High-fat and choline-deficient western diets disrupt the ovarian microenvironment in mice†

Obesity and metabolic dysfunction induced by high-fat and Western-style diets are key contributors to reproductive aging. However, the specific contributions of diet-induced obesity and liver damage to ovarian aging and follicle depletion remain unclear. This study investigated the impact of a high-fat diet (HFD) and a choline-deficient Western diet (CDWD) on ovarian aging in two mouse strains. Three-month-old female mice (C57BL/6 and Swiss) were assigned to a control standard diet (CSD), choline-deficient control diet (CDC), HFD, or CDWD for 10 weeks. C57BL/6 mice fed an HFD exhibited significant body mass gain, intra-abdominal fat accumulation, and insulin resistance, whereas Swiss mice did not develop obesity. Both strains developed hepatomegaly and steatohepatitis under CDWD in the absence of obesity, as expected for this choline-deficient diet. HFD and CDWD increased serum cholesterol and high-density lipoprotein levels in both strains. The ovarian follicle reserve was unaffected by diet or strain, despite a modest increase in follicular atresia in HFD-fed C57BL/6 mice. However, both HFD and CDWD promoted macrophage infiltration, lipofuscin accumulation, stromal fibrosis, and increased stromal proliferative activity. These findings demonstrate that metabolic stress from HFD and CDWD remodels the ovarian microenvironment and induces early hallmarks of ovarian aging independent of follicle depletion. Metabolic responses were strain-dependent; however, both obesity-driven metabolic dysfunction and obesity-independent liver injury led to similar ovarian microenvironment remodeling. This highlights a previously underappreciated pathway linking metabolic diseases to reproductive decline and suggests that ovarian microenvironmental remodeling is an early sign of ovarian aging in response to diet-induced metabolic stress.