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Acta Physiologica 2012; Volume 206, Supplement 693
Joint FEPS and Spanish Physiological Society Scientific Congress 2012
9/8/2012-9/11/2012
Santiago de Compostela, Spain
KATP-CHANNEL-DEPENDENT GLUCOSE SENSING IN THE LOCUS COERULEUS CONTROLS BROWN ADIPOSE TISSUE SYMPATHETIC TRAFFIC AND ENERGY HOMEOSTASIS
Abstract number: P263
Tovar1 S, Paeger2 L, Hess2 S, A Morgan3 D, Bronneke4 H, Hampel1 B, Ackermann1 P, Evers1 N, Buning5 H, Konner C, T Wunderlich1 F, Rahmouni3 K, Kloppenburg6 P, C Bruning1 J
1Department of Mouse Genetics and Metabolism, Institute for Genetics and Center for Molecular Medicine (CMMC), University of Cologne, Germany,
2Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Germany,
3Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA,
4Mouse Phenoytping Facility, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Zlpicher Str. 47a, 50674 Kln, Germany,
5Department I of Internal Medicine and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Robert-Koch-Str. 21, 50931 Kln, Germany,
6Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Zlpicher Str. 47, 50674 Kln, Germany
Objectives:
Brown adipose tissue (BAT) is a critical regulator of glucose and lipid metabolism and energy homeostasis. Its activity is controlled by the sympathetic nervous system (SNS). However, the mechanisms underlying CNS-dependent control of BAT sympathetic nerve activity (SNA) in response to energy availability are still not fully understood. The specific role of KATP-channels, widely expressed in neuronal populations that control glucose metabolism and play a fundamental role as metabolic sensors (linking changes in cellular glucose metabolism to electrical activity) is only partly understood. Our aim was to elucidate the neuronal and molecular pathway linking glucose sensing to control of BAT activity.
Materials:
To address the functional role of Kir6.2 in TH-positive noradrenergic neurons, we used a mutant mice expressed the KATP-channel variant, that renders KATP-channels resistant to closure by ATP, disrupting the ability of increasing glucose concentrations to cause neuronal depolarization and increase neuronal activity. We crossed with THCre-mice, express Cre-recombinase under TH (tyrosine-hydroxylase) promotor, allowing the expression of the variant Kir6.2 subunit specifically in these neurons. We used adeno-associated viral vectors (rAAV) expressing GFP or Cre for injections into the LC of Rosa26Kir6.2-mice. We performanced an analysis of metabolic phenotype, patch recordings and direct recording of BAT, WAT, Adrenal and renal SNA.
Results:
We demonstrate that catecholaminergic neurons in the locus coeruleus (LC) adapt their firing frequency to extracellular glucose concentrations in a KATP-channel-dependent manner. Inhibition of glucose sensing via targeted expression of a variant KATP-channel in TH-expressing neurons, specifically those of the LC, causes diet-sensitive obesity in mice. Obesity results from lower steady state BAT SNA, the prevention of centrally applied glucose to activate BAT SNA, thereby impairing the thermogenic transcriptional program of BAT, and increasing sensitivity to cold.
Conclusions:
Our data reveal a fundamental role of KATP-channel-dependent glucose sensing in the LC in maintaining thermogenic sympathetic tone and energy homeostasis.
To cite this abstract, please use the following information:
Acta Physiologica 2012; Volume 206, Supplement 693 :P263