High-fat diet leads to increased ovarian lipid deposition even in the absence of obesity

We have previously shown that high-fat diet (HFD) feeding leads to depletion of the ovarian reserve, subfertility, and altered expression of key ovarian genes, irrespective of the development of obesity1,2. It has been proposed that HFD-induced ovarian dysfunction is due to increased lipid accumulation in the ovary3,4, however, it is currently unknown if there is increased HFD-induced lipid accumulation in the ovary in the absence of obesity. We hypothesized that HFD exposure would increase ovarian lipid deposition regardless of the induction of obesity. Prospective laboratory animal study. 5-week-old C57BL/6J mice were fed either a 60% HFD or standard chow (N = 15) for 10 weeks. After 10 weeks body weights were determined. Lean and fat mass was measured by quantitative MRI. HFD mice were divided into HFD-lean (HFLn, N=10) and HFD-obese (HFOb, N=9) groups based on body weight: mice < 26 g were considered HFLn and mice ³ 30 g were considered HFOb. Ovaries were collected, one for qRT-PCR analysis of the lipid droplet protein plin2 and the other for immunohistochemical analysis of lipid droplets via anti-plin2 staining. A one-way ANOVA (Tukey’s post hoc) was used for statistical analysis. After 10 weeks of diet HFOb mice weighed more and had a higher percentage of body fat (33.2 ± 0.9 g, 37.2 ± 1.2%, respectively) than both HFLn mice (23.5 ± 0.6g, 17.7 ± 1.5%, respectively) and chow controls (21.6 ± 0.3g, 11.2 ± 0.6%, respectively) (p<0.0001). Ovarian expression of plin2 was dramatically increased after HFD, with a 5-fold increase observed in HFLn mice and a 4.7-fold increase observed in HFOb mice (p = 0.01) compared to chow-fed controls. Immunohistochemical analysis of plin2 in the ovary confirmed our qRT-PCR data showing dramatically increased levels of plin2 in the ovaries of both the HFLn and HFOb mice. In particular, increased lipid deposition was observed in the corpora lutea, ovarian stroma, and outside of the theca cells of large follicles, and to a far lesser extent in the granulosa cells. HFD exposure leads to increased ovarian lipid deposition regardless of the development of obesity in mice. This phenomenon may be responsible for the ovarian dysfunction and reproductive defects observed with HFD exposure, even in the absence of obesity. The presence of increased lipid droplets in the ovaries of lean mice fed a HFD provides further evidence that even if a lean phenotype is maintained, consumption of HFDs will still negatively impact the ovary. More research is needed to determine the exact mechanism by which excessive ovarian lipid accumulation is responsible for the HFD-induced reproductive dysfunction.