Effects of combined oxytocin and beta‐3 receptor agonist (CL 316243) treatment on body weight and adiposity in high fat diet‐induced obese rats

Abstract

Previous studies have indicated that oxytocin (OXT) reduces body weight in high fat diet (HFD)‐induced obese (DIO) rodents, nonhuman primates and obese humans through reductions in energy intake and increases in energy expenditure. Recent findings support a role for brown adipose tissue (BAT) thermogenesis in OXT‐elicited weight loss as chronic administration 1) increases interscapular brown adipose tissue (IBAT) temperature (TIBAT) in DIO rats during a period that coincides with the OXT’s initial weight‐lowering effect and 2) upregulates beta‐3 receptor mRNA expression in IBAT. Based on these findings, we hypothesized that OXT would enhance the effectiveness of the beta‐3 receptor agonist, CL 316243, to evoke weight loss in DIO rats. To test this hypothesis, rats were fed a HFD for approximately 7 months prior to being implanted with a fourth ventricular (4V) cannula (as a strategy to target hindbrain OXT receptors), 28‐day minipump that infused OXT (16 nmol/day) or vehicle (VEH; saline) and temperature transponder underneath an IBAT depot. DIO rats were subsequently matched for body weight and adiposity, as well as OXT‐elicited reductions in body weight during the first week of the infusion period, prior to receiving 1x daily injections of VEH (sterile water, IP) or CL 316243 at a dose (0.5 mg/kg, IP) found to stimulate TIBAT in a separate group of DIO rats (P<0.05; N=4–5/group). Daily energy intake, TIBAT and body weight 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). Preliminary data indicate that OXT (16 nmol/day) alone and CL 316243 alone tended to reduce body weight by approximately 6.5±2.2% (0.05<P<0.1) and 4.7±0.9% (P<0.05), respectively (N=4–5/group), relative to pre‐infusion baseline. However, the combination of OXT and CL 316243 produced a more pronounced reduction in body weight (13.9±1.6%; P<0.05) compared with either treatment alone (N=4–5/group). Weight loss in response to the combination treatment (OXT and CL 316243) was the result of a sustained reduction of body fat adiposity stores (P<0.05) without any change in lean mass (P=NS). These effects were associated with reductions in energy intake (P<0.05) suggesting that decreased energy intake contributes, in part, to the effectiveness of OXT and CL 316243 to reduce body weight. Furthermore, repeated 1x daily administration of CL 316243 alone (0.05<P<0.1), and in combination with OXT (P=0.1), tended to elevate TIBAT at 0.5‐h post‐injection relative to vehicle treatment throughout the entire treatment period (N=4–5/group). Together, these findings support the hypothesis that the combination of OXT and a beta‐3 agonist produces an additive effect to evoke weight loss and body adiposity in DIO rats by reducing energy intake and increasing BAT thermogenesis. Support or Funding Information National Institutes of Health R01 DK115976 and VA Merit Review Award BX004102