Cardiometabolic and reproductive benefits of early dietary energy restriction and voluntary exercise in an obese PCOS-prone rodent model

Abstract

Polycystic ovary syndrome (PCOS) is one of the most common endocrine-metabolic disorders in women of reproductive age characterized by ovulatory dysfunction, hyperandrogenism and cardiometabolic risk. The overweight-obese PCOS phenotype appears to have exacerbated reproductive dysfunction and cardiometabolic risk. In overweight-obese adult women with PCOS, exercise and energy restricted diets have shown limited and inconsistent effects on both cardiometabolic indices and reproductive outcomes. We hypothesized that an early lifestyle intervention involving exercise and dietary energy restriction to prevent or reduce the propensity for adiposity would modulate reproductive indices and cardiometabolic risk in an obese PCOS-prone rodent model. Weanling obese PCOS-prone and Lean-Control JCR:LA-cp rodents were given a chow diet ad libitum or an energyrestricted diet combined with or without voluntary exercise (4 h/day) for 8 weeks. Dietary energy restriction and exercise lowered total body weight gain and body fat mass by 30% compared to free-fed sedentary or exercising obese PCOS-prone animals (P!0.01). Energy restriction induced an increase in exercise intensity compared to free-feeding plus exercise conditions. Energy restriction and exercise decreased fasting plasma triglycerides and apoB48 concentrations in obese PCOS-prone animals compared to free-fed and exercise or sedentary groups. The energy restriction and exercise combination in obese PCOS-prone animals significantly increased plasma sex-hormone binding globulin, hypothalamic cocaine-and amphetamine-regulated transcript (CART) and Kisspeptin mRNA expression to levels of the Lean-Control group, and this was further associated with improvements in estrous cyclicity. The combination of exercise and dietary energy restriction when initiated in early life exerts beneficial effects on cardiometabolic and reproductive indices in an obese PCOS-prone rodent model, and this may be associated with normalization of the hypothalamic neuropeptides, Kisspeptin and CART.

New Therapeutic Approaches in Obesity and Metabolic Syndrome Associated with Polycystic Ovary Syndrome

“…Regarding dietary intervention, thus far, no caloric restricted diet has been recommended in the guidelines. Early initiation of exercise alone, or in combination with dietary energy restrictions, helps in improving reproductive and metabolic indicators in women with PCOS and obesity [ 1 , 6 ]. Also, weight loss alone is insufficient in treating PCOS in women with normal BMI [ 1 ].…”

“…The molecular mechanism underlying the efficacy of lifestyle interventions and its effects was recently explained in a rodent model study [ 6 ]. It appears to be mediated through the normalization of the hypothalamic neuropeptides (cocaine and amphetamine-regulated transcript (CART) and Kisspeptin), and plasma sex-hormone binding globulin (SHBG) [ 6 ].…”

Mechanisms of Comorbidities Associated With the Metabolic Syndrome: Insights from the JCR:LA-cp Corpulent Rat Strain

“…Intervention with flutamide, an androgen receptor (AR) inhibitor, has confirmed that testosterone action via the AR mediates apoB-hyperlipoproteinemia and hypertriglyceridemia, and this appears to be independent of effects on insulin ( 110 ). Fasting plasma apoB100, apoB48, and TG concentrations were lowered by 25–50% in animals treated with flutamide.…”

“…Additionally, the intestinal secretion of TG, cholesterol, and the cholesterol/apoB48 and TG/apoB48 (a marker of lipid per CM particle secreted from the intestine) were markedly reduced following flutamide treatment. Hepatic and intestinal lipogenic gene expression showed that flutamide may lower hepatic SREBP-1, LDLR, and HMGCR in PCOS-prone animals ( 110 ). Interestingly, PCOS-prone animals have reduced IR, MAPK1, AKT2, and PTPN1 mRNA expression in the intestine, but not the liver.…”

“…Overall, these findings indicate that lipogenic and insulin signaling gene expression is altered in PCOS-prone animals compared to lean-prone controls. Effects of AR inhibition and insulin-sensitizing treatments appear to modify these pathways in association with improvements in plasma and intestinal secretion of lipids ( 110 ).…”