Chronic hindbrain administration of oxytocin elicits weight loss in high fat diet‐induced obese mice

Abstract

Previous studies indicate that oxytocin (OXT) reduces body weight (BW) in high fat diet (HFD)‐induced obese (DIO) rodents through mechanisms that may involve an enhanced ability of OXT to reduce food intake as well as increase energy expenditure. We have previously demonstrated that chronic fourth ventricular (4V) infusions of OXT (as a strategy to target hindbrain OXT receptors) evokes weight loss in DIO rats. Based on these findings, we hypothesized that increased hindbrain OXT signaling would elicit BW loss in DIO mice maintained on a HFD (60% kcal from fat). To test this hypothesis, age‐matched mice were fed HFD or chow for 4 months prior to implantation of 4V cannulas and 28‐day minipumps that infused OXT (16 nmol/day) or vehicle (VEH; saline). Food intake and BW were tracked for 28 days. Body composition was assessed immediately prior to VEH or OXT treatment and near treatment completion using Quantitative Magnetic Resonance (QMR; EchoMRI 4‐in‐1). OXT preferentially reduced BW by approximately 4.5±1.4% in DIO mice relative to chow‐fed mice (P<0.05; N=9–11/group). OXT‐elicited BW loss was associated with reductions in body adiposity, adipocyte size [inguinal white adipose tissue (IWAT)] and serum leptin (P<0.05). These effects were attributed, in part, to an enhanced effect of OXT to reduce energy intake in DIO mice (P<0.05) at a dose that was not associated with increased kaolin intake (pica behavior; P=NS). While reductions in energy intake contribute to OXT’s effects on BW, chronic 4V OXT appeared to increase uncoupling protein‐1 (UCP‐1) expression in IWAT (0.05<P<0.1; N=9–10/group) suggesting that OXT may also stimulate beiging of WAT. To assess OXT‐elicited changes in brown adipose tissue (BAT) thermogenesis, we examined the effects of acute 4V injections of OXT on interscapular BAT temperature (TIBAT) in mice. Consistent with our previous findings in rats, preliminary data in mice indicate that acute 4V injections of a lower dose (1 μg) appeared to elevate TIBAT at 0.5‐ (P=0.1) and 1.25‐h post‐injection (P=0.15) while a higher dose (5 μg) appeared to elevate TIBAT at 1.5‐ (P<0.05) and 4‐h (0.05<P<0.1) post‐injection (N=4/group). Together, these findings support the hypothesis that chronic hindbrain OXT treatment evokes sustained weight loss in DIO mice by reducing energy intake and increasing BAT thermogenesis and beiging of WAT at a dose that is not associated with visceral illness. Support or Funding Information National Institutes of Health R01 DK115976 and VA Merit Review Award BX004102