Acute suppression of insulin resistance-associated hepatic miR-29 in vivo improves glycemic control in adult mice

Hung, Yu‐Han; Kanke, Matt; Kurtz, C. Lisa; Cubitt, Rebecca L.; Bunaciu, Rodica P.; Miao, Ji; Zhou, Liye; Graham, James L.; Hussain, M. Mahmood; Havel, Peter J.; Biddinger, Sudha B.; White, Phillip J.; Sethupathy, Praveen

doi:10.1152/physiolgenomics.00037.2019

Cited by 36 publications

(30 citation statements)

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“…We have demonstrated previously that one subcutaneous injection of LNA against miR-29 with this concentration effectively suppresses hepatic miR-29 expressions (Kurtz et al, 2015). We have also demonstrated in a previously published study that saline and LNA-scramble sequence (LNA-scr) exert similar effects on our physiological parameters of interest and therefore both can serve as control treatment for the LNA-29 in vivo study (Hung et al, 2019). We therefore used saline as control treatment in the present study.…”

Section: Methodssupporting

confidence: 53%

“…For example, Enho , Igfbp2 , Lpl , and Sparc are upregulated by LNA29 irrespective of the presence of Sirt1 (Figure 3B) and are known to be involved in improving energy homeostasis and/or lipid metabolism (Bradshaw et al, 2003; Wheatcroft et al, 2007; Kumar et al, 2008; Nie et al, 2011; Ganesh Kumar et al, 2012; Chen et al, 2017). Indeed, Enho , Lpl , and Sparc have been shown to be directly targeted by miR-29 (Yang et al, 2016; Song et al, 2018; Hung et al, 2019) and therefore the suppression of miR-29 would be expected to increase the expression and activity of these genes. Igfbp2 , on the other hand, does not have predicted target sites for miR-29 and its upregulation by LNA29 is possibly through an indirect mechanism.…”

Section: Discussionmentioning

confidence: 99%

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MiR-29 Regulates de novo Lipogenesis in the Liver and Circulating Triglyceride Levels in a Sirt1-Dependent Manner

et al. 2019

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MicroRNAs (miRNAs) are known regulators of lipid homeostasis. We recently demonstrated that miR-29 controls the levels of circulating cholesterol and triglycerides, but the mechanisms remained unknown. In the present study, we demonstrated that systemic delivery of locked nucleic acid inhibitor of miR-29 (LNA29) through subcutaneous injection effectively suppresses hepatic expression of miR-29 and dampens de novo lipogenesis (DNL) in the liver of chow-fed mice. Next, we used mice with liver-specific deletion of Sirtuin 1 (L-Sirt1 KO), a validated target of miR-29, and demonstrated that the LNA29-induced reduction of circulating triglycerides, but not cholesterol, is dependent on hepatic Sirt1. Moreover, lipidomics analysis revealed that LNA29 suppresses hepatic triglyceride levels in a liver-Sirt1 dependent manner. A comparative transcriptomic study of liver tissue from LNA29-treated wild-type/floxed and L-Sirt1 KO mice identified the top candidate lipogenic genes and hepatokines through which LNA29 may confer its effects on triglyceride levels. The transcriptomic analysis also showed that fatty acid oxidation (FAO) genes respond differently to LNA29 depending on the presence of hepatic Sirt1. Overall, this study demonstrates the beneficial effects of LNA29 on DNL and circulating lipid levels. In addition, it provides mechanistic insight that decouples the effect of LNA29 on circulating triglycerides from that of circulating cholesterol.

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Section: Methodssupporting

confidence: 53%

Section: Discussionmentioning

confidence: 99%

MiR-29 Regulates de novo Lipogenesis in the Liver and Circulating Triglyceride Levels in a Sirt1-Dependent Manner

et al. 2019

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“…In myocytes, miR-29 reduces insulin sensitivity by repressing IRS-1 , a target which is also bound in adipose tissue 35 . HITS-CLIP also reveals miR-29 binding sites in Myo1c and Cav2 , two genes involved in downstream propagation of insulin signaling 36,37 , suggesting overlapping function with the insulin de-sensitizing effect of miR-29 in liver 38,39 . In heart, miR-29 suppresses fibrosis by targeting Col3a1, Fbn1 , and Eln 24 .…”

Section: Figmentioning

confidence: 96%

AGO HITS-CLIP in Adipose Tissue Reveals miR-29 as a Post-Transcriptional Regulator of Leptin

O’Connor

Murphy

et al. 2020

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MicroRNAs (miRNAs) are short, non-coding RNAs that associate with Argonaute (AGO) to regulate mRNA stability and translation. While individual miRNAs have been shown to play important roles in white and brown adipose tissue in normal physiology and disease 1,2,3 , a comprehensive analysis of miRNA activity in these tissues has not been performed. We used high-throughput sequencing of RNA isolated by crosslinking immunoprecipitation (HITS-CLIP) to comprehensively characterize the network of high-confidence, in vivo mRNA:miRNA interactions across white and brown fat, revealing over 100,000 unique miRNA binding sites. Targets for each miRNA were ranked to generate a catalog of miRNA binding activity, and the miR-29 family emerged as a top regulator of adipose tissue gene expression. Among the top targets of miR-29 was leptin, an adipocyte-derived hormone that acts on the brain to regulate food intake and energy expenditure 4 . Two independent miR-29 binding sites in the leptin 3'-UTR were validated using luciferase assays, and miR-29 gain and loss-of-function modulated leptin mRNA and protein secretion in primary adipocytes. In mice, miR-29 abundance inversely correlated with leptin levels in two independent models of obesity. This work represents the only experimentally generated miRNA targetome in adipose tissue and identifies the first known post-transcriptional regulator of leptin. Future work aimed at manipulating miR-29:leptin binding may provide a therapeutic opportunity to treat obesity and its sequelae.Much of the work on adipocyte development and function over the last several decades has focused on transcriptional regulators. These include PPARG2, which is necessary and sufficient for the development and maintenance of white and brown adipocytes 5 , and PRDM16, which regulates brown and beige adipocyte identity 6,7 . More recently, it has become clear that post-transcriptional regulators also play 3 a key role in influencing adipocyte phenotype. Studies with adipose-specific dicer KO mice demonstrate that microRNAs (miRNAs) are essential in regulating adipogenesis, insulin sensitivity and non-shivering thermogenesis 8,9 . Several individual miRNAs have been shown to contribute to these phenotypic effects.miR-133 represses BAT function by directly targeting Prdm16 and inhibiting expression of thermogenic genes 2 . miR-196a induces browning of WAT by targeting Hoxc8 1 , and miR-26 protects mice from dietinduced obesity by blocking adipogenesis 10 . These studies, and most others in adipose tissue, rely on computational predictions and low-throughput validation to identify miRNA targets. Although highthroughput crosslinking techniques to map the miRNA targetome have been applied to liver, brain, heart and other tissues 11,12,13 , thus far, no comprehensive targetome has been described for adipose tissue.To profile the complete network of in vivo, adipose-specific miRNA binding activity across both brown and white fat, we used AGO HITS-CLIP on interscapular brown adipose tissue (iBAT) and epididymal white a...

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“…Most interestingly, the miR-29 family also likely plays a role in glycemic control. For example, Praveen Sethupathy and colleagues (16) recently reported that inhibition of miR-29b-3p in vivo resulted in improved glycemic control and reduced insulin resistance, thus supporting a critical role for miR-29 in both cholesterol and glucose metabolism in vivo. In addition, miR-29 has also been shown to play a critical role in glucose metabolism in pancreatic islets and b-cell functions.…”

Section: Recent Success Of Mirna Research In Cardiometabolic Diseasesmentioning

confidence: 99%

Pervasive Small RNAs in Cardiometabolic Research: Great Potential Accompanied by Biological and Technical Barriers

et al. 2020

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Advances in small RNA sequencing have revealed the enormous diversity of small noncoding RNA (sRNA) classes in mammalian cells. At this point, most investigators in diabetes are aware of the success of microRNA (miRNA) research and appreciate the importance of posttranscriptional gene regulation in glycemic control. Nevertheless, miRNAs are just one of multiple classes of sRNAs and likely represent only a minor fraction of sRNA sequences in a given cell. Despite the widespread appreciation of sRNAs, very little research into non-miRNA sRNA function has been completed, likely due to some major barriers that present unique challenges for study. To emphasize the importance of sRNA research in cardiometabolic diseases, we highlight the success of miRNAs and competitive endogenous RNAs in cholesterol and glucose metabolism. Moreover, we argue that sequencing studies have demonstrated that miRNAs are just the tip of the iceberg for sRNAs. We are likely standing at the precipice of immense discovery for novel sRNA-mediated gene regulation in cardiometabolic diseases. To realize this potential, we must first address critical barriers with an open mind and refrain from viewing non-miRNA sRNA function through the lens of miRNAs, as they likely have their own set of distinct regulatory factors and functional mechanisms.

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Acute suppression of insulin resistance-associated hepatic miR-29 in vivo improves glycemic control in adult mice

Cited by 36 publications

References 53 publications

MiR-29 Regulates de novo Lipogenesis in the Liver and Circulating Triglyceride Levels in a Sirt1-Dependent Manner

MiR-29 Regulates de novo Lipogenesis in the Liver and Circulating Triglyceride Levels in a Sirt1-Dependent Manner

AGO HITS-CLIP in Adipose Tissue Reveals miR-29 as a Post-Transcriptional Regulator of Leptin

Pervasive Small RNAs in Cardiometabolic Research: Great Potential Accompanied by Biological and Technical Barriers

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