Central insulin action regulates peripheral glucose and fat metabolism in mice
Linda Koch, … , Frieder Schwenk, Jens C. Brüning
Linda Koch, … , Frieder Schwenk, Jens C. Brüning
Published May 1, 2008
Citation Information: J Clin Invest. 2008;118(6):2132-2147. https://doi.org/10.1172/JCI31073.
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Central insulin action regulates peripheral glucose and fat metabolism in mice

Abstract

Insulin resistance is a hallmark of type 2 diabetes, and many insights into the functions of insulin have been gained through the study of mice lacking the IR. To gain a better understanding of the role of insulin action in the brain versus peripheral tissues, we created 2 mouse models with inducible IR inactivation, 1 in all tissues including brain (IRΔwb), and 1 restricted to peripheral tissues (IRΔper). While downregulation of IR expression resulted in severe hyperinsulinemia in both models, hyperglycemia was more pronounced in IRΔwb mice. Both strains displayed a dramatic upregulation of hepatic leptin receptor expression, while only IRΔper mice displayed increased hepatic Stat3 phosphorylation and Il6 expression. Despite a similar reduction in IR expression in white adipose tissue (WAT) mass in both models, IRΔwb mice had a more pronounced reduction in WAT mass and severe hypoleptinemia. Leptin replacement restored hepatic Stat3 phosphorylation and normalized glucose metabolism in these mice, indicating that alterations in glucose metabolism occur largely as a consequence of lipoathrophy upon body-wide IR deletion. Moreover, chronic intracerebroventricular insulin treatment of control mice increased fat mass, fat cell size, and adipose tissue lipoprotein lipase expression, indicating that CNS insulin action promotes lipogenesis. These studies demonstrate that central insulin action plays an important role in regulating WAT mass and glucose metabolism via hepatic Stat3 activation.

Authors

Linda Koch, F. Thomas Wunderlich, Jost Seibler, A. Christine Könner, Brigitte Hampel, Sigrid Irlenbusch, Georg Brabant, C. Ronald Kahn, Frieder Schwenk, Jens C. Brüning

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Figure 3

Generation of IRΔwb mice.

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Generation of IRΔwb mice. (A) General scheme of the inducible whole ...
(A) General scheme of the inducible whole body IR knockout mouse strain. Expression of an IR-specific shRNA is dependent on the RNA-polymerase III–dependent (Pol III–dependent) promoters H1/U6 containing the operator sequences (tetOs) of the E. coli tetracycline resistance operon. Binding of the tetracycline repressor (tetR) to tetO prevents transcription. Doxycycline (Dox) sequesters tetR and enables the binding of polymerase III to the H1/U6 promoter, which results in transcription of the shRNA. Binding of the shRNA to complementary mRNAs results in the degradation of the IR mRNA. (B) Western blot analysis of IR and AKT (loading control) in whole brain, skeletal muscle, liver, and WAT of 11- to 15-week-old ControlΔwb, IRΔwb, ControlΔper, and IRΔper mice. Tissues were dissected 30 days after the start of inducer administration, except for WAT of ControlΔwb and IRΔwb mice, which was extracted 7 days after start of doxycycline administration. Animal groups were comprised of 3-4 IRΔwb, 3–4 ControlΔwb, 7–15 IRΔper, and 9–17 ControlΔper mice. (C) Comparative densitometric analysis of IR expression of 11- to 15-week-old ControlΔper (black bars), IRΔper mice (white bars), ControlΔwb (dark gray bars), and IRΔwb mice (light gray bars) of the western blot analysis shown in B. Values are mean ± SEM. *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001 versus control. ANOVA values: brain, 0.027; muscle, 0.004; liver, 0.000; WAT, 0.000.