Oxytocin regulates body composition

Abstract

The primitive neurohypophyseal nonapeptide oxytocin (OXT) has established functions in parturition, lactation, appetite, and social behavior. We have shown that OXT has direct actions on the mammalian skeleton, stimulating bone formation by osteoblasts and modulating the genesis and function of bone-resorbing osteoclasts. We deleted OXT receptors (OXTRs) selectively in osteoblasts and osteoclasts using <i>Col2.3Cre</i> and <i>Acp5Cre</i> mice, respectively. Both male and female <i>Col2.3Cre</i>^<i>+</i>:<i>Oxtr</i>^<i>fl/fl</i> mice recapitulate the low-bone mass phenotype of <i>Oxtr</i>^<i>+/-</i> mice, suggesting that OXT has a prominent osteoblastic action in vivo. Furthermore, abolishment of the anabolic effect of estrogen in <i>Col2.3Cre</i>^<i>+</i>:<i>Oxtr</i>^<i>fl/fl</i> mice suggests that osteoblastic OXTRs are necessary for estrogen action. In addition, the high bone mass in <i>Acp5Cre</i>^<i>+</i>:<i>Oxtr</i>^<i>fl/fl</i> mice indicates a prominent action of OXT in stimulating osteoclastogenesis. In contrast, we found that in pregnant and lactating <i>Col2.3Cre</i>^<i>+</i>:<i>Oxtr</i>^<i>fl/fl</i> mice, elevated OXT inhibits bone resorption and rescues the bone loss otherwise noted during pregnancy and lactation. However, OXT does not contribute to ovariectomy-induced bone loss. Finally, we show that OXT acts directly on OXTRs on adipocytes to suppress the white-to-beige transition gene program. Despite this direct antibeiging action, injected OXT reduces total body fat, likely through an action on OXT-ergic neurons. Consistent with an antiobesity action of OXT, <i>Oxt</i>^<i>-/-</i> and <i>Oxtr</i>^<i>-/-</i> mice display increased total body fat. Overall, the actions of OXT on bone mass and body composition provide the framework for future therapies for osteoporosis and obesity.