Progressive Obesity Alters Ovarian Folliculogenesis with Impacts on Pro-Inflammatory and Steroidogenic Signaling in Female Mice1

Abstract

Diet-induced obesity induces immune cell infiltration and inflammation in peri-ovarian adipose tissue and mRNA expression of inflammatory markers in ovarian tissue. Whether these changes are associated with obesity-related ovarian dysfunction remains unknown. In the present study, qRT-PCR and Western blotting techniques were used to compare mRNA and protein abundance of ovarian immune cell and inflammation markers, along with NF-kappaB and steroidogenic pathway members in normal wild-type non-agouti (a/a; lean) and lethal yellow mice (KK.CG-A(y/)J; obese) at 6, 12, 18, or 24 wk of age. Our data revealed that, beginning at 12 wk of age, NF-kappaB inflammatory signaling members were elevated (P < 0.05) in obese females. Interestingly obesity had opposing and temporal effects on the steroidogenic enzyme pathway. Obesity decreased (P < 0.05) STAR protein at 12, 18, and 24 wk of age. CYP11A1 and CYP19A1 proteins were increased (P < 0.05) at 12 wk but were decreased (P < 0.05) at 18 and 24 wk. Interestingly, CYP19A1 was increased in lethal yellow mouse ovaries at 6 wk of age, potentially indicating early puberty onset. These data demonstrate that obesity alters expression of ovarian inflammatory and steroidogenic pathway genes in ways which could adversely affect ovarian function.

Maternal obesity is associated with ovarian inflammation and upregulation of early growth response factor 1

“…Obesity is characterized by a subclinical chronic inflammatory response that is seen both systemically and localized within tissues, as illustrated by an increase in inflammatory cytokine expression and immune cell infiltration (13,26). Yet there is limited research exploring the impact of obesity on the inflammatory state in the ovary and how activation of inflammatory pathways could lead to ovarian dysfunction (37,38). The present study provides new insights on the effects of obesity induced by overfeeding prior to conception on the ovary during the peri-implantation period.…”

“…Higher adiposity leads to hormonal dysregulation, decreased primordial follicle numbers at the initiation of follicular development, lower ovulation rates, a reduced number of cleaved blastocysts developing to eight cell stage and reduced implantation rates, and ultimately impaired reproductive function (11,16,17,22,33,35,61). Similarly, in experimental models, obesity leads to decreased primordial and preovulatory follicle numbers, increased follicular atresia and changes in steroidogenesis via decreased steroidogenic acute regulatory protein, and increased Cyp11a1 protein content in ovarian tissue (7,16,23,37,38,53,61). Evidence of lipid accumulation, endoplasmic reticulum stress, and oxidative stress in ovaries from obese dams compared with lean controls may result partially in altered oocyte maturation, increased anovulation, and decreased in vivo fertilization rates (7,9,47,53,64,65).…”

“…Similarly, in experimental models, obesity leads to decreased primordial and preovulatory follicle numbers, increased follicular atresia and changes in steroidogenesis via decreased steroidogenic acute regulatory protein, and increased Cyp11a1 protein content in ovarian tissue (7,16,23,37,38,53,61). Evidence of lipid accumulation, endoplasmic reticulum stress, and oxidative stress in ovaries from obese dams compared with lean controls may result partially in altered oocyte maturation, increased anovulation, and decreased in vivo fertilization rates (7,9,47,53,64,65).Although cytokines and macrophages play an important role in regulating cellular proliferation, follicular growth, steroidogenesis, and the activation and recruitment of leukocytes during ovulation and luteinization (10, 37, 51), low-grade systemic inflammation has been shown to be concurrent with obesity-associated reproductive function problems leading to infertility (34,37,38,40,(42)(43)(44). Nteeba et al (38) identified higher immune cell filtration and an upregulation of proinflammatory cytokine/chemokine gene expression in the periovarian adipose tissues as well as proinflammatory and oxidative stress gene expression signatures in the ovaries of mice fed a high fat diet.…”

“…Although cytokines and macrophages play an important role in regulating cellular proliferation, follicular growth, steroidogenesis, and the activation and recruitment of leukocytes during ovulation and luteinization (10,37,51), low-grade systemic inflammation has been shown to be concurrent with obesity-associated reproductive function problems leading to infertility (34,37,38,40,(42)(43)(44). Nteeba et al (38) identified higher immune cell filtration and an upregulation of proinflammatory cytokine/chemokine gene expression in the periovarian adipose tissues as well as proinflammatory and oxidative stress gene expression signatures in the ovaries of mice fed a high fat diet.…”

“…Nteeba et al (38) identified higher immune cell filtration and an upregulation of proinflammatory cytokine/chemokine gene expression in the periovarian adipose tissues as well as proinflammatory and oxidative stress gene expression signatures in the ovaries of mice fed a high fat diet. In addition, genetically modified obese mice, lethal yellow, have increased ovarian proinflammatory protein content through elevation of ovarian nuclear factor-B (NF-B) signaling proteins compared with wild type (37).…”