Metabolic alterations in ovarian NGF overexpressing mice (#233)
We have previously reported that transgenic overexpression of NGF directed to the ovary by the mouse 17α-hydroxylase promoter (17NF mice), results in reproductive abnormalities similar to those seen in PCOS women including ovarian follicular arrest, ovulatory deficiency and reduced fertility (1). PCOS is also associated with a number of metabolic perturbations including insulin resistance, hyperinsulinemia, dyslipidemia and cardiovascular disorders and as such is now recognized as an important metabolic disorder. To investigate whether ovarian overproduction of NGF also induces common metabolic alterations of PCOS we assessed body composition, glucose homeostasis and sympathetic nerve activity in 17NF mice compared to WT mice. 17NF mice exhibited increased body weight and alterations in body fat distribution with a greater accumulation of visceral fat compared to subcutaneous fat (p<0.01). 17NF mice also displayed glucose intolerance (p<0.01) and hyperinsulinemia (p<0.05), which, similar to PCOS patients, occurred independently of body weight. Additionally, two markers of sympathetic outflow to interscapular brown adipose tissue (iBAT), iBAT temperature and UCP1 expression were increased in 17NF mice than WT mice (p<0.05). Interestingly, 17NF mice also exhibited cardiac dysfunction similar to what has been reported in chronic hypertensive subjects. Echocardiography revealed left ventricular enlargement (p<0.01) and left ventricular posterior wall thinning (p<0.01). Moreover, the internal diameter of the right common carotid artery (RCCA) was increased during systole and diastole (p<0.001) and systolic-diastolic changes in the diameter of the RCCA and area of the left ventricle were decreased compared to WT mice (p<0.001). These findings suggest an overexpression of NGF in the ovary may be sufficient to cause both reproductive and metabolic alterations that are characteristic of PCOS and are in support of the hypothesis that sympathetic hyperactivity may play a primary pathological role in the development and/or progression of PCOS.
- 1. Dissen GA, Garcia-Rudaz C, Paredes A, Mayer C, Mayerhofer A, Ojeda SR 2009 Excessive Ovarian Production of Nerve Growth Factor Facilitates Development of Cystic Ovarian Morphology in Mice and Is a Feature of Polycystic Ovarian Syndrome in Humans. Endocrinology 150:2906-2914