Peer review process
Not revised: This Reviewed Preprint includes the authors’ original preprint (without revision), an eLife assessment, and public reviews.
Read more about eLife’s peer review process.Editors
- Reviewing EditorMarcelo MoriState University of Campinas, Campinas, Brazil
- Senior EditorPramod MistryYale University, New Haven, United States of America
Reviewer #1 (Public Review):
Summary:
This study demonstrated a novel exciting link between the conserved miRNA-target axis of miR-182-Lrp6 in liver metabolism which causatively contributes to type 2 diabetes and NAFLD in mice and, potentially, humans.
Strengths:
The direct interaction and inhibition of Lrp6 by miR-182 are convincingly shown. The effects of miR-182-5p on insulin sensitivity are also credible for the in vivo and in vitro gain-of-function experiments.
Weaknesses:
However, the DIO cohorts lack key assays for insulin sensitivity such as ITT or insulin-stimulated pAKT, as well as histological evidence to support their claims and strengthen the link between miR-182-5p and T2D or NAFLD. Besides, the lack of loss-of-function experiments limits its aptitude as a potential therapeutic target.
Reviewer #2 (Public Review):
Summary:
In this study, Christin Krause et al mapped the hepatic miRNA-transcriptome of type 2 diabetic obese subjects, and identified miR-182-5p and its target genes LRP6 as potential drivers of dysregulated glucose tolerance and fatty acid metabolism in obese T2-diabetics.
Strengths:
This study contains some interesting findings and is valuable for the understanding of the key regulatory role of miRNAs in the pathogenesis of T2D.
Weaknesses:
The authors didn't systemically investigate the function of miR-182 in T2DM or NAFLD.
Reviewer #3 (Public Review):
Summary:
In this manuscript, Krause and colleagues identify miR-182 as diabetes-associated microRNA: miR-182 is increased in bariatric surgery patients with versus without T2D; miR-182 was the only microRNA associated with three metabolic traits; miR-182 levels were associated with increased body weight in mice under different dietary manipulations; overexpression in Hep-G2 led to a decrease in LRP6; and overexpression in HFD fed mice led to increased insulin and liver TG. The manuscript provides a potentially useful resource for microRNA expression in human livers, though the functional importance of miR-182 remains unclear.
Strengths:
The use of human tissues and good sample sizes is strong.
Weaknesses:
The study is primarily correlative; the in vivo overexpression is non-physiological; and the mechanisms by which miR-182 exerts its effects are not rigorously tested.
