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 4

Rpl13a-snoless islets demonstrate enhanced glucose-stimulated insulin secretion.

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Rpl13a-snoless islets demonstrate enhanced glucose-stimulated insulin s...
(A) Representative insulin-stained pancreas sections with morphometric quantification of β cell mass for WT and Rpl13a-snoless (–/–) mice (n = 4 mice/genotype). Mean + SEM; n = 4 mice/genotype; scale bars: 25 μm. (B) Mean islet protein content (+SEM) quantified in 8 mice/genotype (10 islets/mouse) obtained from 3 independent experiments. (C) Mean islet insulin content (+SEM) quantified in 12 mice/genotype (10 islets/mouse) obtained from 3 independent experiments. (D) Mean islet insulin secretion (+SEM) in response to low and high glucose quantified in a minimum of 9 mice/genotype over 3 independent experiments. (E) Mean islet insulin secretion (+SEM) in response to 30 mM KCl and 1 μM glibenclamide quantified in 3–4 mice/genotype over 3 independent experiments. (F) Changes in Fluo-4–quantified calcium activity of islets relative to basal, expressed as Δf/f0 for differing glucose concentrations. Data from 20 independent cells from 4 mice/genotype. (G) RT-qPCR-quantified expression of Rpl13a snoRNAs and mRNA in islets (relative to Rplp0). n = 3 independent islet preparations/genotype. **P < 0.001; *P < 0.05; for –/– vs. WT determined by unpaired t test.