Misaligned Feeding Uncouples Daily Rhythms Within Brown Adipose Tissue and Between Peripheral Clocks

Abstract

Extended consumption of food into the rest period perturbs the phase relationship between circadian clocks in the periphery and the brain and has deleterious effects on health through mechanisms that remain incompletely understood. Beyond the liver, how other metabolic organs respond to hypocaloric diet (amount and timing) is largely unexplored. We investigated how feeding time impacts circadian gene expression in white (eWAT) and brown (BAT) adipose tissues in comparison to liver and hypothalamus. With automated feeders, we restricted food to either daytime or nighttime in C57BL/6J male mice, with or without caloric restriction. We found tissue-specific changes in the phase and amplitude of genomewide mRNA expression patterns induced by daytime feeding in liver and eWAT, whereas BAT exhibited resilience and remained predominately entrained to the light-dark cycle, similar to hypothalamus. We uncovered an internal split within the BAT in response to conflicting environmental cues, displaying inverted oscillations on a subset of metabolic genes without modifying its local core circadian machinery. Integrating intra- and inter-tissue disruptions in circadian clock-controlled transcriptional networks with metabolic outcomes may help elucidate the mechanism underlying the health burden of eating at the wrong time of the day.

Note:

Funding Information: Research was supported by the Howard Hughes Medical Institute (J.S.T.) and NIH/NIA grant R01 AG045795 (J.S.T. and C.B.G.), NIH/NIGMS R35 GM127122 (C.B.G), NIH/NIGMS R00GM132557 (F.R-F.), Milky Way Research Foundation MWRF210823 (J.S.T and C.B.G), NIDDK/1R01DK132647- 01 (J.B.), NIDDK/R01DK090625 (J.B.), NIDDK/R01DK127800 (J.B.), NIA/R01AG065988 (J.B.), NIDDK/F32DK122675 (C.H.).

Declaration of Interests: The authors declare no competing interests.

Ethical Approval Statement: The Institutional Animal Care and Use Committee (IACUC) of the University of Texas Southwestern Medical Center (AP 100925) approved animal protocol.

Keywords: Circadian clocks, brown adipose tissue, liver, mouse behavior, misaligned feeding, dietary interventions, caloric restriction, time-restricted feeding