Establishing the New Zealand obese mouse as a model for weight-cycling in polygenic obesity

Effective treatment of obesity has two components: body weight (BW) loss and BW loss maintenance. Weight loss results from a negative energy balance in which total energy expenditure (TEE, kcal/day) exceeds energy intake (kcal/day). Sustained negative energy balance triggers a compensatory reduction in the largest component of TEE—resting metabolic rate (RMR, kcal/day). A reduced RMR contributes to BW loss plateau and increases susceptibility to BW regain. This results in weight-cycles—a process by which a person repeatedly loses and regains BW. The mechanism behind sustained reduction of RMR must be elucidated to address this barrier to BW loss maintenance. The New Zealand obese (NZO) mouse is a polygenic model of obesity which replicates the genetic complexity as well as two prominent behaviors that promote human obesity: hyperphagia and physical inactivity. The objective of this study was to develop a protocol to replicate a weight-cycle in NZO mice and assess their viability as a model of weight-loss induced reductions in energy expenditure. We hypothesized that weight-reduced NZO mice would display a sustained reduction in TEE and RMR. To test this, we provided 8-week old female NZO mice (n=16) with ad libitum low fat diet (LFD, Research Diets D12450Ki) for 12 weeks, which induced obesity. Male NZO mice develop severe diabetes between 12-14 weeks of age, so it was not feasible to include males in this preliminary study. At obesity, mice were assigned to one of two groups each with equivalent adiposity indices (fat mass/lean mass, t-test, p > 0.05): 1) weight-cycled mice (n=9) underwent a 40% caloric reduction to achieve a 20% reduction in BW and 2) control mice (n=7) received continuous ad libitum LFD. Following 10 weeks of BW loss maintenance, ad libitum LFD was restored for 4 weeks to facilitate BW regain. Total energy expenditure was measured using Sable Promethion indirect calorimetry cages and body composition was measured via EchoMRI at five time points: baseline, peak of obesity, post BW-loss, post BW-loss maintenance, and post BW-regain. We used a linear mixed model to generate estimates for the value of TEE and RMR after adjusting for repeated measures, lean mass, and the interaction between treatment groups and time points. Post BW-loss, weight-cycled mice had significantly lower adjusted TEE and RMR compared to peak obesity (estimated marginal means, ΔTEE= 3.07 kcal/day, p< 0.01; ΔRMR= 3.26 kcal/day, p< 0.0001). Post BW-regain, weight-cycled NZO mice had significantly lower adjusted TEE and RMR compared to mice that remained obese throughout the study (estimated marginal means, post BW-regain adjusted TEEcontrol - TEEweight-cycled = 2.38 kcal/day, p= 0.02; post BW-regain adjusted RMRcontrol - RMRweight-cycled = 1.34 kcal/day, p= 0.03). Taken together, these data suggest that the protocol used resulted in weight-cycling in NZO mice. The NZO mice recapitulate the suppressed TEE and RMR observed after BW loss, as observed in humans. These results support the viability of using NZO mice in future studies of energy expenditure and weight-cycling. This work was funded by the following grants: NIH R01DK134468, VA BLRD I01RX003901, and VA RRD I01RX003901. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.