Encapsulated Leptin-Producing Cells Facilitate Entrainment of Circadian Rhythms in Rodents and Nonhuman Primates

Both the timing and composition of food intake have gained recognition for their effects on circadian (daily) rhythms in mammals, however the mechanisms by which these effects are exerted are incompletely understood. The present studies focus on synchronization of circadian rhythms to the environmental light-dark cycle, particularly re-entrainment following a phase shift such as occurs with travel across time zones or shift work. To examine the role and therapeutic potential of the peptide hormone leptin in these effects, we create and characterize injectable leptin factories consisting of encapsulated human retinal pigment epithelium (RPE) cells engineered to constitutively produce leptin. Subcutaneous injections of these leptin factories result in sustained elevation of blood leptin over more than a day, and accelerate entrainment to both phase delays and phase advances. Leptin factory administration to diurnal cynomolgus macaques is safe and effectively reduced entrainment rate by approximately 1 day. In addition, capsule administration in cynomolgus macaques has no demonstrable adverse effects on sleep, increasing Non-Rapid Eye Movement sleep (NREM sleep) slow-wave energy. Taken together, these results implicate metabolic regulation as a novel approach to accelerating adaptation to changing schedules and suggest that leptin can be used to therapeutically decrease entrainment time.