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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Research Article Endocrinology Metabolism

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 7

Rpl13a-snoless mice are resistant to diabetogenic stimuli.

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Rpl13a-snoless mice are resistant to diabetogenic stimuli. (A–E) strept...
(A–E) streptozotocin- (STZ-) or vehicle-treated (control) 8-week-old WT and –/– mice. (A) Mean fasting blood glucose over time (+SEM) for n = 9 mice per genotype/treatment. (B) Mean blood glucose (+SEM) during GTT at 16 weeks for n = 9 mice per genotype/treatment. (C) Representative pancreas sections stained for 4-hydroxynonenal 5 days after STZ. Scale bar: 25 μm (n = 4 mice per genotype/treatment). (D) Pancreas tissue triol 5 days after STZ for n = 7 mice per genotype/treatment. (E) Representative pancreas sections stained for TUNEL 5 days after STZ. Scale bar: 25 μm. Quantification for n = 4 mice per genotype/treatment. Magnification ×2. (F) Ins2C96Y Akita allele bred into Rpl13a-snoless model. Mean (+SEM) random blood glucose at indicated time points for a minimum of n = 7 per group. (G) Rpl13a-snoless alleles were bred into the NOD model. Diabetes-free survival over 24 weeks for NOD (n = 26) vs. NOD Rpl13a-snoless (n = 16) female mice. *P < 0.05 for (–/–, STZ) vs. (WT, STZ); **P < 0.05 for (WT, STZ) vs. (WT); #P < 0.001 for (WT, C96Y) vs. (WT); †P < 0.0005 for (–/–, C96Y) vs. (WT, C96Y); determined by unpaired t test. §P < 0.04 by log-rank testing.