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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Research Article Metabolism

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 1

Generation of IRΔper mice.

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Generation of IRΔper mice. (A) General scheme of the inducible perip...
(A) General scheme of the inducible peripheral IR knockout mouse strain. Mice expressing a CreERT2 fusion protein under the control of the Rosa26 promoter were crossed with mice homozygous for the floxed IR allele. Binding of tamoxifen (T) to the mutated ligand binding domain of the ER (ERLBD) promotes a nuclear import of the fusion protein and results in the excision of exon 4 by the Cre recombinase. (B) Genomic map of the mouse IR locus surrounding exon 4. Location of the probe used for Southern blot analysis is indicated by black bars. NcoI, restriction enzyme sites; 4, exon 4 of the IR gene; 2.5 kb, size of floxed allele band; 5 kb, size of deleted allele band. (C) Southern blot analysis of IR deletion in whole brain, heart, skeletal muscle, liver, pancreas, and WAT of 12-week-old IRΔper mice over a period of 12 days. Day 1, beginning of tamoxifen treatment; Δ, 5-kb band of the deleted allele; flox, 2.5-kb band of the floxed allele. (D) Western blot analysis of IR and AKT (loading control) in whole brain, heart, skeletal muscle, liver, pancreas, and WAT of tamoxifen-treated 13-week-old IRΔper mice and control mice over a period of 24 days. Day 1, beginning of tamoxifen feeding.