Obesity induces morphological and functional changes in female reproductive system through increases in NF-\u03baB and MAPK signaling in mice

Xiuxiu Gao,Yue Liu,Yangyang Li,Jia Jing,Zhengqing Zhang,Zhuoyao Ma,Zhide Ding

doi:10.1186/s12958-021-00833-x

Abstract

BackgroundRecently, human infertility incidence is increasing in obese women causing it to become an emerging global health challenge requiring improved treatment. There is extensive evidence that obesity caused female reproductive dysfunction is accompanied by an endocrinological influence. Besides, systemic and tissue-specific chronic inflammatory status are common characteristics of obesity. However, the underlying molecular mechanism is unclear linking obesity to infertility or subfertility.MethodsTo deal with this question, we created an obese mouse model through providing a high fat diet (HFD) and determined the fertility of the obese mice. The morphological alterations were evaluated in both the reproductive glands and tracts, such as uterus, ovary and oviduct. Furthermore, to explore the underlying mechanism of these functional changes, the expressions of pro-inflammatory cytokines as well as the activations of MAPK signaling and NF-κB signaling were detected in these reproductive tissues.ResultsThe obese females were successful construction and displayed subfertility. They accumulated lipid droplets and developed morphological alterations in each of their reproductive organs including uterus, ovary and oviduct. These pathological changes accompanied increases in pro-inflammatory cytokine expression levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in all of these sites. Such effects also accompanied increases in nuclear factor kappa B (NF-kB) expression and mitogen-activated protein kinase (MAPK) signaling pathway stimulation based on uniform time dependent increases in the NF-κB (p-NF-κB), JNK (p-JNK), ERK1/2 (p-ERK) and p38 (p-p38) phosphorylation status.ConclusionsThese HFD-induced increases in pro-inflammatory cytokine expression levels and NF-κB and MAPKs signaling pathway activation in reproductive organs support the notion that increases of adipocytes resident and inflammatory status are symptomatic of female fertility impairment in obese mice.

Highlights

Human infertility incidence is increasing in obese women causing it to become an emerging global health challenge requiring improved treatment
Higher levels of CHOL, high density lipoprotein (HDL) and low density lipoprotein (LDL) were detected in the high fat diet (HFD) group than those in the normal diet (ND) fed mice (CHOL: 3.04 ± 0.36 vs. 2.16 ± 0.69 mmol/L; HDL: 1.52 ± 0.17 vs. 1.03 ± 0.37 mmol/L; LDL: 0.44 ± 0.10 vs. 0.34 ± 0.09 mmol/L, n = 20, P < 0.01)
In order to simulate the conditions leading to human obesity, we generated the female obese HFD mouse model by providing a diet in which fats provided 60% of the caloric value whereas in the ND control group it was reduced to 10%

Summary

Introduction

Human infertility incidence is increasing in obese women causing it to become an emerging global health challenge requiring improved treatment. There is extensive evidence that obesity caused female reproductive dysfunction is accompanied by an endocrinological influence. The gradual rises in overweight and obesity prevalence has reached global epidemic proportions and is becoming a huge burden on the health care systems in many communities. Their prevalence rose 27.5% in adults and 47.1% in children respectively during the last three. Obesity is associated with many deleterious and chronic diseases such as cardiovascular disease, diabetes, stroke, cancers, etc. Experimental data from mouse models suggest that obesity can suppress oocyte maturation, increase both apoptosis of granulosa cells and oocyte dysfunction [9]

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