MicroRNA miR-7 and miR-17-92 in the Arcuate Nucleus of Mouse Hypothalamus Regulate Sex-Specific Diet-Induced Obesity

  • Yanxia Gao
  • Jiaheng Li
  • Zhen Zhang
  • Ruihan Zhang
  • Andrew Pollock
  • Tao SunEmail author


Proper appetite, energy expenditure, and glucose and fat metabolisms are regulated by neurons in the arcuate nucleus (ARC) of mammalian hypothalamus. Studies have shown sex-specific difference in diet-induced obesity, but the underlying mechanisms remain unclear. Here, we show that microRNA (miRNA) miR-7 and miR-17-92 are expressed in proopiomelanocortin (POMC)-expressing neurons in the mouse ARC. Specific knockdown of miR-7 and knockout of miR-17-92 in POMC-expressing neurons aggravate diet-induced obesity only in females and males, respectively. Sex-differentially expressed genes are identified in the male and female ARC of wild-type adult mice using RNA sequencing. Interestingly, some target genes for miR-7 and miR-17-92 not only display sex-differential expression in the male and female ARC but also respond to high-fat diet treatment in miR-7 knockdown and miR-17-92 knockout mice. Our results demonstrate an important role of miRNAs in regulating sex-specific diet-induced obesity, likely through modulating expression of target genes that show sex-differential expression in the ARC of the hypothalamus.


miR-7 miR-17-92 Obesity POMC neurons Sex-differential gene 



We thank the members of the Sun Laboratory for their valuable discussions and advice.

Authors’ Contribution

Conceived and designed the experiments: Y.G. and T.S.; experiment: Y.G., Z.Z., and A.P.; result analysis: Y.G., J.L., and R.Z.; wrote the paper: Y.G. and T.S; edited the paper: T.S.

Funding Information

This work was supported by an R01-MH083680 grant from the NIH/NIMH (T. S.) and the National Natural Science Foundation of China (81471152 and 31771141).

Compliance with Ethical Standards

All animal experiments were approved by the Animal Ethics Committee of Shanghai Jiao Tong University.

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12035_2019_1618_MOESM1_ESM.docx (2.2 mb)
ESM 1 (DOCX 2298 kb)
12035_2019_1618_MOESM2_ESM.xlsx (11 kb)
Supplementary Table 1 (XLSX 11 kb)


  1. 1.
    Clifford BS, Bradford BL (2015) The hypothalamus. Curr Biol 24(23)Google Scholar
  2. 2.
    Dietrich MO, Horvath TL (2013) Hypothalamic control of energy balance: insights into the role of synaptic plasticity. Trends Neurosci 36(2):65–73. CrossRefPubMedGoogle Scholar
  3. 3.
    Saper CB, Scammell TE, Lu J (2005) Hypothalamic regulation of sleep and circadian rhythms. Nature 437(7063):1257–1263. CrossRefPubMedGoogle Scholar
  4. 4.
    Toda C, Santoro A, Kim JD, Diano S (2017) POMC neurons: from birth to death. Annu Rev Physiol 79(79):209–236. CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Mcclellan KM, Calver AR, Tobet SA (2008) GABA(B) receptors role in cell migration and positioning within the ventromedial nucleus of the hypothalamus. Neuroscience 151(4):1119–1131. CrossRefPubMedGoogle Scholar
  6. 6.
    Shimogori T, Lee DA, Miranda-Angulo A, Yang Y, Wang H, Jiang L, Yoshida AC, Kataoka A et al (2010) A genomic atlas of mouse hypothalamic development. Nat Neurosci 13(6):767–U153. CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Joly A, Denis R, Castel J, Palmiter R, Magnan C, Luquet S (2010) Role of neural NPY/AgRP in the control of energy balance. Diabetes Metab 36:A10–A10. CrossRefGoogle Scholar
  8. 8.
    Mercer RE, Chee MJ, Colmers WF (2011) The role of NPY in hypothalamic mediated food intake. Front Neuroendocrinol 32(4):398–415. CrossRefPubMedGoogle Scholar
  9. 9.
    Gao Y, Sun T (2016) Molecular regulation of hypothalamic development and physiological functions. Mol Neurobiol 53(7):4275–4285. CrossRefPubMedGoogle Scholar
  10. 10.
    Greenman Y, Kuperman Y, Drori Y, Asa SL, Navon I, Forkosh O, Gil S, Stern N et al (2013) Postnatal ablation of POMC neurons induces an obese phenotype characterized by decreased food intake and enhanced anxiety-like behavior. Mol Endocrinol 27(7):1091–1102. CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Coupe B, Bouret SG (2013) Development of the hypothalamic melanocortin system (POMC). Front Endocrinol 4:38. CrossRefGoogle Scholar
  12. 12.
    Parton LE, Ye CP, Coppari R, Enriori PJ, Choi B, Zhang CY, Xu C, Vianna CR et al (2007) Glucose sensing by POMC neurons regulates glucose homeostasis and is impaired in obesity. Nature 449(7159):228–U227. CrossRefPubMedGoogle Scholar
  13. 13.
    Smith MA, Katsouri L, Irvine EE, Hankir MK, Pedroni SMA, Voshol PJ, Gordon MW, Choudhury AI et al (2015) Ribosomal S6K1 in POMC and AgRP neurons regulates glucose homeostasis but not feeding behavior in mice. Cell Rep 11(3):335–343. CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Berglund ED, Vianna CR, Donato J, Kim MH, Chuang JC, Lee CE, Lauzon DA, Lin P et al (2012) Direct leptin action on POMC neurons regulates glucose homeostasis and hepatic insulin sensitivity in mice. J Clin Investig 122(3):1000–1009. CrossRefPubMedGoogle Scholar
  15. 15.
    Dodd GT, Decherf S, Loh K, Simonds SE, Wiede F, Balland E, Merry TL, Munzberg H et al (2015) Leptin and insulin act on POMC neurons to promote the browning of white fat. Cell 160(1–2):88–104. CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Burke LK, Doslikova B, D'Agostino G, Greenwald-Yarnell M, Georgescu T, Chianese R, Martinez de Morentin PB, Ogunnowo-Bada E et al (2016) Sex difference in physical activity, energy expenditure and obesity driven by a subpopulation of hypothalamic POMC neurons. Molecular Metabolism 5(3):245–252. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Plum L, Rother E, Munzberg H, Wunderlich FT, Morgan DA, Hampel B, Shanabrough M, Janoschek R et al (2007) Enhanced leptin-stimulated Pi3k activation in the CNS promotes white adipose tissue transdifferentiation. Cell Metab 6(6):431–445. CrossRefPubMedGoogle Scholar
  18. 18.
    Wang C, He Y, Xu P, Yang Y, Saito K, Xia Y, Yan X, Hinton A Jr et al (2018) TAp63 contributes to sexual dimorphism in POMC neuron functions and energy homeostasis. Nat Commun 9(1):1544. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Nohara K, Zhang Y, Waraich RS, Laque A, Tiano JP, Tong J, Munzberg H, Mauvais-Jarvis F (2011) Early-life exposure to testosterone programs the hypothalamic melanocortin system. Endocrinology 152(4):1661–1669. CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136(2):215–233. CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Pasquinelli AE (2012) MicroRNAs and their targets: recognition, regulation and an emerging reciprocal relationship. Nat Rev Genet 13(4):271–282. CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Lai EC (2002) Micro RNAs are complementary to 3′ UTR sequence motifs that mediate negative post-transcriptional regulation. Nat Genet 30(4):363–364. CrossRefPubMedGoogle Scholar
  23. 23.
    Rajman M, Schratt G (2017) MicroRNAs in neural development: from master regulators to fine-tuners. Development 144(13):2310–2322. CrossRefPubMedGoogle Scholar
  24. 24.
    Bian S, Xu TL, Sun T (2013) Tuning the cell fate of neurons and glia by microRNAs. Curr Opin Neurobiol 23(6):928–934. CrossRefPubMedGoogle Scholar
  25. 25.
    Gao FB (2008) Posttranscriptional control of neuronal development by microRNA networks. Trends Neurosci 31(1):20–26. CrossRefPubMedGoogle Scholar
  26. 26.
    Bak M, Silahtaroglu A, Moller M, Christensen M, Rath MF, Skryabin B, Tommerup N, Kauppinen S (2008) MicroRNA expression in the adult mouse central nervous system. Rna 14(3):432–444. CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Crepin D, Benomar Y, Riffault L, Amine H, Gertler A, Taouis M (2014) The over-expression of miR-200a in the hypothalamus of ob/ob mice is linked to leptin and insulin signaling impairment. Mol Cell Endocrinol 384(1–2):1–11. CrossRefPubMedGoogle Scholar
  28. 28.
    Derghal A, Djelloul M, Airault C, Pierre C, Dallaporta M, Troadec JD, Tillement V, Tardivel C, Bariohay B, Trouslard J, Mounien L (2015) Leptin is required for hypothalamic regulation of miRNAs targeting POMC 3′UTR. Front Cell Neurosci 9. doi:Artn 172
  29. 29.
    Vinnikov IA, Hajdukiewicz K, Reymann J, Beneke J, Czajkowski R, Roth LC, Novak M, Roller A et al (2014) Hypothalamic miR-103 protects from hyperphagic obesity in mice. J Neurosci 34(32):10659–10674. CrossRefPubMedGoogle Scholar
  30. 30.
    Schneeberger M, Altirriba J, Garcia A, Esteban Y, Castano C, Garcia-Lavandeira M, Alvarez CV, Gomis R et al (2012) Deletion of miRNA processing enzyme Dicer in POMC-expressing cells leads to pituitary dysfunction, neurodegeneration and development of obesity. Molecular Metabolism 2(2):74–85. CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Bian S, Hong J, Li Q, Schebelle L, Pollock A, Knauss JL, Garg V, Sun T (2013) MicroRNA cluster miR-17-92 regulates neural stem cell expansion and transition to intermediate progenitors in the developing mouse neocortex. Cell Rep 3(5):1398–1406. CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Jin J, Kim SN, Liu X, Zhang H, Zhang C, Seo JS, Kim Y, Sun T (2016) miR-17-92 cluster regulates adult hippocampal neurogenesis, anxiety, and depression. Cell Rep 16(6):1653–1663. CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Pollock A, Bian S, Zhang C, Chen Z, Sun T (2014) Growth of the developing cerebral cortex is controlled by microRNA-7 through the p53 pathway. Cell Rep 7(4):1184–1196. CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Latreille M, Hausser J, Stutzer I, Zhang Q, Hastoy B, Gargani S, Kerr-Conte J, Pattou F et al (2014) MicroRNA-7a regulates pancreatic beta cell function. J Clin Invest 124(6):2722–2735. CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Madisen L, Zwingman TA, Sunkin SM, Oh SW, Zariwala HA, Gu H, Ng LL, Palmiter RD et al (2010) A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nat Neurosci 13(1):133–140. CrossRefPubMedGoogle Scholar
  36. 36.
    Ma W, Fuentes G, Shi XH, Verma C, Radda GK, Han WP (2015) FoxO1 negatively regulates leptin-induced POMC transcription through its direct interaction with STAT3. Biochem J 466:291–298. CrossRefPubMedGoogle Scholar
  37. 37.
    Liu XS, Chopp M, Wang XL, Zhang L, Hozeska-Solgot A, Tang T, Kassis H, Zhang RL et al (2013) MicroRNA-17-92 cluster mediates the proliferation and survival of neural progenitor cells after stroke. J Biol Chem 288(18):12478–12488. CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Reddy OL, Cates JM, Gellert LL, Crist HS, Yang ZH, Yamashita H, Taylor JA, Smith JA et al (2015) Loss of FOXA1 drives sexually dimorphic changes in urothelial differentiation and is an independent predictor of poor prognosis in bladder cancer. Am J Pathol 185(5):1385–1395. CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Li Z, Tuteja G, Schug J, Kaestner KH (2012) Foxa1 and Foxa2 are essential for sexual dimorphism in liver cancer. Cell 148(1–2):72–83. CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Hurtado A, Holmes KA, Ross-Innes CS, Schmidt D, Carroll JS (2011) FOXA1 is a key determinant of estrogen receptor function and endocrine response. Nat Genet 43(1):27–U42. CrossRefPubMedGoogle Scholar
  41. 41.
    Sahu B, Laakso M, Ovaska K, Mirtti T, Lundin J, Rannikko A, Sankila A, Turunen JP et al (2011) Dual role of FoxA1 in androgen receptor binding to chromatin, androgen signalling and prostate cancer. EMBO J 30(19):3962–3976. CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Yang YA, Yu J (2015) Current perspectives on FOXA1 regulation of androgen receptor signaling and prostate cancer. Genes & Diseases 2(2):144–151. CrossRefGoogle Scholar
  43. 43.
    Salinero AE, Anderson BM, Zuloaga KL (2018) Sex differences in the metabolic effects of diet-induced obesity vary by age of onset. Int J Obes 42:1088–1091. CrossRefGoogle Scholar
  44. 44.
    Medrikova D, Jilkova ZM, Bardova K, Janovska P, Rossmeisl M, Kopecky J (2012) Sex differences during the course of diet-induced obesity in mice: adipose tissue expandability and glycemic control. Int J Obes 36(2):262–272. CrossRefGoogle Scholar
  45. 45.
    Seeger T, Fischer A, Muhly-Reinholz M, Zeiher AM, Dimmeler S (2014) Long-term inhibition of miR-21 leads to reduction of obesity in db/db mice. Obesity 22(11):2352–2360. CrossRefPubMedGoogle Scholar
  46. 46.
    Gaudet AD, Fonken LK, Gushchina LV, Aubrecht TG, Maurya SK, Periasamy M, Nelson RJ, Popovich PG (2016) miR-155 deletion in female mice prevents diet-induced obesity. Sci Rep 6:22862. CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Schroeder M, Drori Y, Ben-Efraim YJ, Chen A (2018) Hypothalamic miR-219 regulates individual metabolic differences in response to diet-induced weight cycling. Molecular Metabolism 9:176–186. CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Piwecka M, Glazar P, Hernandez-Miranda LR, Memczak S, Wolf SA, Rybak-Wolf A, Filipchyk A, Klironomos F et al (2017) Loss of a mammalian circular RNA locus causes miRNA deregulation and affects brain function. Science 357. CrossRefGoogle Scholar
  49. 49.
    Garg N, Po A, Miele E, Campese AF, Begalli F, Silvano M, Infante P, Capalbo C et al (2013) microRNA-17-92 cluster is a direct Nanog target and controls neural stem cell through Trp53inp1. EMBO J 32(21):2819–2832. CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Ebert MS, Sharp PA (2012) Roles for microRNAs in conferring robustness to biological processes. Cell 149(3):515–524. CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Leung AKL, Sharp PA (2010) MicroRNA functions in stress responses. Mol Cell 40(2):205–215. CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Challis BG, Coll AP, Yeo GSH, Pinnock SB, Dickson SL, Thresher RR, Dixon J, Zahn D et al (2004) Mice lacking pro-opiomelanocortin are sensitive to high-fat feeding but respond normally to the acute anorectic effects of peptide-YY3-36. Proc Natl Acad Sci U S A 101(13):4695–4700. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.School of Life Sciences and BiotechnologyShanghai Jiao Tong UniversityShanghaiChina
  2. 2.Center for Precision Medicine, School of Medicine and School of Biomedical SciencesHuaqiao UniversityXiamenChina
  3. 3.Zhiyuan CollegeShanghai Jiao Tong UniversityShanghaiChina
  4. 4.Department of Cell and Developmental BiologyCornell University Weill Medical CollegeNew YorkUSA

Personalised recommendations