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Published on: April 12, 2021
Tissue-specific ablation of Tsc1 in pancreatic beta-cells
Hiroyuki Mori1, Kun-Liang Guan
1Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA. morimori@umich.edu
Abstract:
Tuberous sclerosis complex 1 (TSC1) is a tumor suppressor that associates with TSC2 to inactivate Rheb, thereby inhibiting signaling by the mammalian target of rapamycin (mTOR) complex 1 (mTORC1). mTORC1 stimulates cell growth by promoting anabolic cellular processes, such as translation, in response to growth factors and nutrient signals. In order to test roles for TSC1 and mTORC1 in β-cell function, we utilized Rip2/Cre to generate mice lacking Tsc1 in pancreatic β cells (Rip-Tsc1cKO mice). While obesity developed due to hypothalamic Tsc1 excision in older Rip-Tsc1cKO animals, young animals displayed a prominent gain-of-function β-cell phenotype prior to the onset of obesity. The young Rip-Tsc1cKO animals displayed improved glycemic control due to mTOR-mediated enhancement of β-cell size and insulin production, but not β-cell number consistent with an important anabolic role for mTOR in β-cell function. Thus, mTOR promulgates a dominant signal to promote β-cell/islet size and insulin production, and this pathway is crucial for β-cell function and glycemic control. Here, we describe the methods of analyzing tissue-specific ablation of Tsc1 in pancreatic β cells.
Insights
Tuberous sclerosis complex 1 (TSC1) loss in pancreatic beta cells enhances their size and insulin production, improving glycemic control. This highlights the mammalian target of rapamycin (mTOR) pathway's crucial role in beta cell function.
Area of Science:
- Endocrinology
- Molecular Biology
- Metabolic Diseases
Background:
- Tuberous sclerosis complex 1 (TSC1) is a tumor suppressor.
- TSC1, with TSC2, inhibits Rheb, thus suppressing mammalian target of rapamycin (mTOR) complex 1 (mTORC1) signaling.
- mTORC1 promotes anabolic processes like translation, crucial for cell growth.
Purpose of the Study:
- To investigate the roles of TSC1 and mTORC1 in pancreatic beta cell function.
- To analyze the impact of Tsc1 ablation in beta cells on glycemic control and beta cell physiology.
Main Methods:
- Generated mice with tissue-specific Tsc1 ablation in pancreatic beta cells using Rip2/Cre (Rip-Tsc1cKO mice).
- Analyzed metabolic parameters, beta cell size, insulin production, and beta cell number in young and aged Rip-Tsc1cKO mice.
- Examined the influence of mTOR signaling on beta cell function.
Main Results:
- Young Rip-Tsc1cKO mice exhibited improved glycemic control.
- Enhanced beta cell size and insulin production were observed, mediated by mTOR signaling.
- Beta cell number remained unchanged, indicating mTOR's anabolic role in beta cell function, not proliferation.
- Obesity developed in older mice due to hypothalamic Tsc1 excision.
Conclusions:
- mTOR signaling is a dominant pathway promoting pancreatic beta cell and islet size and insulin production.
- This mTOR-mediated pathway is critical for maintaining beta cell function and effective glycemic control.
- Targeting the mTOR pathway in beta cells may offer therapeutic strategies for metabolic disorders.
