Dataset Information

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 ?-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 ?-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 ?-secretase blockade reduces adipose insulin sensitivity, suggesting that specific Notch inhibitors would be preferable to GSIs for application in T2D.

SUBMITTER: Sparling DP

PROVIDER: S-EPMC4735659 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Publications

Adipocyte-specific blockade of gamma-secretase, but not inhibition of Notch activity, reduces adipose insulin sensitivity.

Sparling David P DP Yu Junjie J Kim KyeongJin K Zhu Changyu C Brachs Sebastian S Birkenfeld Andreas L AL Pajvani Utpal B UB

Molecular metabolism 20151202 2

<h4>Objective</h4>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 ...[more]

PMID: 26909319

Similar Datasets

Project description:BackgroundTraumatic heterotopic ossification (THO) is a devastating sequela following traumatic injuries and orthopedic surgeries. To date, the exact molecular mechanism of THO formation is still unclear, which hinders the development of effective treatments. The process of THO formation is believed to recapitulate a series of spatiotemporal cellular and signaling events that occur during skeletal development. The Notch signaling pathway is a critical genetic regulator in embryological bone development and fracture healing. However, few data are available concerning whether Notch signaling regulates THO development and maturation.MethodsWe firstly detected the expressions of Notch target genes in both mouse and human THO samples with quantitative RT-PCR and immunohistochemistry (IHC). Then, tissue-resident mesenchymal progenitor cells (TMPCs) were isolated, and the abilities of the proliferation and osteogenic and chondrogenic differentiation of TMPCs were examined under the intervention of the gamma-secretase inhibitor-DAPT at different time points. Finally, DAPT was also administrated in THO mice by burn and Achilles tenotomy injury, and ectopic cartilage and bone formation were monitored by histology and micro-CT.ResultsSeveral Notch target genes were upregulated in both mouse and human THO tissues. Sustained Notch signaling inhibition by DAPT reduced proliferation, osteogenic and chondrogenic differentiation of TMPCs in a time-dependent manner. Moreover, DAPT administration within 3 weeks could inhibit ectopic cartilage and bone formation in a mouse THO model without affecting the total body bone mass.ConclusionsThe Notch signaling serves as an important therapeutic target during THO formation. And sustained gamma-secretase inhibition by DAPT has great potential in repressing chondrogenic and osteogenic differentiation of TMPCs, as well as inhibited ectopic cartilage and bone formation in vivo.The translational potential of this articleSustained Notch inhibition via systemic DAPT (or other similar gamma-secretase inhibitors) administration has promising clinical utility for inhibiting THO formation, providing new insight into THO prophylaxis and treatment.

Dataset Information

Adipocyte-specific blockade of gamma-secretase, but not inhibition of Notch activity, reduces adipose insulin sensitivity.

Objective

Methods

Results

Conclusions

Publications

Adipocyte-specific blockade of gamma-secretase, but not inhibition of Notch activity, reduces adipose insulin sensitivity.

Similar Datasets

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