Characterization of adipokines receptors in bovine granulosa cells at the follicular phase of the estrous cycle and emerging role of Neuregulin-4 as a regulator of granulosa cells' function
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Authors
Batalha, Isadora Maria
Issue Date
2024
Type
Dissertation
Language
en_US
Keywords
Adipose tissue , Cattle , Endocrinology , Follicle , Ovary , Women
Alternative Title
Abstract
Adipokines, hormones produced by adipose tissue, were originally described to be solely secreted by white adipose tissue (WAT). However, recent evidence suggests that brown adipose tissue (BAT), in addition to its thermogenic role, also secretes hormones that can modulate both energy and reproductive metabolism. This finding expands and integrates the class of adipokines, traditionally associated with WAT, with those derived from BAT. Adipokines are known to affect ovarian physiology, especially granulosa cells (GC) function, regulating both steroidogenesis and folliculogenesis, which are important processes for female reproductive health. However, most of these studies are restricted to investigating their effects throughout the luteal phase of the reproductive cycle or in vitro without control of ovarian folliculogenesis. Although adipokines' role as GC function regulators is well-established, studies integrating in vivo and in vitro data to develop targeted strategies to aid female fertility are still required. Bovines and humans share several similarities regarding ovarian physiology, and studies presented here used the bovine model to provide valuable insights into improving female fertility in both species. In our first study, we explored the effects of a promising regulator of ovarian physiology, Neuregulin-4 (NRG4). Through in vivo and in vitro experiments, we demonstrated for the first time that NRG4 is expressed by ovarian cells. NRG4 and its receptor (ErBb-4) are more (p<0.001) abundant in bovine GC from small (SM) follicles at the follicular phase of the estrous cycle. Additionally, in vitro treatments of GC with luteinizing hormone (LH) alone or in combination with follicle-stimulating hormone (FSH) increased (p<0.05) NRG4 mRNA abundance. Furthermore, NRG4 (20ng/mL) stimulated (p<0.05) GC proliferation, whereas NRG4 (10ng/mL) suppressed estradiol secretion. These findings suggest that NRG4 and its receptor may be involved in follicle development, and their impact on GC physiology varies with the stage of the reproductive cycle.
Our second study explored whether mRNA abundances of adipokines receptors change at the follicular phase of the bovine estrous cycle and their response to GC physiology regulators. Receptors for apelin, asprosin, chemerin, gremlin, irisin, leptin, resistin, and vaspin were more abundant (p≤0.01) in GC from SM follicles, whereas adiponectin receptor 2 was significantly more expressed (p≤0.001) in GC from large (LG) follicles. Additionally, Spearman’s correlation revealed a significative negative (average ρ = - 0.753; p≤0.05) correlation between follicular fluid estradiol levels and GC abundance of four adipokines receptors in SM follicles. In LG follicles, GC abundance of adiponectin receptor 1 and leptin receptor had a strong positive (average ρ = 0.95; p≤0.05) correlation with estradiol levels. The in vitro treatments with known regulators of GC at the follicular phase influenced the mRNA abundance of eight adipokines receptors. These findings demonstrate that adipokines receptors’ expressions in GC are follicle size-dependent and are directly correlated with estradiol secretion. Also, their follicle size-dependent abundance and regulation by known factors involved in GC steroidogenesis suggest a potential role in follicular development throughout the estrous cycle. Collectively, these studies reinforce the essential role of adipokines in ovarian physiology and reveal new influences on their regulation during a crucial phase of the reproductive cycle. These insights may contribute to the development of strategies to overcome ovulatory impairment.