The central clock suffices to drive the majority of circulatory metabolic rhythms

Abstract

Life on Earth anticipates recurring 24-h environmental cycles via genetically-encoded molecular clocks active in all mammalian organs. Communication between these clocks is believed to control circadian homeostasis. Metabolism can be considered a form of inter-tissue communication language that results in temporal coordination of systemic metabolism between tissues. Here we characterize the extent to which clocks in different organs employ this means of communication, an area which remains largely unexplored. For this, we analysed the metabolome of serum from mice with tissue-specific expression of the clock gene Bmal1. Notably, having functional hepatic and muscle clocks can only drive a minority (13%) of the oscillating metabolites in circulation. Conversely, limiting Bmal1 expression to Syt10-expressing neurons (which are enriched in the suprachiasmatic nucleus [SCN], the master pacemaker that regulates circadian rhythms) restores rhythms to 57% of circulatory metabolites and 28% of liver transcripts, and rescues glucose intolerance. Importantly, these parameters were also restored in clock-less mice upon rhythmic feeding, indicating that the central clock mainly regulates metabolic rhythms via behavior. These findings explicate the circadian communication between tissues and highlight the importance of the central clock in governing those signals.

Interrogating Metabolic Interactions Between Skeletal Muscle and Liver Circadian Clocks In Vivo

“…In summary, we reveal tissue-specific differences in the autonomous capacities of peripheral clocks, showing that the muscle clock is less autonomous than the liver clock regarding both the robustness of core clock oscillations and extent of rhythmic transcriptional output. Combined with our reports on liver and skin ( 4 , 5 , 7 , 8 , 25 ), this reveals a differential dependence of each peripheral tissue clock on inputs from the rest of the clock network for full transcriptional function ( 26 ). Even though rhythmic transcriptional output of the autonomous muscle clock is low, we still find restoration of aspects of glucose metabolism, revealing a core autonomous function of the muscle clock and supporting previous findings from muscle-specific Bmal1-KO mice which demonstrated necessity of the muscle clock for efficient glucose uptake ( 12 , 13 ).…”

“…1f). Due to loss of brain clock function (7), and as reported previously for Liver-RE mice (4,8,9), KO and RE mice lacked robust 24h-rhythms of food intake and displayed severely blunted dark phase locomotor activity under 12h light: 12 dark conditions and ad libitum feeding (Fig. 1c).…”

“…For example, though pancreas BMAL1 regulates glucose-stimulated insulin secretion from beta cells and is a key peripheral node of the clock system with respect to feeding-fasting behavior ( 27 , 28 ), night feeding of Liver+Muscle-RE mice induced a serum insulin rhythm and rescued systemic glucose tolerance even in the absence of pancreas BMAL1. In addition, central clock reconstituted mice also exhibit improved glucose tolerance, at least in part due to reinstated feeding-fasting behavior ( 7 ). Considering then all evidence, it is likely that in the wildtype setting, liver, muscle and pancreas clocks, as well as the endogenous feeding rhythm set by hypothalamic clocks, constitute layers of regulation on daily systemic glucose homeostasis that work in concert.…”

Epidermal clock integration and gating of brain signals guarantees skin homeostasis

“…1C and fig S1, A and B). Importantly, BMAL1 expression in the SCN was sufficient to drive daily cycles of activity, feeding and metabolism (see accompanying article, ( 16 )), indicating that the SCN clock was functioning correctly.…”

“…However, these approaches cannot isolate or allow interrogation of the individual clock-driven interactions between signaling nodes, in turn obscuring the specific aspects of daily physiology they drive, and the mechanisms by which they do so. To circumvent this, we reconstructed a minimal clock network in vivo constituting only the central clock (brain) (see accompanying article, ( 16 )) and a single peripheral clock in the interfollicular epidermis. This approach allowed us to dissect the specific contributions of key signaling nodes within the network in driving a tissue’s daily rhythmic physiology.…”