Circadian clock, nutrient quality, and eating pattern tune diurnal rhythms in the mitochondrial proteome

Abstract

Life on our planet evolved under predictable light:dark cycles and dependent rhythms of nutrient availability. Accordingly, a vast majority of living organisms, ranging from archaea to humans, have adopted molecular mechanisms to anticipate and respond to daily metabolic rhythms. Central to this timing mechanism in mammals is a cell-autonomous molecular circadian oscillator based on transcription–translation feedback loops. CLOCK, BMAL, and ROR classes of transcriptional activators, and CRY, PER, and REV-ERB classes of repressors act in concert to generate daily rhythms in their own protein levels as well as thousands of target genes (1). The circadian oscillator in the hypothalamic suprachiasmatic nucleus (SCN) functions as a master pacemaker by imposing a daily rhythm on activity–rest and feeding–fasting cycles. The SCN also responds to changes in ambient light in a time-of-day–specific manner (2) that ultimately leads to the activity–rest cycle adapting to seasonal changes in day length. Time-series transcriptome studies in the SCN (2) and liver (3) of WT mice fed a standard diet demonstrated daily rhythms in thousands of transcripts in a tissue-specific manner. These rhythms in liver arising from synergistic action of both the cell-autonomous circadian clock and feeding–fasting driven molecular programs (4) are thought to temporally coordinate metabolism to the appropriate time of the day to sustain metabolic homeostasis. Clock-deficient mice lack both cell-autonomous circadian oscillations and feeding–fasting rhythms, compromising transcriptional rhythms in the liver. As a result, these mice exhibit disrupted metabolic homeostasis, giving rise to metabolic diseases (5). Furthermore, in WT mice chronic ad libitum feeding of a high-fat diet dampens the daily rhythm of both the molecular oscillator and feeding–fasting cycles, leading to metabolic diseases (6). An imposed feeding–fasting rhythm in these high-fat fed mice can prevent or reverse metabolic diseases (7, 8). Taken together, these observations have highlighted the paramount significance of circadian rhythms … [↵][1]1To whom correspondence should be addressed. Email: satchin{at}salk.edu. [1]: #xref-corresp-1-1