Mir193b–365 is essential for brown fat differentiation
TL;DR: It is demonstrated that a brown-fat-enriched miRNA cluster, MiR-193b–365, serves as an essential regulator for brown fat differentiation, in part by repressing myogenesis.
Abstract: PRDM16 is known to promote the differentiation of myoblastic progenitors to brown adipocytes. The miR-193b/365 microRNAs are shown to be induced by PRDM16 and promote brown fat differentiation, as well as block myogenesis.
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TL;DR: Transplantation of both white and brown adipose tissue—brown especially—into ADicerKO mice restores the level of numerous circulating miRNAs that are associated with an improvement in glucose tolerance and a reduction in hepatic Fgf21 mRNA and circulating FGF21.
Abstract: Adipose tissue is a major site of energy storage and has a role in the regulation of metabolism through the release of adipokines. Here we show that mice with an adipose-tissue-specific knockout of the microRNA (miRNA)-processing enzyme Dicer (ADicerKO), as well as humans with lipodystrophy, exhibit a substantial decrease in levels of circulating exosomal miRNAs. Transplantation of both white and brown adipose tissue-brown especially-into ADicerKO mice restores the level of numerous circulating miRNAs that are associated with an improvement in glucose tolerance and a reduction in hepatic Fgf21 mRNA and circulating FGF21. This gene regulation can be mimicked by the administration of normal, but not ADicerKO, serum exosomes. Expression of a human-specific miRNA in the brown adipose tissue of one mouse in vivo can also regulate its 3' UTR reporter in the liver of another mouse through serum exosomal transfer. Thus, adipose tissue constitutes an important source of circulating exosomal miRNAs, which can regulate gene expression in distant tissues and thereby serve as a previously undescribed form of adipokine.
1,025 citations
TL;DR: Dysregulation of miRNAs may contribute to metabolic abnormalities, suggesting that mi RNAs may potentially serve as therapeutic targets for ameliorating cardiometabolic disorders.
Abstract: MicroRNAs (miRNAs) have recently emerged as key regulators of metabolism. For example, miR-33a and miR-33b have a crucial role in controlling cholesterol and lipid metabolism in concert with their host genes, the sterol-regulatory element-binding protein (SREBP) transcription factors. Other metabolic miRNAs, such as miR-103 and miR-107, regulate insulin and glucose homeostasis, whereas miRNAs such as miR-34a are emerging as key regulators of hepatic lipid homeostasis. The discovery of circulating miRNAs has highlighted their potential as both endocrine signalling molecules and disease markers. Dysregulation of miRNAs may contribute to metabolic abnormalities, suggesting that miRNAs may potentially serve as therapeutic targets for ameliorating cardiometabolic disorders.
998 citations
TL;DR: Stimulating the development of beige adipocytes in WAT (so called 'browning') might reduce adverse effects of WAT and could help to improve metabolic health, as well as inspire new avenues to increase the capacity for adaptive thermogenesis.
Abstract: Accumulation of excess white adipose tissue (WAT) has deleterious consequences for metabolic health. The activation of brown adipose tissue (BAT), the primary organ for heat production, confers beneficial effects on adiposity, insulin resistance and hyperlipidaemia, at least in mice. As the amount of metabolically active BAT seems to be particularly low in patients with obesity or diabetes mellitus who require immediate therapy, new avenues are needed to increase the capacity for adaptive thermogenesis. In this light, we review the findings that BAT in human adults might consist of not only classic brown adipocytes but also inducible brown adipocytes (also called beige, brown-in-white, or brite adipocytes), which are phenotypically distinct from both white and brown adipocytes. Stimulating the development of beige adipocytes in WAT (so called 'browning') might reduce adverse effects of WAT and could help to improve metabolic health. This article focuses on the development and regulatory control of beige adipocytes at the transcriptional and hormonal levels. Emerging insights into the metabolic role of beige adipocytes are also discussed, along with the developments that can be expected from these promising targets for therapy of metabolic disease in the future.
821 citations
TL;DR: A deeper understanding of the molecular processes involved in the development and function of these cell types may lead to new therapeutics for obesity, diabetes, and other metabolic diseases.
Abstract: One of the most promising areas in the therapeutics for metabolic diseases centers around activation of the pathways of energy expenditure. Brown adipose tissue is a particularly appealing target for increasing energy expenditure, given its amazing capacity to transform chemical energy into heat. In addition to classical brown adipose tissue, the last few years have seen great advances in our understanding of inducible thermogenic adipose tissue, also referred to as beige fat. A deeper understanding of the molecular processes involved in the development and function of these cell types may lead to new therapeutics for obesity, diabetes, and other metabolic diseases.
745 citations
Cites background from "Mir193b–365 is essential for brown ..."
...It has been shown that PRDM16 expression can be regulated by microRNAs (Sun et al. 2011; Trajkovski et al. 2012)....
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TL;DR: This work aims to discuss recent insights regarding the developmental lineages, molecular regulation, and new functions for brown and beige adipocytes.
701 citations
References
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TL;DR: This work overhauled its tool for finding preferential conservation of sequence motifs and applied it to the analysis of human 3'UTRs, increasing by nearly threefold the detected number of preferentially conserved miRNA target sites.
Abstract: MicroRNAs (miRNAs) are small endogenous RNAs that pair to sites in mRNAs to direct post-transcriptional repression. Many sites that match the miRNA seed (nucleotides 2–7), particularly those in 3 untranslated regions (3UTRs), are preferentially conserved. Here, we overhauled our tool for finding preferential conservation of sequence motifs and applied it to the analysis of human 3UTRs, increasing by nearly threefold the detected number of preferentially conserved miRNA target sites. The new tool more efficiently incorporates new genomes and more completely controls for background conservation by accounting for mutational biases, dinucleotide conservation rates, and the conservation rates of individual UTRs. The improved background model enabled preferential conservation of a new site type, the “offset 6mer,” to be detected. In total, >45,000 miRNA target sites within human 3UTRs are conserved above background levels, and >60% of human protein-coding genes have been under selective pressure to maintain pairing to miRNAs. Mammalian-specific miRNAs have far fewer conserved targets than do the more broadly conserved miRNAs, even when considering only more recently emerged targets. Although pairing to the 3 end of miRNAs can compensate for seed mismatches, this class of sites constitutes less than 2% of all preferentially conserved sites detected. The new tool enables statistically powerful analysis of individual miRNA target sites, with the probability of preferentially conserved targeting (PCT) correlating with experimental measurements of repression. Our expanded set of target predictions (including conserved 3-compensatory sites), are available at the TargetScan website, which displays the PCT for each site and each predicted target.
7,744 citations
4,041 citations
TL;DR: Defined regions of functionally active brown adipose tissue are present in adult humans, are more frequent in women than in men, and may be quantified noninvasively with the use of (18)F-FDG PET-CT.
Abstract: Background Obesity results from an imbalance between energy intake and expenditure. In rodents and newborn humans, brown adipose tissue helps regulate energy expenditure by thermogenesis mediated by the expression of uncoupling protein 1 (UCP1), but brown adipose tissue has been considered to have no physiologic relevance in adult humans. Methods We analyzed 3640 consecutive 18F-fluorodeoxyglucose (18F-FDG) positron-emission tomographic and computed tomographic (PET–CT) scans performed for various diagnostic reasons in 1972 patients for the presence of substantial depots of putative brown adipose tissue. Such depots were defined as collections of tissue that were more than 4 mm in diameter, had the density of adipose tissue according to CT, and had maximal standardized uptake values of 18F-FDG of at least 2.0 g per milliliter, indicating high metabolic activity. Clinical indexes were recorded and compared with those of date-matched controls. Immunostaining for UCP1 was performed on biopsy specimens from t...
3,805 citations
"Mir193b–365 is essential for brown ..." refers background in this paper
...Uc p1 Co x5 b Ci de a Pp arα 0 1 2 3 4 5 50 100 150 200 250 R el at iv e ex pr es sio n WAT WAT C2C12 C2C12 * * * * * * * 13450k 13451k 13452k 13453k 13454k mir-193b mir-365 Am pli co n 1 Am pli co n 2 Am pli co n 3 Am pli co n 4 Am pli co n 1 Am pli co n 2 Am pli co n 3 Am pli co n 4 0.0 0.5 1.0 1.5 WTPPARα KO * * R el at iv e ex pr es si on Am pli co n 1 Am pli co n 2 Am pli co n 3 Am pli co n 4 0 5 10 15 20 Vector PRDM16 * * * * R el at iv e ex pr es si on C2C12 Am pli co n 1 Am pli co n 2 Am pli co n 3 Am pli co n 4 0.0 0.5 1.0 1.5 Vector sh-PRDM16 R el at iv e ex pr es si on * * * BAT Am pli co n 1 Am pli co n 2 Am pli co n 3 Am pli co n 4 0 5 10 15 Vector PRDM16 * * * * R el at iv e ex pr es si on WAT Am pli co n 1 Am pli co n 2 Am pli co n 3 Am pli co n 4 0.0 0.5 1.0 1.5 siNCsiPPARa * R el at iv e ex pr es si on LN A- NC LN A m iR19 3a +b LN A m iR36 5 Adipogenesis markers Ad ipo Q Ce bp a Fa bp 4 Pp arg 0.0 0.5 1.0 1.5 LNA-NC LNA miR-193a+b LNA miR-365 * * * * * * * * Re lat ive e xp re ss io n Brown fat markers Cid ea Dio 2 Uc p1 Pp ara Prd m1 6 0.0 0.5 1.0 1.5 LNA-NC LNA miR-193a+b LNA miR-365 * * * * * * * * * * * Re lat ive e xp re ss io n Day (-3) Day (-1) Day (0) Day (3) Retroviral PRDM16 Adipogenic inductionInhibitor ORO staining RNA extraction b c d e f g h i j k l PRDM16 PRDM16 miR-193b-365 miR-193b miR-365 PPARα Myf5+ Muscle Brown adipocytes Runx1t1 Cdon Igfbp5 m © 2011 Macmillan Publishers Limited....
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...Representative micrographs of cells (Day 6) differentiated from C2C12 myoblasts expressing retroviral miR-193a or the control vector....
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...* * * * * * * * * * * Re lat ive e xp re ss io n Day (-3) Day (-1) Day (0) Day (3) Retroviral PRDM16 Adipogenic induction Inhibitor...
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01 Feb 1964
TL;DR: This article marks the beginning of Rodbell's interest in cell receptors and related his discovery that fat cells could be isolated from other cells by treating them with preparations of collagenase, and also found that insulin could stimulate glucose uptake.
Abstract: This article marks the beginning of Rodbell's interest in cell receptors. In it, he related his discovery that fat cells
could be isolated from other cells by treating them with preparations of collagenase, and also found that insulin could stimulate
glucose uptake. This had far-reaching implications for the treatment of various diseases, as it was the first demonstration
that insulin acted on individual cells.
3,787 citations
TL;DR: Detailed polling of transcription start and termination sites and analysis of previously unidentified full-length complementary DNAs derived from the mouse genome provide a comprehensive platform for the comparative analysis of mammalian transcriptional regulation in differentiation and development.
Abstract: This study describes comprehensive polling of transcription start and termination sites and analysis of previously unidentified full-length complementary DNAs derived from the mouse genome. We identify the 5' and 3' boundaries of 181,047 transcripts with extensive variation in transcripts arising from alternative promoter usage, splicing, and polyadenylation. There are 16,247 new mouse protein-coding transcripts, including 5154 encoding previously unidentified proteins. Genomic mapping of the transcriptome reveals transcriptional forests, with overlapping transcription on both strands, separated by deserts in which few transcripts are observed. The data provide a comprehensive platform for the comparative analysis of mammalian transcriptional regulation in differentiation and development.
3,412 citations