.forename: Changyu
authors.initials: C
authors.lastname: Zhu
authors.affiliation: Department of Endocrinology, Diabetes and Nutrition, Center for Cardiovascular Research, Charité - University School of Medicine, Berlin, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Brachs
authors.affiliation: Section of Metabolic Vascular Medicine, Medical Clinic III and Paul Langerhans Institute Dresden (PLID), a member of the German Center for Diabetes Research (DZD), Technische Universität Dresden, Germany; Section of Diabetes and Nutritional Sciences, Rayne Institute, Denmark Hill Campus, King's College London, UK.
authors.forename: Andreas L
authors.initials: AL
authors.lastname: Birkenfeld
authors.affiliation: Department of Medicine, Columbia University, New York, NY 10032, USA. Electronic address: up2104@cumc.columbia.edu.
authors.forename: Utpal B
authors.initials: UB
authors.lastname: Pajvani
keywords: 2DOG, 2-Deoxy-glucose; DBZ, Dibenzazepine; GSI, γ-secretase inhibitor; Insulin resistance; NICD, Notch intracellular domain; Notch; Rbp-Jκ, Recombination signal binding protein-Jκ; T2D, Type 2 diabetes; γ-secretase complex