Obesity is associated with increased circulating triglycerides and free fatty acids which cause lipotoxicity in non-adipose tissues, characterised by endoplasmic reticulum (ER) stress. How lipotoxicity or ER stress may impact hormone production and secretion in the hypothalamus-pituitary-gonadal (HPG) axisand thereby affect female fertility is not known. ‘Blobby’ mice exhibit hyperphagia and extreme obesity even on a chow diet and at 14 weeks of age have increased circulating cholesterol (1.6-fold), triglycerides (1.68-fold), free fatty acids (1.74-fold), and insulin (9.67-fold) but not glucose compared to non-obese littermates. Hypothalamus from female Blobby mice have increased mRNA expression of ER stress markers (Atf4, Atf6, Xbp1s) and heat shock protein chaperones (Hspa1a, Hspa1b) characteristic of an ER stress response. Blobby mice show altered estrous cycles with increased number of days at estrus and a reduced number of days at proestrus. Blobby mice at diestrus have significantly fewer corpora lutea and lower plasma estradiol levels than non-obese littermates; while plasma FSH and LH levels were not different.
Treatment of obese Blobby mice with ER stress inhibitors (one of which is in clinical trials for human use) for one estrous cycle, normalized mRNA levels of ER stress markers and heat shock protein chaperones in hypothalamus, shorted their estrous cycle length, increased the number of corpora lutea in ovaries, and normalized the plasma estradiol levels.
These results demonstrate that obesity leads to reproductive defects in the HPG axis but these can be reversed in order to normalise estrous cycle, improve HPG signalling and natural ovulation capacity.