ArticleMolecular metabolism2016
Adipocyte-specific blockade of gamma-secretase, but not inhibition of Notch activity, reduces adipose insulin sensitivity.
Article in Molecular metabolism, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 22 citations in OpenAlex.
- Next-Generation Hepatocyte Expansion: Bridging Molecular Reprogramming with Multicellular Organoids for Clinical Translation.Stem cell reviews and reports · 2026Review
- Glycemic variability associated with gamma secretase inhibitor therapy in a type 1 diabetic patient undergoing treatment for desmoid tumor: a case report.Frontiers in endocrinology · 2026Article
- Notch signaling in liver diseases: mechanistic insights and therapeutic implications.Frontiers in cell and developmental biology · 2026Review
- Maladaptive regeneration - the reawakening of developmental pathways in NASH and fibrosis.Nature reviews. Gastroenterology & hepatology · 2021Review
- Inhibition of γ-secretase in adipocytes leads to altered IL-6 secretion and adipose inflammation.Adipocyte · 2020Article
- NOTCH Receptors and DLK Proteins Enhance Brown Adipogenesis in Mesenchymal C3H10T1/2 Cells.Cells · 2020Article
- An Approach towards a GMP Compliant In-Vitro Expansion of Human Adipose Stem Cells for Autologous Therapies.Bioengineering (Basel, Switzerland) · 2020Article
- Liver-selective γ-secretase inhibition ameliorates diet-induced hepatic steatosis, dyslipidemia and atherosclerosis.Biochemical and biophysical research communications · 2020Article
- Targeted Delivery of Notch Inhibitor Attenuates Obesity-Induced Glucose Intolerance and Liver Fibrosis.ACS nano · 2020Article
- Next Generation Precision Medicine: CRISPR-mediated Genome Editing for the Treatment of Neurodegenerative Disorders.Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology · 2019Review
- Hepatocyte Notch activation induces liver fibrosis in nonalcoholic steatohepatitis.Science translational medicine · 2018Article
- iPSC-derived familial Alzheimer's PSEN2Molecular neurodegeneration · 2018Article
- γ-Secretase Inhibition Lowers Plasma Triglyceride-Rich Lipoproteins by Stabilizing the LDL Receptor.Cell metabolism · 2018Article
- MTORC1 Regulates both General Autophagy and Mitophagy Induction after Oxidative Phosphorylation Uncoupling.Molecular and cellular biology · 2017Article
- Dibenzazepine-Loaded Nanoparticles Induce Local Browning of White Adipose Tissue to Counteract Obesity.Molecular therapy : the journal of the American Society of Gene Therapy · 2017Article
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Authors and funding
7 authors at 3 institutions in 3 countries.
Funding
Abstract
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.
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