A human missense variant in BSX decouples circadian behaviour from metabolic rhythmicity while preserving lifespan in mice

Abstract Mammalian circadian organisation is orchestrated by a light-entrained master pacemaker in the suprachiasmatic nucleus (SCN) and SCN-independent, food- and metabolism-responsive oscillators in the brain and periphery; feeding can entrain these systems, enabling anticipation of feeding time. Here, we show that a human missense variant (Q159K) in the homeodomain of the brain-specific transcription factor BSX causes profound loss of circadian behavioural rhythms and food anticipatory activity (FAA) in mice. Whole-brain imaging reveals failure of the compact dorsomedial hypothalamus (DMHc) to form and the absence of histaminergic neurons in the tuberomammillary nucleus (TMN) in BsxQ159K/Q159K mice. Consequently, under light-dark (LD) and constant darkness (DD), sleep-wake cycles and circadian locomotor rhythmicity are profoundly lost, whereas total wake time and spontaneous locomotor activity are preserved, with daily caloric intake substantially shifted from the dark to the light cycle. Therefore, in DD, metabolic recordings reveal a rhythmic respiratory exchange ratio (RER) pattern that differs substantially from that of wild-type mice and is markedly attenuated under LD conditions. In addition, BsxQ159K/Q159K mice lack FAA during restricted feeding and fail to increase locomotor activity upon food deprivation. Despite the loss of circadian behavioural rhythms and altered daily feeding behaviour, BsxQ159K/Q159Kmice maintain metabolic homeostasis, a lean body composition into advanced age, and a normal lifespan under ad libitum feeding and controlled LD. These findings provide genetic evidence that circadian organization is not universally required for metabolic homeostasis, suggesting instead that circadian rhythmicity is an adaptive feature advantageous primarily under diurnal conditions. Competing Interest Statement I.S.F. has consulted for a number of companies involved in the development of weight loss drugs (Rhythm Pharmaceuticals, Eli Lilly, Sanofi, Astra Zeneca, Nodthera and Novo Nordisk). The other authors declare that they have no conflict of interest.