Hypothalamic resistin induces hepatic insulin resistance
Evan D. Muse, … , Philipp E. Scherer, Luciano Rossetti
Evan D. Muse, … , Philipp E. Scherer, Luciano Rossetti
Published June 1, 2007
Citation Information: J Clin Invest. 2007;117(6):1670-1678. https://doi.org/10.1172/JCI30440.
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Research Article

Hypothalamic resistin induces hepatic insulin resistance

Abstract

Circulating resistin stimulates endogenous glucose production (GP). Here, we report that bi-directional changes in hypothalamic resistin action have dramatic effects on GP and proinflammatory cytokine expression in the liver. The infusion of either resistin or an active cysteine mutant in the third cerebral ventricle (icv) or in the mediobasal hypothalamus stimulated GP independent of changes in circulating levels of glucoregulatory hormones. Conversely, central antagonism of resistin action markedly diminished the ability of circulating resistin to enhance GP. We also report that centrally mediated mechanisms partially control resistin-induced expression of TNF-α, IL-6, and SOCS-3 in the liver. These results unveil what we believe to be a novel site of action of resistin on GP and inflammation and suggest that hypothalamic resistin action can contribute to hyperglycemia in type 2 diabetes mellitus.

Authors

Evan D. Muse, Tony K.T. Lam, Philipp E. Scherer, Luciano Rossetti

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Figure 6

The increased expression of inflammatory genes in the liver following peripheral (i.v.) resistin infusion is ameliorated by central Rs Ab.

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The increased expression of inflammatory genes in the liver following pe...
(A) The increase in hepatic gene expression of key inflammatory mediators TNF-α and IL-6 in animals receiving a peripheral resistin infusion (30 μg total over 5 h) with central (IH) Con Ab (black bar) compared with vehicle-infused animals (white bars) was attenuated in animals receiving the same peripheral resistin infusion (30 μg total over 5 h) but with IH Rs Ab treatment (gray bars), blockade of central resistin signaling was unable to repress SOCS-3 expression. No change on IKK-β, FAS, ACCα, SCD1, or PPARγ gene expression was noticed following peripheral resistin infusion in either group. (B and C) Parallel to changes in hepatic gene expression, SOCS-3 protein levels as analyzed by Western blot were elevated following i.v. resistin infusion, with no amelioration of this effect by central Rs Ab. The decrease of hepatic STAT3 protein and p-GSK3β levels also remained unaffected by central resistin blockade. No changes in p–IκB-α were detected following peripheral resistin administration in either cohort (black and gray bars) compared with vehicle (white bars). *P < 0.05 compared with vehicle; #P < 0.05 compared with Con Ab.