Abstract
OBJECTIVE: This study sought to determine whether the drive to regain weight following weight loss was truly long-lived in mice. METHODS: We generated a model of reduced dietary obesity (ReDO) whereby male mice with diet-induced obesity (DIO) mice were calorically restricted until weight matched to control mice, and then after a 24-hour food assessment period were pair-fed relative to control mice. We subsequently generated ReDO mice that, after CR were pair-fed relative to control mice for 0, 8, or 28 days, or chronically. Body weight, food intake, and select metabolic parameters were measured, along with whole hypothalamic Pomc gene expression. RESULTS: ReDO mice in both experiments exhibited hyperphagia following CR, while a persistent form of hyperphagia was detected in ReDO_8d and ReDO_28d mice relative to control and chronically pair-fed mice. 4-week initial weight gain was predictive of the degree of weight regain across ReDO_8 and ReDO_28 mice. CONCLUSIONS: ReDO mice exhibit a long-lived form of hyperphagia and an apparent drive to reclaim an upwardly shifted body weight set point. There was considerable variability with regard to ReDO_8 and ReDO_28 body weight regain which was correlated with the of initial degree of 4-week body-weight gain when first exposed to a high-fat diet. This study showcases the perdurance of weight loss-associated hyperphagia and introduces a prognostic tool for identifying mice that are prone towards weight regain, while setting the stage for future inquiries into the neurobiological basis of persistent hunger following weight loss owed to a dietary intervention in mice.