Hypothalamic and Cell-Specific Transcriptomes Unravel a Dynamic Neuropil Remodeling in Leptin-Induced and Typical Pubertal Transition in Female Mice

Overview

Journal iScience

Publisher Cell Press

Date 2020 Oct 21

PMID 33083731

Citations 7

Authors

Xingfa Han

Laura L Burger

David Garcia-Galiano

Seokmin Sim

Susan J Allen

David P Olson

Martin G Myers Jr

Carol F Elias

Affiliations

Soon will be listed here.

Abstract

Epidemiological and genome-wide association studies (GWAS) have shown high correlation between childhood obesity and advance in puberty. Early age at menarche is associated with a series of morbidities, including breast cancer, cardiovascular diseases, type 2 diabetes, and obesity. The adipocyte hormone leptin signals the amount of fat stores to the neuroendocrine reproductive axis via direct actions in the brain. Using mouse genetics, we and others have identified the hypothalamic ventral premammillary nucleus (PMv) and the agouti-related protein (AgRP) neurons in the arcuate nucleus (Arc) as primary targets of leptin action in pubertal maturation. However, the molecular mechanisms underlying leptin's effects remain unknown. Here we assessed changes in the PMv and Arc transcriptional program during leptin-stimulated and typical pubertal development using overlapping analysis of bulk RNA sequecing, TRAP sequencing, and the published database. Our findings demonstrate that dynamic somatodendritic remodeling and extracellular space organization underlie leptin-induced and typical pubertal maturation in female mice.

Citing Articles

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References

Farooqi I, Matarese G, Lord G, Keogh J, Lawrence E, Agwu C . Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. J Clin Invest. 2002; 110(8):1093-103. PMC: 150795. DOI: 10.1172/JCI15693. View

Wojcik-Gladysz A, Polkowska J . Neuropeptide Y--a neuromodulatory link between nutrition and reproduction at the central nervous system level. Reprod Biol. 2007; 6 Suppl 2:21-8. View

Gearing L, Cumming H, Chapman R, Finkel A, Woodhouse I, Luu K . CiiiDER: A tool for predicting and analysing transcription factor binding sites. PLoS One. 2019; 14(9):e0215495. PMC: 6726224. DOI: 10.1371/journal.pone.0215495. View

True C, Verma S, Grove K, Smith M . Cocaine- and amphetamine-regulated transcript is a potent stimulator of GnRH and kisspeptin cells and may contribute to negative energy balance-induced reproductive inhibition in females. Endocrinology. 2013; 154(8):2821-32. PMC: 3713223. DOI: 10.1210/en.2013-1156. View

Simavli S, Thompson I, Maguire C, Gill J, Carroll R, Wolfe A . Substance p regulates puberty onset and fertility in the female mouse. Endocrinology. 2015; 156(6):2313-22. PMC: 4430622. DOI: 10.1210/en.2014-2012. View

Rodrigues B, C Cavalcante J, Elias C . Expression of cocaine- and amphetamine-regulated transcript in the rat forebrain during postnatal development. Neuroscience. 2011; 195:201-14. PMC: 4235957. DOI: 10.1016/j.neuroscience.2011.08.036. View

Lam B, Cimino I, Polex-Wolf J, Nicole Kohnke S, Rimmington D, Iyemere V . Heterogeneity of hypothalamic pro-opiomelanocortin-expressing neurons revealed by single-cell RNA sequencing. Mol Metab. 2017; 6(5):383-392. PMC: 5404100. DOI: 10.1016/j.molmet.2017.02.007. View

Bjornholm M, Munzberg H, Leshan R, Villanueva E, Bates S, Louis G . Mice lacking inhibitory leptin receptor signals are lean with normal endocrine function. J Clin Invest. 2007; 117(5):1354-60. PMC: 1838925. DOI: 10.1172/JCI30688. View

Mizuno T, Mobbs C . Hypothalamic agouti-related protein messenger ribonucleic acid is inhibited by leptin and stimulated by fasting. Endocrinology. 1999; 140(2):814-7. DOI: 10.1210/endo.140.2.6491. View

10.

Egan O, Inglis M, Anderson G . Leptin Signaling in AgRP Neurons Modulates Puberty Onset and Adult Fertility in Mice. J Neurosci. 2017; 37(14):3875-3886. PMC: 6596709. DOI: 10.1523/JNEUROSCI.3138-16.2017. View

11.

Singireddy A, Inglis M, Zuure W, Kim J, Anderson G . Neither signal transducer and activator of transcription 3 (STAT3) or STAT5 signaling pathways are required for leptin's effects on fertility in mice. Endocrinology. 2013; 154(7):2434-45. DOI: 10.1210/en.2013-1109. View

12.

Heiman M, Kulicke R, Fenster R, Greengard P, Heintz N . Cell type-specific mRNA purification by translating ribosome affinity purification (TRAP). Nat Protoc. 2014; 9(6):1282-91. PMC: 4102313. DOI: 10.1038/nprot.2014.085. View

13.

Biro F, Khoury P, Morrison J . Influence of obesity on timing of puberty. Int J Androl. 2005; 29(1):272-7. DOI: 10.1111/j.1365-2605.2005.00602.x. View

14.

Leshan R, Louis G, Jo Y, Rhodes C, Munzberg H, Myers Jr M . Direct innervation of GnRH neurons by metabolic- and sexual odorant-sensing leptin receptor neurons in the hypothalamic ventral premammillary nucleus. J Neurosci. 2009; 29(10):3138-47. PMC: 2675106. DOI: 10.1523/JNEUROSCI.0155-09.2009. View

15.

Cravo R, Frazao R, Perello M, Osborne-Lawrence S, Williams K, Zigman J . Leptin signaling in Kiss1 neurons arises after pubertal development. PLoS One. 2013; 8(3):e58698. PMC: 3591417. DOI: 10.1371/journal.pone.0058698. View

16.

Abreu A, Dauber A, Macedo D, Noel S, Brito V, Gill J . Central precocious puberty caused by mutations in the imprinted gene MKRN3. N Engl J Med. 2013; 368(26):2467-75. PMC: 3808195. DOI: 10.1056/NEJMoa1302160. View

17.

Safe S, Jin U, Morpurgo B, Abudayyeh A, Singh M, Tjalkens R . Nuclear receptor 4A (NR4A) family - orphans no more. J Steroid Biochem Mol Biol. 2015; 157:48-60. PMC: 4618773. DOI: 10.1016/j.jsbmb.2015.04.016. View

18.

Ross R, Leon S, Madara J, Schafer D, Fergani C, Maguire C . PACAP neurons in the ventral premammillary nucleus regulate reproductive function in the female mouse. Elife. 2018; 7. PMC: 6013253. DOI: 10.7554/eLife.35960. View

19.

Ozcan L, Ergin A, Lu A, Chung J, Sarkar S, Nie D . Endoplasmic reticulum stress plays a central role in development of leptin resistance. Cell Metab. 2009; 9(1):35-51. DOI: 10.1016/j.cmet.2008.12.004. View

20.

Cheng T, Day F, Lakshman R, Ong K . Association of puberty timing with type 2 diabetes: A systematic review and meta-analysis. PLoS Med. 2020; 17(1):e1003017. PMC: 6944335. DOI: 10.1371/journal.pmed.1003017. View