High-Fat Diet and Female Fertility

Abstract

The prevalence of obesity is high among reproductive-age women and is associated with impaired reproductive function. Obesity is multifactorial in origin, yet many cases of obesity result from overconsumption of a diet high in fat. Excess dietary fat increases both adipose and nonadipose tissue lipid content and, through lipotoxicity, leads to cell dysfunction and death. High dietary fat intake, with or without the development of obesity, impairs female hypothalamic-pituitary-ovarian (HPO) axis functionality and fertility. Based on the current evidence, it appears the reproductive dysfunction involves increased leptin and insulin signaling at the various levels of the HPO axis, as well as changes in peroxisome proliferator-activated receptor γ actions and increased inflammation, yet other mechanisms may also be involved. This review summarizes the current body of knowledge on impaired female reproductive function after high-fat diet exposure, as well as discusses proposed mechanisms through which this may occur.

Figure 1.

Proposed mechanisms for HFD-induced central reproductive dysfunction. HFD feeding leads to the development of increased leptin and insulin levels systemically. Elevated leptin levels lead to leptin resistance in the hypothalamus, causing decreased leptin signaling and its ability to inhibit NPY, as seen by an increase in NPY, which inhibits GnRH and likely affects pituitary function as addition of gonadotropin stimulus in this model restored fertility. Inhibiting PPARγ’s actions in the brain protects against leptin resistance and reproductive dysfunction. Elevated insulin levels in the hypothalamus increase GnRH pulse amplitude and lead to increased LH secretion from the pituitary. Alterations in hypothalamic function from both increased leptin and insulin signaling contribute to reproductive dysfunction. Increased insulin and likely increased leptin in the pituitary increase PI3K activation, which alters LH levels and contributes to reproductive dysfunction. LEPR-B, leptin receptor type B.

Figure 2.

HFD-induced ovarian dysfunction. In the ovary, elevated leptin signaling increases CART, which decreases intracellular cAMP levels and MAPK3/1 activation, leading to decreased aromatase and estradiol production. Elevated levels of leptin, insulin, and KITLG increase PI3K activation, which leads to increased primordial follicle activation, resulting in the depletion of the ovarian reserve. Increased lipid accumulation in the ovary leads to lipotoxicity. Both increased PI3K signaling and lipotoxicity may contribute to increased follicle atresia. These alterations in ovarian function contribute to the reproductive dysfunction. cAMP, cyclic adenosine monophosphate; CART, cocaine- and amphetamine-regulated transcript; MAPK3/1, mitogen-activated protein kinase 3/1.