Rpl13a small nucleolar RNAs regulate systemic glucose metabolism
Jiyeon Lee, … , Daniel S. Ory, Jean E. Schaffer
Jiyeon Lee, … , Daniel S. Ory, Jean E. Schaffer
Published November 7, 2016
Citation Information: J Clin Invest. 2016;126(12):4616-4625. https://doi.org/10.1172/JCI88069.
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Rpl13a small nucleolar RNAs regulate systemic glucose metabolism

Abstract

Small nucleolar RNAs (snoRNAs) are non-coding RNAs that form ribonucleoproteins to guide covalent modifications of ribosomal and small nuclear RNAs in the nucleus. Recent studies have also uncovered additional non-canonical roles for snoRNAs. However, the physiological contributions of these small RNAs are largely unknown. Here, we selectively deleted four snoRNAs encoded within the introns of the ribosomal protein L13a (Rpl13a) locus in a mouse model. Loss of Rpl13a snoRNAs altered mitochondrial metabolism and lowered reactive oxygen species tone, leading to increased glucose-stimulated insulin secretion from pancreatic islets and enhanced systemic glucose tolerance. Islets from mice lacking Rpl13a snoRNAs demonstrated blunted oxidative stress responses. Furthermore, these mice were protected against diabetogenic stimuli that cause oxidative stress damage to islets. Our study illuminates a previously unrecognized role for snoRNAs in metabolic regulation.

Authors

Jiyeon Lee, Alexis N. Harris, Christopher L. Holley, Jana Mahadevan, Kelly D. Pyles, Zeno Lavagnino, David E. Scherrer, Hideji Fujiwara, Rohini Sidhu, Jessie Zhang, Stanley Ching-Cheng Huang, David W. Piston, Maria S. Remedi, Fumihiko Urano, Daniel S. Ory, Jean E. Schaffer

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Figure 5

Increased mitochondrial leak in Rpl13a-snoless islets.

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Increased mitochondrial leak in Rpl13a-snoless islets. (A) OCR of WT and...
(A) OCR of WT and –/– islets at 3 mM glucose with injection of oligomycin (OM), FCCP, and rotenone and antimycin A (Rot/AntA). Data points in line graphs (left) represent mean values (±SEM) from 3 independent experiments in which islets pooled by genotype were used to generate a total of 9 (WT) or 8 (–/–) technical replicates from n = 11 WT and n = 12 –/– mice. Bar graphs (right) report calculated mean (+SEM) oxygen consumption for basal and maximal (Max) respiration, proton leak, ATP production and spare respiratory capacity. (B) OCR of WT and –/– islets at 20 mM glucose, as in A. Data points from 3 independent experiments in which islets pooled by genotype were used to generate a total of 9 (WT) or 11 (–/–) technical replicates from n = 13 WT and n = 14 –/– animals. Graphs as in A. (C) OCR of WT and –/– islets initially maintained at 3 mM glucose; this was changed at the time indicated to 20 mM glucose. Data points represent mean values (±SEM) from 3 independent experiments in which islets pooled by genotype generated 12 (WT) or 8 (–/–) technical replicates from n = 15 WT and n = 10 –/– animals. *P < 0.05 for –/– vs. WT; **P < 0.01 for –/– vs. WT determined by unpaired t test.