Weight gain is a hallmark of decreased
estradiol (E2) levels because of menopause or following surgical
ovariectomy (OVX) at younger ages. Of note, this
weight gain tends to be around the abdomen, which is frequently associated with impaired metabolic homeostasis and greater cardiovascular risk in both rodents and humans. However, the molecular underpinnings and the neuronal basis for these effects remain to be elucidated. The aim of this study is to elucidate whether the
kappa-opioid receptor (k-OR) system is involved in mediating
body weight changes associated with E2 withdrawal. Here, we document that
body weight gain induced by OVX occurs, at least partially, in a k-OR dependent manner, by modulation of energy expenditure independently of food intake as assessed in Oprk1-/-global KO mice. These effects were also observed following central pharmacological blockade of the k-OR system using the k-OR-selective antagonist
PF-04455242 in wild type mice, in which we also observed a decrease in OVX-induced
weight gain associated with increased UCP1 positive immunostaining in brown adipose tissue (BAT) and browning of white adipose tissue (WAT). Remarkably, the hypothalamic mTOR pathway plays an important role in regulating
weight gain and adiposity in OVX mice. These findings will help to define new
therapies to manage metabolic disorders associated with low/null E2 levels based on the modulation of central k-OR signaling.