Neuronal XRN1 is required for maintenance of whole-body metabolic homeostasis

Shohei Takaoka; Akiko Yanagiya; Haytham Mohamed Aly Mohamed; Rei Higa; Takaya Abe; Ken-Ichi Inoue; Akinori Takahashi; Patrick Stoney; Tadashi Yamamoto

doi:10.1016/j.isci.2021.103151

Neuronal XRN1 is required for maintenance of whole-body metabolic homeostasis

iScience. 2021 Sep 21;24(10):103151. doi: 10.1016/j.isci.2021.103151. eCollection 2021 Oct 22.

Authors

Shohei Takaoka¹, Akiko Yanagiya¹, Haytham Mohamed Aly Mohamed¹, Rei Higa^{1

2}, Takaya Abe³, Ken-Ichi Inoue³, Akinori Takahashi¹, Patrick Stoney¹, Tadashi Yamamoto¹

Affiliations

¹ Cell Signal Unit, Okinawa Institute of Science and Technology Graduate University, 1919-1 Tancha, Onna, Okinawa 904-0495, Japan.
² Department of Bioresources Engineering, National Institute of Technology, Okinawa College, 905 Henoko, Nago, Okinawa 905-2192, Japan.
³ Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, 2-2-3 Minatojima Minami-machi, Chuou-ku, Kobe 650-0047, Japan.

Abstract

Control of mRNA stability and degradation is essential for appropriate gene expression, and its dysregulation causes various disorders, including cancer, neurodegenerative diseases, diabetes, and obesity. The 5'-3' exoribonuclease XRN1 executes the last step of RNA decay, but its physiological impact is not well understood. To address this, forebrain-specific Xrn1 conditional knockout mice (Xrn1-cKO) were generated, as Xrn1 null mice were embryonic lethal. Xrn1-cKO mice exhibited obesity with leptin resistance, hyperglycemia, hyperphagia, and decreased energy expenditure. Obesity resulted from dysregulated communication between the central nervous system and peripheral tissues. Moreover, expression of mRNAs encoding proteins that regulate appetite and energy expenditure was dysregulated in the hypothalamus of Xrn1-cKO mice. Therefore, we propose that XRN1 function in the hypothalamus is critical for maintenance of metabolic homeostasis.

Keywords: Molecular biology; Physiology.