miR-133a Regulates Adipocyte Browning In Vivo
Prdm16 determines the bidirectional fate switch of skeletal muscle/brown adipose tissue (BAT) and regulates the thermogenic gene program of subcutaneous white adipose tissue (SAT) in mice. Here we show that miR-133a, a microRNA that is expressed in both BAT and SATs, directly targets the 3′ UTR of Prdm16. The expression of miR-133a dramatically decreases along the commitment and differentiation of brown preadipocytes, accompanied by the upregulation of Prdm16. Overexpression of miR-133a in BAT and SAT cells significantly inhibits, and conversely inhibition of miR-133a upregulates, Prdm16 and brown adipogenesis. More importantly, double knockout of miR-133a1 and miR-133a2 in mice leads to elevations of the brown and thermogenic gene programs in SAT. Even 75% deletion of miR-133a (a1−/−a2+/−) genes results in browning of SAT, manifested by the appearance of numerous multilocular UCP1-expressing adipocytes within SAT. Additionally, compared to wildtype mice, miR-133a1−/−a2+/− mice exhibit increased insulin sensitivity and glucose tolerance, and activate the thermogenic gene program more robustly upon cold exposure. These results together elucidate a crucial role of miR-133a in the regulation of adipocyte browning in vivo.
Vyšlo v časopise:
miR-133a Regulates Adipocyte Browning In Vivo. PLoS Genet 9(7): e32767. doi:10.1371/journal.pgen.1003626
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1003626
Souhrn
Prdm16 determines the bidirectional fate switch of skeletal muscle/brown adipose tissue (BAT) and regulates the thermogenic gene program of subcutaneous white adipose tissue (SAT) in mice. Here we show that miR-133a, a microRNA that is expressed in both BAT and SATs, directly targets the 3′ UTR of Prdm16. The expression of miR-133a dramatically decreases along the commitment and differentiation of brown preadipocytes, accompanied by the upregulation of Prdm16. Overexpression of miR-133a in BAT and SAT cells significantly inhibits, and conversely inhibition of miR-133a upregulates, Prdm16 and brown adipogenesis. More importantly, double knockout of miR-133a1 and miR-133a2 in mice leads to elevations of the brown and thermogenic gene programs in SAT. Even 75% deletion of miR-133a (a1−/−a2+/−) genes results in browning of SAT, manifested by the appearance of numerous multilocular UCP1-expressing adipocytes within SAT. Additionally, compared to wildtype mice, miR-133a1−/−a2+/− mice exhibit increased insulin sensitivity and glucose tolerance, and activate the thermogenic gene program more robustly upon cold exposure. These results together elucidate a crucial role of miR-133a in the regulation of adipocyte browning in vivo.
Zdroje
1. WaldenTB, HansenIR, TimmonsJA, CannonB, NedergaardJ (2012) Recruited vs. nonrecruited molecular signatures of brown, “brite,” and white adipose tissues. Am J Physiol Endocrinol Metab 302: E19–31.
2. SealeP, ConroeHM, EstallJ, KajimuraS, FrontiniA, et al. (2011) Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice. J Clin Invest 121 : 96–105.
3. SealeP, BjorkB, YangW, KajimuraS, ChinS, et al. (2008) PRDM16 controls a brown fat/skeletal muscle switch. Nature 454 : 961–967.
4. KajimuraS, SealeP, KubotaK, LunsfordE, FrangioniJV, et al. (2009) Initiation of myoblast to brown fat switch by a PRDM16-C/EBP-beta transcriptional complex. Nature 460 : 1154–U1125.
5. SealeP, KajimuraS, YangW, ChinS, RohasLM, et al. (2007) Transcriptional control of brown fat determination by PRDM16. Cell Metabolism 6 : 38–54.
6. OhnoH, ShinodaK, SpiegelmanBM, KajimuraS (2012) PPARgamma agonists induce a white-to-brown fat conversion through stabilization of PRDM16 protein. Cell Metab 15 : 395–404.
7. WaldenTB, TimmonsJA, KellerP, NedergaardJ, CannonB (2009) Distinct expression of muscle-specific microRNAs (myomirs) in brown adipocytes. J Cell Physiol 218 : 444–449.
8. SunL, XieH, MoriMA, AlexanderR, YuanB, et al. (2011) Mir193b-365 is essential for brown fat differentiation. Nat Cell Biol 13 : 958–965.
9. MoriM, NakagamiH, Rodriguez-AraujoG, NimuraK, KanedaY (2012) Essential Role for miR-196a in Brown Adipogenesis of White Fat Progenitor Cells. Plos Biology 10: e1001314.
10. SoukasA, SocciND, SaatkampBD, NovelliS, FriedmanJM (2001) Distinct transcriptional profiles of adipogenesis in vivo and in vitro. J Biol Chem 276 : 34167–34174.
11. TchoukalovaYD, SarrMG, JensenMD (2004) Measuring committed preadipocytes in human adipose tissue from severely obese patients by using adipocyte fatty acid binding protein. Am J Physiol Regul Integr Comp Physiol 287: R1132–1140.
12. ShanT, LiuW, KuangS (2013) Fatty acid binding protein 4 expression marks a population of adipocyte progenitors in white and brown adipose tissues. FASEB J 27 : 277–287.
13. LiuN, BezprozvannayaS, WilliamsAH, QiXX, RichardsonJA, et al. (2008) microRNA-133a regulates cardiomyocyte proliferation and suppresses smooth muscle gene expression in the heart. Genes & Development 22 : 3242–3254.
14. LiuN, BezprozvannayaS, SheltonJM, FrisardMI, HulverMW, et al. (2011) Mice lacking microRNA 133a develop dynamin 2-dependent centronuclear myopathy. J Clin Invest 121 : 3258–3268.
15. WuJ, BostromP, SparksLM, YeL, ChoiJH, et al. (2012) Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 150 : 366–376.
16. MishimaY, Abreu-GoodgerC, StatonAA, StahlhutC, ShouC, et al. (2009) Zebrafish miR-1 and miR-133 shape muscle gene expression and regulate sarcomeric actin organization. Genes Dev 23 : 619–632.
17. TrajkovskiM, AhmedK, EsauCC, StoffelM (2012) MyomiR-133 regulates brown fat differentiation through Prdm16. Nat Cell Biol 14 : 1330–1335.
18. YinH, PasutA, SoleimaniVD, BentzingerCF, AntounG, et al. (2013) MicroRNA-133 Controls Brown Adipose Determination in Skeletal Muscle Satellite Cells by Targeting Prdm16. Cell metabolism 17 : 210–224.
19. SongY, AltarejosJ, GoodarziMO, InoueH, GuoXQ, et al. (2010) CRTC3 links catecholamine signalling to energy balance. Nature 468 : 933–U329.
20. TateishiK, OkadaY, KallinEM, ZhangY (2009) Role of Jhdm2a in regulating metabolic gene expression and obesity resistance. Nature 458 : 757–761.
21. LeanMEJ, JamesWPT, JenningsG, TrayhurnP (1986) Brown Adipose-Tissue Uncoupling Protein-Content in Human Infants, Children and Adults. Clinical Science 71 : 291–297.
22. van Marken LichtenbeltWD, VanhommerigJW, SmuldersNM, DrossaertsJM, KemerinkGJ, et al. (2009) Cold-activated brown adipose tissue in healthy men. N Engl J Med 360 : 1500–1508.
23. VirtanenKA, LidellME, OravaJ, HeglindM, WestergrenR, et al. (2009) Functional brown adipose tissue in healthy adults. N Engl J Med 360 : 1518–1525.
24. CypessAM, LehmanS, WilliamsG, TalI, RodmanD, et al. (2009) Identification and importance of brown adipose tissue in adult humans. N Engl J Med 360 : 1509–1517.
25. SharpLZ, ShinodaK, OhnoH, ScheelDW, TomodaE, et al. (2012) Human BAT Possesses Molecular Signatures That Resemble Beige/Brite Cells. PLoS One 7: e49452.
26. LiuWY, LiuYQ, LaiXS, KuangSH (2012) Intramuscular adipose is derived from a non-Pax3 lineage and required for efficient regeneration of skeletal muscles. Developmental Biology 361 : 27–38.
27. LiuWY, WenYF, BiPP, LaiXS, LiuXS, et al. (2012) Hypoxia promotes satellite cell self-renewal and enhances the efficiency of myoblast transplantation. Development 139 : 2857–2865.
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2013 Číslo 7
- Gynekologové a odborníci na reprodukční medicínu se sejdou na prvním virtuálním summitu
- Je „freeze-all“ pro všechny? Odborníci na fertilitu diskutovali na virtuálním summitu
Najčítanejšie v tomto čísle
- Bacterial Adaptation through Loss of Function
- SLC26A4 Targeted to the Endolymphatic Sac Rescues Hearing and Balance in Mutant Mice
- The Cohesion Protein SOLO Associates with SMC1 and Is Required for Synapsis, Recombination, Homolog Bias and Cohesion and Pairing of Centromeres in Drosophila Meiosis
- Gene × Physical Activity Interactions in Obesity: Combined Analysis of 111,421 Individuals of European Ancestry