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

Xing Xiao,Anna Sieben,Donald A Morgan,Gagik Yeghiazaryan,Paul Klemm,Simon Hess,Jens C Brüning,Bradford B Lowell,Peter Kloppenburg,Kamal Rahmouni,Dong Kong,F Thomas Wunderlich,André Kleinridders,A Christine Hausen,Thomas E Scammell

doi:10.1038/s41467-021-25380-2

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.

Highlights

The wake-active orexin system plays a central role in the dynamic regulation of glucose homeostasis
Within a defined cell population of serotonergic neurons in raphe nuclei (RN), RNA sequencing (RNA-seq) experiments revealed that mainly Ox2R but not Ox1R is differentially expressed among the subpopulations in dorsal raphe nucleus (DR), median raphe nucleus (MR) and caudal raphe nuclei including the raphe pallidus nucleus (RPa)[20]
DR and MR in the midbrain and pons contain the majority of serotonergic neurons, which mainly project to the forebrain, while serotonergic neurons in caudal RN, such as RPa, mainly project to the brain stem and periphery[35]

Summary

Introduction

The wake-active orexin system plays a central role in the dynamic regulation of glucose homeostasis. 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. 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. Within a defined cell population of serotonergic neurons in raphe nuclei (RN), RNA sequencing (RNA-seq) experiments revealed that mainly Ox2R but not Ox1R is differentially expressed among the subpopulations in dorsal raphe nucleus (DR), median raphe nucleus (MR) and caudal raphe nuclei including the raphe pallidus nucleus (RPa)[20]. Serotonergic neurons in subregions of RN have been described as very heterogeneous in aspects of morphology, electrophysiological behavior, projections, and functions[20,21]

Methods

Results

Conclusion