Skip to main content

Advertisement

SpringerLink
Log in

The brain neuropeptides and STAT3 mediate the inhibitory effect of 17-β Estradiol on central leptin resistance in young but not aged female high-fat diet mice

  • Original Article
  • Published:
Metabolic Brain Disease Aims and scope Submit manuscript

Abstract

Aging and menopause effect on body composition and energy balance. Estrogen (E2) plays an important role in body’s metabolism. The aim of the present study was to determine changes in leptin function in young intact and ovariectomized (OVX) animals in comparison to the aged animals treated with E2. Young (Intact and OVX 4 months) and aged (19–21 months) female mice were fed High-fat diet (HFD) for 12 weeks and, then they were divided into eight groups including: Intact + OIL, Intact + E2, Intact + Pair body weight (PBW), OVX + OIL, OVX + E2, OVX + PBW, Aged + OIL, and Aged + E2. E2 was administered subcutaneously every four days for four weeks. Responsiveness to leptin was assessed by measuring energy balance components. Results showed that eating HFD increased weight and calorie consumption in young mice, and chronic treatment with E2 decreased both these variables in young animals. E2 only improved the sensitivity to leptin in young animals. Treatment with E2 resulted in increased α-MSH neuropeptide, reduced NPY and AgRP neuropeptides in the brain, and decreased serum leptin in the young animals. Also, treatment with E2 increased the expression of p-STAT3 molecular level in the hypothalamic arcuate nucleus (ARC) in the young animals. Our results indicated that response to E2 depended on age and E2 protects young HFD fed mice from obesity and improves leptin sensitivity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Data availability

The data that support the findings of this study are available on request from the corresponding author, [initials]. The data are not publicly available due to [restrictions e.g. their containing information that could compromise the privacy of research participants].

Code availability

Not applicable.

Abbreviations

E2:

17-β Estradiol

ERα:

Estrogen receptor α

ERβ:

Estrogen receptor β

POMC:

Pro-opiomelanocortin

p-STAT3:

Phosphorylated signal transducer and activator of transcription 3

HFD:

High-fat diet

OVX:

Ovariectomized

ICV:

Intracerebroventricular

NPY:

Neuropeptide Y

α-MSH:

Alpha-melanocyte stimulating hormone

AgRP:

Agouti-related protein

PBS:

Phosphate-buffered saline

PBW:

Pair-body weight

Lep:

Leptin

Sal:

Saline

ARC:

Arcuate

References

  • Ainslie D, Morris M, Wittert G, Turnbull H, Proietto J, Thorburn A (2001) Estrogen deficiency causes central leptin insensitivity and increased hypothalamic neuropeptide Y. Int J Obes 25:1680–1688

    Article  CAS  Google Scholar 

  • Al-Sofiani ME, Ganji SS, Kalyani RR (2019) Body composition changes in diabetes and aging. J Diabetes Complications 33:451–459

    Article  Google Scholar 

  • Argente-Arizón P, Guerra-Cantera S, Garcia-Segura LM, Argente J. & Chowen JA (2017) Glial cells and energy balance. J Mol Endocrinol 58:R59-R71

  • BALASKó, M., SOóS, S., SZEKELY, M. & PETERVáRI, E. (2014) Leptin and aging: Review and questions with particular emphasis on its role in the central regulation of energy balance. J Chem Neuroanat 61:248–255

    Google Scholar 

  • Binai NA, Damert A, Carra G, Steckelbroeck S, Löwer J, Löwer R. & Wessler S (2010) Expression of estrogen receptor alpha increases leptin-induced STAT3 activity in breast cancer cells. Int J Cancer 127:55-66

  • Carter S, Caron A, Richard D, Picard F (2013) Role of leptin resistance in the development of obesity in older patients. Clin Interv Aging 8:829

    CAS  PubMed  PubMed Central  Google Scholar 

  • Dardeno TA, Chou SH, Moon H-S, Chamberland JP, Fiorenza CG, Mantzoros CS (2010) Leptin in human physiology and therapeutics. Front Neuroendocrinol 31:377–393

    Article  CAS  Google Scholar 

  • Enriori PJ, Evans AE, Sinnayah P, Jobst EE, Tonelli-Lemos L, Billes SK, Glavas MM, Grayson BE, Perello M, Nillni EA (2007) Diet-induced obesity causes severe but reversible leptin resistance in arcuate melanocortin neurons. Cell Metab 5:181–194

    Article  CAS  Google Scholar 

  • Esmailidehaj M, Kuchakzade F, Rezvani ME, Farhadi Z, Esmaeili H & Azizian H (2020) 17β-Estradiol improves insulin signalling and insulin resistance in the aged female hearts: role of inflammatory and anti-inflammatory cytokines. Life Sci 253:117673

  • Farhadi Z, Khaksari M, Azizian H, Dabiri S, Fallah H & Nozari M (2020a) Aging is associated with loss of beneficial effects of estrogen on leptin responsiveness in mice fed high fat diet: Role of estrogen receptor α and cytokines. Mech Ageing Dev 186:111198

  • Farhadi Z, Khaksari M, Azizian H, Mortazaeizadeh A, Shabani M & Shahrokhi N (2020b) Beneficial effects of tamoxifen on leptin sensitivity in young mice fed a high fat diet: Role of estrogen receptor alpha and cytokines. Life Sci, 246:117384.

  • Fernández-Agulló T, Arribas C, Andres A & Carrascosa JM (2001) Decreased leptin uptake in hypothalamic nuclei with ageing in Wistar rats J Endocrinol 171:23-32

  • Filippi BM, Lam TK (2014) Leptin and Aging Aging (albany NY) 6:82

    Google Scholar 

  • Foster TC (2012) Role of estrogen receptor alpha and beta expression and signaling on cognitive function during aging Hippocampus 22:656-669

  • Gabriely I, Ma XH, Yang XM, Rossetti L, Barzilai N (2002) Leptin resistance during aging is independent of fat mass. Diabetes 51:1016–1021

    Article  CAS  Google Scholar 

  • Gao Q, Horvath TL (2008) Cross-talk between estrogen and leptin signaling in the hypothalamus. American Journal of Physiology-Endocrinology and Metabolism 294:E817–E826

    Article  CAS  Google Scholar 

  • Hariri N, Thibault L (2010) High-fat diet-induced obesity in animal models. Nutr Res Rev 23:270–299

    Article  CAS  Google Scholar 

  • He Z, Zhang SS, Meng Q, Li S, Zhu HH, Raquil M-A, Alderson N, Zhang H, Wu J, Rui L (2012) Shp2 controls female body weight and energy balance by integrating leptin and estrogen signals. Mol Cell Biol 32:1867–1878

    Article  CAS  Google Scholar 

  • Hosoi T, Okuma Y, Ono A, Nomura Y (2005) Alteration of leptin-induced STAT3 activation in the brain of senescence-accelerated mouse (SAM) P8. Biol Pharm Bull 28:1514–1516

    Article  CAS  Google Scholar 

  • Khaksari M, Keshavarzi Z, Gholamhoseinian A, Bibak B (2013) The effect of female sexual hormones on the intestinal and serum cytokine response after traumatic brain injury: different roles for estrogen receptor subtypes. Can J Physiol Pharmacol 91(9):700–707. https://doi.org/10.1139/cjpp-2012-0359

  • Khaksari M, Hajializadeh Z, Shahrokhi N, Esmaeili-Mahani S (2015) Changes in the gene expression of estrogen receptors involved in the protective effect of estrogen in rat׳ s trumatic brain injury. Brain Res 1618:1–8

    Article  CAS  Google Scholar 

  • Kimura M, Irahara M, Yasui T, Saito S, Tezuka M, Yamano S, Kamada M, Aono T (2002) The obesity in bilateral ovariectomized rats is related to a decrease in the expression of leptin receptors in the brain. Biochem Biophys Res Commun 290:1349–1353

    Article  CAS  Google Scholar 

  • Lei S, Liu M, Chen X, Deng F, Lv J, Jian W, Xu H, Tan L, Yang Y, Wang Y (2006) Relationship of total body fatness and five anthropometric indices in Chinese aged 20–40 years: different effects of age and gender. Eur J Clin Nutr 60:511–518

    Article  Google Scholar 

  • Litwak SA, Wilson JL, Chen W, Garcia-Rudaz C, Khaksari M, Cowley MA, Enriori PJ (2014) Estradiol prevents fat accumulation and overcomes leptin resistance in female high-fat diet mice. Endocrinology 155:4447–4460

    Article  Google Scholar 

  • Ludgero-Correia JR, A., Aguila MB, Mandarim-De-Lacerda CA & Faria TS (2012) Effects of high-fat diet on plasma lipids, adiposity, and inflammatory markers in ovariectomized C57BL/6 mice. Nutrition 28:316-323

  • Maruyama S, Minami S, Kaseki H, Ishihara K, Araki T, Suzue R (2001) A comparison of serum leptin concentrations in obese and normal weight Japanese women with regular menstrual cycle. J Nutr Sci Vitaminol 47:87–89

    Article  CAS  Google Scholar 

  • Matyšková R, Železná B, Maixnerova J, Koutova D, Haluzik M & Maletinska L (2010) Estradiol supplementation helps overcome central leptin resistance of ovariectomized mice on a high fat diet. Horm Metab Res 42:182-186

  • Mauvais-Jarvis F, Clegg DJ, Hevener AL (2013) The role of estrogens in control of energy balance and glucose homeostasis. Endocr Rev 34:309–338

    Article  CAS  Google Scholar 

  • Miller CN, Brown LM, Rayalam S, Della-Fera MA, Baile CA (2012) Estrogens, inflammation and obesity: an overview. Frontiers in Biology 7:40–47

    Article  CAS  Google Scholar 

  • Münzberg H, Flier JS, Bjørbæk C (2004) Region-specific leptin resistance within the hypothalamus of diet-induced obese mice. Endocrinology 145:4880–4889

    Article  Google Scholar 

  • Park CJ, Zhao Z, Glidewell-Kenney C, Lazic M, Chambon P, Krust A, Weiss J, Clegg DJ, Dunaif A, Jameson JL (2011) Genetic rescue of nonclassical ERα signaling normalizes energy balance in obese Erα-null mutant mice. J Clin Investig 121:604–612

    Article  CAS  Google Scholar 

  • Pelletier G, Li S, Luu-The V, Labrie F (2007) Oestrogenic regulation of pro-opiomelanocortin, neuropeptide Y and corticotrophin-releasing hormone mRNAs in mouse hypothalamus. J Neuroendocrinol 19:426–431

    Article  CAS  Google Scholar 

  • Ramadhinara A, Widia F, Soegondo S, Setiawati A (2008) The role of SOCS-3 in leptin resistance and obesity. Acta Med Indones 40:89–95

    Google Scholar 

  • Troen BR (2003) The biology of aging The Mount Sinai Journal of Medicine, New York 70:3-22

  • Wolden-Hanson T, Marck BT, Matsumoto AM (2004) Blunted hypothalamic neuropeptide gene expression in response to fasting, but preservation of feeding responses to AgRP in aging male Brown Norway rats. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 287:R138–R146

    Article  CAS  Google Scholar 

  • Wu Y, Yu Y, Szabo A, Han M. & Huang X.-F (2014) Central inflammation and leptin resistance are attenuated by ginsenoside Rb1 treatment in obese mice fed a high-fat diet. PloS one 9:e92618.

  • Wysokiński A, Sobów T, Kłoszewska I & Kostka T (2015) Mechanisms of the anorexia of aging—a review. Age 37:1-14

  • Xu Y, Nedungadi TP, Zhu L, Sobhani N, Irani BG, Davis KE, Zhang X, Zou F, Gent LM, Hahner LD (2011) Distinct hypothalamic neurons mediate estrogenic effects on energy homeostasis and reproduction. Cell Metab 14:453–465

    Article  CAS  Google Scholar 

  • Zhang Q-J, Yang C-C, Zhang S-Y, Zhang L-H, Li J (2016) Alteration of NPY in hypothalamus and its correlation with leptin and ghrelin during the development of T2DM in a rat model. Springerplus 5:1–10

    Article  Google Scholar 

Download references

Funding

The present work was financially supported Iran National Science Foundation (INSF) under grant ID 94811516 to professor Mohammad Khaksari.

Author information

Authors and Affiliations

  1. Department of Physiology and Pharmacology, Kerman University of Medical Sciences, Kerman, Iran

    Zeinab Farhadi

  2. Endocrinology and Metabolism Research Center, Kerman University of Medical Sciences, Kerman, Iran

    Mohammad Khaksari

  3. Department of Physiology, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran

    Hossein Azizian

  4. Pathology and Stem Cell Research Center, Kerman University of Medical Sciences, Kerman, Iran

    Shahriar Dabiri

Authors
  1. Zeinab Farhadi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mohammad Khaksari
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hossein Azizian
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shahriar Dabiri
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Farhadi Z performed the majority of experiments, analyzed the data, and drafted the manuscript. Khaksari M and Azizian H designed the research and provided critical revision of the manuscript for important intellectual content. Dabiri SH conducted the molecular biology assays and assisted in writing the manuscript. The authors declare that all data were generated in-house and that no paper mill was used.

Corresponding author

Correspondence to Mohammad Khaksari.

Ethics declarations

Ethical approval

All animal experiments were performed in accordance with the ethical guidelines of the Kerman University of Medical Sciences Animal Ethics Committee (Permission No: 95/264 KA).

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Farhadi, Z., Khaksari, M., Azizian, H. et al. The brain neuropeptides and STAT3 mediate the inhibitory effect of 17-β Estradiol on central leptin resistance in young but not aged female high-fat diet mice. Metab Brain Dis 37, 625–637 (2022). https://doi.org/10.1007/s11011-021-00884-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11011-021-00884-4

Keywords

Search

Navigation