Hypothalamic resistin induces hepatic insulin resistance
Evan D. Muse, Tony K.T. Lam, Philipp E. Scherer, Luciano Rossetti
Evan D. Muse, Tony K.T. Lam, Philipp E. Scherer, Luciano Rossetti
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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 4

The effects of increased levels of circulating plasma resistin are attenuated in animals treated with IH anti-resistin antibodies.

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The effects of increased levels of circulating plasma resistin are atten...
(A) Experimental design for hyperinsulinemic-euglycemic clamp studies. IH infusion of Con Ab or Rs Ab (0.33 μl bolus followed 0.5 μl/h infusion) was initiated at 0 minutes and continued throughout the 360-minute course of study. Resistin (30 μg total dose) was infused i.v. at a constant rate starting at 60 minutes. The remainder of the study was completed as described in Figure 1. (B) Rates of glucose uptake during the insulin clamp studies were unaffected in all groups. (C) The rate of endogenous GP for i.v. resistin–infused animals also receiving an IH infusion of Con Ab was greatly increased compared with controls but was attenuated in animals receiving the IH infusion of Rs Ab. (D) Changes in the percentage suppression of endogenous GP in animals receiving i.v. resistin and IH Ab infusions. *P < 0.05 compared with vehicle; #P < 0.05 compared with Con Ab.