The Lin28/let-7 Axis Regulates Glucose Metabolism

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• 作者：Hao Zhu¹ ;   ; ² ;   ; ³ ;   ; ⁴ ;   ; ¹⁴ ; Ng Shyh-Chang¹ ;   ; ² ;   ; ⁸ ;   ; ¹⁴ ; Ayellet  ; V. Segrè ; ⁵ ;   ; ⁶ ; Gen Shinoda¹ ;   ; ² ; Samar  ; P. Shah¹ ;   ; ² ; William  ; S. Einhorn¹ ;   ; ² ;   ; ⁴ ; Ayumu Takeuchi¹ ;   ; ² ; Jesse  ; M. Engreitz⁷ ; John  ; P. Hagan¹ ;   ; ² ;   ; ⁸ ;   ; ⁹ ; Michael  ; G. Kharas¹ ;   ; ² ;   ; ⁴ ; Achia Urbach¹ ;   ; ² ; James  ; E. Thornton¹ ;   ; ² ;   ; ⁸ ; Robinson Triboulet¹ ;   ; ² ;   ; ⁸ ; Richard  ; I. Gregory¹ ;   ; ² ;   ; ⁸ ; DIAGRAM Consortium ; MAGIC Investigators ; David Altshuler⁵ ;   ; ⁶ ;   ; ¹⁰ ; George  ; Q. Daley¹ ;   ; ² ;   ; ⁴ ;   ; ⁸ ;   ; ¹¹ ;   ; ¹² ;   ; ^{george.daley@childrens.harvard.edu}
• 刊名：Cell
• 出版年：2011
• 出版时间：30 September 2011
• 年：2011
• 卷：147
• 期：1
• 页码：81-94
• 全文大小：1391 K

文摘

Summary

The let-7 tumor suppressor microRNAs are known for their regulation of oncogenes, while the RNA-binding proteins Lin28a/b promote malignancy by inhibiting let-7 biogenesis. We have uncovered unexpected roles?for the Lin28/let-7 pathway in regulating metabolism. When overexpressed in mice, both Lin28a and LIN28B promote an insulin-sensitized state that resists high-fat-diet induced diabetes. Conversely, muscle-specific loss of Lin28a or overexpression of?let-7 results in insulin resistance and impaired glucose tolerance. These phenomena occur, in part, through the let-7-mediated repression of multiple components of the insulin-PI3K-mTOR pathway, including IGF1R, INSR, and IRS2. In addition, the mTOR inhibitor, rapamycin, abrogates Lin28a-mediated insulin sensitivity and enhanced glucose uptake. Moreover, let-7 targets are enriched for genes containing SNPs associated with type 2 diabetes and control of fasting glucose in?human genome-wide association studies. These data establish the Lin28/let-7 pathway as a central regulator of mammalian glucose metabolism.