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ATP-sensitive K+ channels in the hypothalamus are essential for the maintenance of glucose homeostasis

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Abstract

Glucose-responsive (GR) neurons in the hypothalamus are thought to be critical in glucose homeostasis, but it is not known how they function in this context. Kir6.2 is the pore-forming subunit of KATP channels in many cell types, including pancreatic β-cells and heart. Here we show the complete absence of both functional ATP-sensitive K+ (KATP) channels and glucose responsiveness in the neurons of the ventromedial hypothalamus (VMH) in Kir6.2−/− mice. Although pancreatic α-cells were functional in Kir6.2−/−, the mice exhibited a severe defect in glucagon secretion in response to systemic hypoglycemia. In addition, they showed a complete loss of glucagon secretion, together with reduced food intake in response to neuroglycopenia. Thus, our results demonstrate that KATP channels are important in glucose sensing in VMH GR neurons, and are essential for the maintenance of glucose homeostasis.

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Acknowledgements

This work was supported by Grants-in-Aid for Creative Basic Research (10NP0201) and for Scientific Research from the Ministry of Education, Science, Sports and Culture, Japan; by Research Grants from the Ministry of Health and Welfare, Japan, by grants from Novo Nordisk Pharma, the Yamanouchi Foundation for Research on Metabolic Disorders, the Wellcome Trust; and the Medical Research Council. J.R. is supported by the Monsanto Senior Research Fellowship; B.L., by the Todd-Bird Junior Research Fellowship and the Blaschko Visiting Research Scholarship.

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Correspondence to Susumu Seino.

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Figure 1: Blood glucose levels, epinephrine and glucagon secretion in Kir6.2+/+ and Kir6.2−/− mice.
Figure 2: Electrophysiological properties and glucose responsiveness of VMH neurons.
Figure 3: Characterization of KATP channels in VMH neurons of Kir6.2+/+ and Kir6.2−/−.
Figure 4: Single-cell RT-PCR of KATP channel subunits in VMH neurons in Kir6.2+/+.
Figure 5: The effects of 2DG, leptin and NPY on food intake in Kir6.2+/+ and Kir6.2−/− mice.