Dysregulation of insulin receptor substrate 2 in β cells and brain causes obesity and diabetes
Xueying Lin, … , Yedan Li, Morris F. White
Xueying Lin, … , Yedan Li, Morris F. White
Published October 1, 2004
Citation Information: J Clin Invest. 2004;114(7):908-916. https://doi.org/10.1172/JCI22217.
View: Text | PDF
Article Metabolism

Dysregulation of insulin receptor substrate 2 in β cells and brain causes obesity and diabetes

Abstract

The molecular link between obesity and β cell failure that causes diabetes is difficult to establish. Here we show that a conditional knockout of insulin receptor substrate 2 (Irs2) in mouse pancreas β cells and parts of the brain — including the hypothalamus —increased appetite, lean and fat body mass, linear growth, and insulin resistance that progressed to diabetes. Diabetes resolved when the mice were between 6 and 10 months of age: functional β cells expressing Irs2 repopulated the pancreas, restoring sufficient β cell function to compensate for insulin resistance in the obese mice. Thus, Irs2 signaling promotes regeneration of adult β cells and central control of nutrient homeostasis, which can prevent obesity and diabetes in mice.

Authors

Xueying Lin, Akiko Taguchi, Sunmin Park, Jake A. Kushner, Fan Li, Yedan Li, Morris F. White

×

Figure 1

Options: View larger image (or click on image) Download as PowerPoint
Creation of fIrs2 mice and cr2-mediated recombination/deletion of fIrs2....
Creation of fIrs2 mice and cr2-mediated recombination/deletion of fIrs2. (A) A schematic diagram of the 4 steps in the generation of the fIrs2 containing embryonic stem cells (see Methods for details). Homol recomb, homologous recombination. (B) Recombination/deletion of fIrs2 was revealed in various mouse tissues at 4 weeks of age by PCR analysis of genomic DNA. L, liver; K, kidney; H, heart; S, spleen; B, brain, F, fat; M, muscle. The intact fIrs2 allele (fIrs2+) yields a 750-bp fragment, whereas the recombined/deleted allele (fIrs2_) yields a 250-bp fragment. (C) Real-time PCR analysis of Irs2 expression in isolated islets, normalized by cyclophilin expression. (D) PCR analysis of hypothalamic DNA to reveal recombination event. (E) Immunoprecipitation and Western blot analysis of hypothalamus with antibodies against Irs2. (F) Brain sections were immunostained with antibodies against Irs2 (red) and Cre (green), and the images were merged in Openlab Image software (version 3.14; Improvision). Similar results were obtained with multiple sections from 2 to 8 mice. Asterisks indicate third ventricle. Magnification, ×20.