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Published on: May 4, 2021
The Lin28/let-7 axis regulates glucose metabolism
Hao Zhu1, Ng Shyh-Chang, Ayellet V Segrè
1Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Children's Hospital Boston and Dana Farber Cancer Institute, Boston, MA, USA.
Cell
|October 4, 2011
Summary
The Lin28/let-7 pathway unexpectedly regulates metabolism. Lin28a/b overexpression improves insulin sensitivity and diabetes resistance, while let-7 overexpression causes insulin resistance.
Area of Science:
- Molecular Biology
- Metabolic Regulation
- Genetics
Background:
- The let-7 microRNA family acts as tumor suppressors by regulating oncogenes.
- RNA-binding proteins Lin28a/b inhibit let-7 biogenesis, promoting cancer.
- The Lin28/let-7 pathway's role in metabolism was previously unknown.
Purpose of the Study:
- To investigate the role of the Lin28/let-7 pathway in mammalian glucose metabolism.
- To determine the impact of Lin28a/b and let-7 on insulin sensitivity and glucose homeostasis.
Main Methods:
- Overexpression and knockout studies in mice.
- Analysis of insulin-PI3K-mTOR pathway components.
- Assessment of glucose tolerance and insulin sensitivity.
- Bioinformatic analysis of human genetic data.
Main Results:
- Lin28a/b overexpression in mice conferred insulin sensitivity and resistance to high-fat diet-induced diabetes.
- Muscle-specific Lin28a loss or let-7 overexpression led to insulin resistance and impaired glucose tolerance.
- let-7 repressed key insulin-PI3K-mTOR pathway components (IGF1R, INSR, IRS2).
- Rapamycin treatment abolished Lin28a-mediated insulin sensitivity.
- let-7 targets included genes with SNPs linked to type 2 diabetes and fasting glucose control.
Conclusions:
- The Lin28/let-7 pathway is a critical regulator of glucose metabolism.
- This pathway influences insulin sensitivity through the insulin-PI3K-mTOR signaling cascade.
- Genetic variations in let-7 targets are associated with human type 2 diabetes.
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