Revisiting the Impact of Local Leptin Signaling in Folliculogenesis and Oocyte Maturation in Obese Mothers

Abstract

The complex nature of folliculogenesis regulation accounts for its susceptibility to maternal physiological fitness. In obese mothers, progressive expansion of adipose tissue culminates with severe hyperestrogenism and hyperleptinemia with detrimental effects for ovarian performance. Indeed, maternal obesity is associated with the establishment of ovarian leptin resistance. This review summarizes current knowledge on potential effects of impaired leptin signaling throughout folliculogenesis and oocyte developmental competence in mice and women.

Leptin Signaling in the Ovary of Diet-Induced Obese Mice Regulates Activation of NOD-Like Receptor Protein 3 Inflammasome

“…Importantly, other genes were highlighted in the network, as solute carrier family 22 member 15 (Slc22a15) , a cell membrane transporter and metabolic gene ( Nigam, 2018 ), or stress-associated endoplasmic reticulum protein 1 (Serp1) involved in protein unfolding and stress response ( Yamaguchi et al, 1999 ). Indeed, metabolic performance in the preovulatory follicle is tightly regulated and involves the crosstalk between GC and oocyte ( Figure 4D ; Wołodko et al, 2021 ). The gene ontology analysis for the presented network revealed three main events: negative regulation of glucose transport, positive regulation of cytokine biosynthesis, and response to ATP ( Figure 4E , p < 0.05).…”

“…Next, we reanalyzed our datasets on global gene expression in CCs collected from DIO and pharmacological hyperleptinemic mice in order to test the association between leptin signaling and activation of NLRP3 inflammasome in the somatic companions of the oocyte. Importantly, CCs are known as faithful indicators of intrafollicular environment ( Wołodko et al, 2021 ), and their transcriptome has been previously used to predict oocyte and embryo quality ( Uyar et al, 2013 ). Despite no changes in 4- week HFD, we confirmed the overexpression of NLRP3 inflammasome genes in CCs from 16 L. Consequently, we interrogated whether DEGs overlapping both 16 L and 4- week HFD treatment could interact with NLRP3 inflammasome genes.…”

“…Indeed, gene ontology for associated genes revealed key terms for oocyte maturation, such as regulation of glucose transport, response to ATP, and regulation of cytokine biosynthesis. Metabolic regulation in preovulatory follicles appears to control major steps for maturation of female gamete, such as meiosis resumption, chromatin condensation, and cytoplasm maturation ( Wołodko et al, 2021 ). For instance, glucose metabolism, which takes place mostly in CCs ( Sanfins et al, 2018 ) was shown to be a key for oocyte competence ( Wilding et al, 2009 ).…”

“…Furthermore, NLRP3 inflammasome was previously reported to be involved in ovulation ( Zhang et al, 2019 ). Given both direct and indirect roles of leptin in ovulation ( Wołodko et al, 2021 ), the failure in leptin signaling and NLRP3 inflammasome activation in late obesity could account for increased anovulatory rates in obese mothers ( Wu et al, 2010 ; Hou et al, 2016 ). Finally, the absence of changes in 4- week HFD in NLRP3 inflammasome genes can be ascribed to the low levels of coverage of our reduced-cell libraries and also the low levels of Nlrp3 mRNA expression.…”

“…Hence, early increase in ovarian leptin signaling and overexpression of SOCS3 protein after 4 weeks of DIO, was followed by failure in leptin receptor (ObR) b activation and leptin resistance after 16 week DIO ( Wołodko et al, 2020 ). Furthermore, leptin is a well-known regulator of ovarian function ( Karlsson et al, 1997 ; Ryan et al, 2002 ), with the aforementioned changes in leptin signaling in the ovaries of obese mothers potentially affecting major functional events like follicular pool activation, oocyte maturation, and ovulation ( Wołodko et al, 2021 ).…”