Rlim coordinates diurnal regulation of food intake and thermogenesis

Abstract Energy homeostasis in mice is maintained through coordinated activity among hypothalamic nuclei that regulate food intake and thermogenesis. These processes must adapt to the sleep–wake cycle, yet the underlying pathways, cell types, and molecular mechanisms governing their diurnal regulation remain poorly understood. We show that mice lacking the E3 ubiquitin ligase Rlim are lean and resistant to diet-induced obesity, owing to reduced food intake and enhanced brown adipose tissue (BAT) thermogenesis. We identify GABAergic neurons in the suprachiasmatic nucleus (SCN)—components of the central circadian clock—as mediators of these effects. Specifically, Rlim in RIP-Cre+ neurons governs daily thermogenic rhythms, while Rlim in vasoactive intestinal peptide (VIP)-expressing neurons modulates diurnal feeding behavior. Thus, Rlim is a key regulator of diurnal rhythms controlling energy balance. Competing Interest Statement The University of Massachusetts Chan Medical School holds a patent Targeting Rlim to modulate weight and obesity that covers the treatment of weight-related disorders, by modulating Rlim levels and/or activity (patent application # US 17/760,504, Publication number: 20220340903) (I.B., F.W.).