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Decreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats

Abstract

We investigated the role of hypothalamic insulin signaling in the regulation of energy balance and insulin action in rats through selective decreases in insulin receptor expression in discrete hypothalamic nuclei. We generated an antisense oligodeoxynucleotide directed against the insulin receptor precursor protein and administered this directly into the third cerebral ventricle. Immunostaining of rat brains after 7-day administration of the oligodeoxynucleotide showed a selective decrease of insulin receptor protein within cells in the medial portion of the arcuate nucleus (decreased by 80% as compared to rats treated with a control oligodeoxynucleotide). Insulin receptors in other hypothalamic and extra-hypothalamic areas were not affected. This selective decrease in hypothalamic insulin receptor protein was accompanied by rapid onset of hyperphagia and increased fat mass. During insulin-clamp studies, physiological hyperinsulinemia decreased glucose production by 55% in rats treated with control oligodeoxynucleotides but by only 25% in rats treated with insulin receptor antisense oligodeoxynucleotides. Thus, insulin receptors in discrete areas of the hypothalamus have a physiological role in the control of food intake, fat mass and hepatic action of insulin.

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Figure 1: Schematic representation of the experimental procedures.
Figure 2: Representative images of brain insulin-receptor immunostaining.
Figure 3: Effects of IR antisense in discrete nuclei of the hypothalamus.
Figure 4: Selective attenuation of hypothalamic insulin receptors increases food intake and fat mass.
Figure 5: Selective attenuation of hypothalamic insulin receptors impairs hepatic insulin action.

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Acknowledgements

We thank J.N. Livingston for the gift of the IR antiserum and J. Murphy for performing the immunostaining. This work was supported by grants from the National Institutes of Health to L.R. (DK 48321 and DK 45024), from the AECOM Diabetes Research & Training Center (DK 20541), the Union of Washington Diabetes Endocrinology Research Center (DK 17047) and the Career Scientist and Merit Review Research Programs of the Department of Veteran Affairs. S.O. received a postdoctoral fellowship from the American Diabetes Association.

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Correspondence to Luciano Rossetti.

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Obici, S., Feng, Z., Karkanias, G. et al. Decreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats. Nat Neurosci 5, 566–572 (2002). https://doi.org/10.1038/nn0602-861

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