Metabolic changes following relief of upper airway obstruction promote rebound weight gain in mice

The mechanisms driving weight gain after removal of upper airway obstruction and restoration of normal respiration remain unclear. We examined how increased respiratory loading alters energy balance, body weight, and metabolism in mice during and after airway obstruction (AO). Increased work of breathing in AO is associated with increased sympathetic tone and induced weight loss via a negative energy balance. Following obstruction removal, persistent sympathetic activation, increased thermogenesis, and hyperphagia drive a positive energy balance and weight gain despite normalized respiration. Pharmacological β3-adrenergic blockade with L-748,337 and chemical sympathectomy using 6-hydroxydopamine restored energy balance but only partially reversed weight gain and glucose intolerance. Brown adipose tissue exhibited robust expression of uncoupling protein 1, while inguinal white adipose tissue showed elevated thermogenic transcriptional markers without complete browning, indicating complex interactions between sympathetic regulation and adipose remodeling. Our findings reveal, for the first time, that AO induces a persistent metabolic memory that limits full recovery, reflecting a predominantly anabolic trajectory driven by mechanometabolic coupling. Our results support the use of lifestyle and endocrine interventions to restore healthy metabolism after relief of chronic upper airway loading.