Deletion of the clock gene Bmal2 leads to alterations in hypothalamic clocks, circadian regulation of feeding and energy balance.

BMAL2 (ARNTL2) is a paralog of BMAL1 that can form heterodimers with the other circadian factors CLOCK and NPAS2 to activate transcription of clock and clock-controlled genes. To assess a possible role of Bmal2 in the circadian regulation of metabolism, we investigated daily variations of energy metabolism, feeding behavior, and locomotor behavior, as well as ability to anticipate restricted food access in male mice knock-out for Bmal2 (B2KO). While their amount of food intake and locomotor activity were normal compared to wild-type mice, B2KO mice displayed increased adiposity (1.5-fold higher) and fasted hyperinsulinemia (4-fold higher) and tended to have lower energy expenditure at night. Impairment of the master clock in the suprachiasmatic nuclei was evidenced by the shorter free-running period (-14 min/cycle) of B2KO mice compared to wild-type controls, and by a loss of daily rhythmicity in expression of intracellular metabolic regulators (e.g. , Lipoprotein lipase and Uncoupling protein 2 ). The circadian window of eating was longer in B2KO mice. The circadian patterns of food intake and meal numbers were bimodal in control mice, but not in B2KO mice. In response to restricted feeding, food-anticipatory activity was almost prevented in B2KO mice, suggesting altered food clock that controls anticipation of food availability. In the mediobasal hypothalamus of B2KO mice, expression of genes coding orexigenic neuropetides (including Neuropeptide y and Agouti-Related Peptide ) was down-regulated, while Lipoprotein lipase expression lost its rhythmicity. Together, these data highlight that BMAL2 has major impacts on brain regulation of metabolic rhythms, sleep-wake cycle and food anticipation. Significance statement Circadian misalignment is now recognized as a condition triggering metabolic disorders. Using a combination of behavioral, physiological and molecular approaches in the hypothalamus, we report here that ablation of Bmal2 impairs function of hypothalamic clocks, modifies temporal distribution of food intake and energy expenditure, and leads to increased adiposity. These findings highlighting that close interactions between circadian rhythmicity and metabolic pathways are dysfunctional in the absence of Bmal2 , and reveal that the transcription factor BMAL2 plays a role in the brain regulation of circadian clocks and energy metabolism. Accordingly, this work provides new evidence that altered circadian rhythmicity can be involved in the etiology of metabolic diseases.