Orexin receptors 1 and 2 in serotonergic neurons differentially regulate peripheral glucose metabolism in obesity

Xing Xiao, Gagik Yeghiazaryan, Simon Hess, Paul Klemm, Anna Sieben, André Kleinridders, Donald A. Morgan, F. Thomas Wunderlich, Kamal Rahmouni, Dong Kong, Thomas E. Scammell, Bradford B. Lowell, Peter Kloppenburg, Jens C. Brüning and A. Christine Hausen ()
Additional contact information
Xing Xiao: Max Planck Institute for Metabolism Research, Department of Neuronal Control of Metabolism
Gagik Yeghiazaryan: University of Cologne
Simon Hess: University of Cologne
Paul Klemm: Max Planck Institute for Metabolism Research, Department of Neuronal Control of Metabolism
Anna Sieben: Max Planck Institute for Metabolism Research, Department of Neuronal Control of Metabolism
André Kleinridders: Max Planck Institute for Metabolism Research, Department of Neuronal Control of Metabolism
Donald A. Morgan: University of Iowa, Carver College of Medicine
F. Thomas Wunderlich: Max Planck Institute for Metabolism Research, Department of Neuronal Control of Metabolism
Kamal Rahmouni: University of Iowa, Carver College of Medicine
Dong Kong: Boston Children’s Hospital and Harvard Medical School
Thomas E. Scammell: Beth Israel Deaconess Medical Center and Harvard Medical School
Bradford B. Lowell: Beth Israel Deaconess Medical Center and Harvard Medical School
Peter Kloppenburg: University of Cologne
Jens C. Brüning: Max Planck Institute for Metabolism Research, Department of Neuronal Control of Metabolism
A. Christine Hausen: Max Planck Institute for Metabolism Research, Department of Neuronal Control of Metabolism

Nature Communications, 2021, vol. 12, issue 1, 1-20

Abstract: Abstract The wake-active orexin system plays a central role in the dynamic regulation of glucose homeostasis. Here we show orexin receptor type 1 and 2 are predominantly expressed in dorsal raphe nucleus-dorsal and -ventral, respectively. Serotonergic neurons in ventral median raphe nucleus and raphe pallidus selectively express orexin receptor type 1. Inactivation of orexin receptor type 1 in serotonin transporter-expressing cells of mice reduced insulin sensitivity in diet-induced obesity, mainly by decreasing glucose utilization in brown adipose tissue and skeletal muscle. Selective inactivation of orexin receptor type 2 improved glucose tolerance and insulin sensitivity in obese mice, mainly through a decrease in hepatic gluconeogenesis. Optogenetic activation of orexin neurons in lateral hypothalamus or orexinergic fibers innervating raphe pallidus impaired or improved glucose tolerance, respectively. Collectively, the present study assigns orexin signaling in serotonergic neurons critical, yet differential orexin receptor type 1- and 2-dependent functions in the regulation of systemic glucose homeostasis.

Date: 2021
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DOI: 10.1038/s41467-021-25380-2

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