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Funding was provided by NIH grants P01NS074969 (D.M.H.)
and 5K08NS079405 (E.S.M.), and a New Investigator Research
Grant from the Alzheimer’s Association (E.S.M.). E.S.M. has
received consulting fees from Eisai, Inc. D.M.H. cofounded and is
on the scientific advisory board of C2N Diagnostics and consults
for Genentech, AbbVie, Eli Lilly, Neurophage, and Denali.
Circadian physiology of metabolism
A majority of mammalian genes exhibit daily fluctuations in expression levels, making
circadian expression rhythms the largest known regulatory network in normal physiology.
Cell-autonomous circadian clocks interact with daily light-dark and feeding-fasting cycles
to generate approximately 24-hour oscillations in the function of thousands of genes.
Circadian expression of secreted molecules and signaling components transmits timing
information between cells and tissues. Such intra- and intercellular daily rhythms
optimize physiology both by managing energy use and by temporally segregating
incompatible processes. Experimental animal models and epidemiological data indicate
that chronic circadian rhythm disruption increases the risk of metabolic diseases.
Conversely, time-restricted feeding, which imposes daily cycles of feeding and fasting
without caloric reduction, sustains robust diurnal rhythms and can alleviate metabolic
diseases. These findings highlight an integrative role of circadian rhythms in physiology
and offer a new perspective for treating chronic diseases in which metabolic disruption
is a hallmark.
Atransient rise in blood sugar after a meal indicates metabolic health. A larger meal produces a larger spike, whereas a fat- or protein-rich meal produces a muted spike (compared with a normal meal of
equivalent caloric content). Physiological responses to what and how much we eat represent the foundation for basic and translational
science aimed at preventing and treating obesity, diabetes, and metabolic diseases, which
together afflict close to a billion people worldwide. However, the timing of food consumption independent of total caloric intake and
macronutrient quality has emerged as a critical factor in maintaining metabolic health. For
instance, when healthy adults eat identical meals
at breakfast, lunch, or dinner, the postprandial
glucose rise is lowest after breakfast and highest
after dinner (1), as if the dinner were twice the
size of the breakfast. In addition, when healthy
adults are given a constant glucose infusion
over 24 hours, glycemia rises at night and falls
around dawn (1), indicating that in addition
to what and how much we eat, when we eat
helps determine the physiological response to
Daily rhythms in nutrient use were first doc-
umented almost 40 years ago in cells of the
master circadian pacemaker located in the hy-
pothalamic suprachiasmatic nucleus (SCN). Ex-
periments in rats fed 14C-labeled deoxyglucose
during their habitual (nighttime) feeding period
showed that entry of glucose into the SCN was
almost negligible, whereas during the day, radio-
labeled glucose was readily detected (2). Such
glucose uptake rhythms were sustained even in
the absence of light cues. In all, this elegant
experiment proved the existence of a circadian
rhythm in nutrient demand and/or uptake in
tissues. Over the next decades, research into cir-
cadian rhythms has shown that daily rhythms
in the function of numerous genes prime the
organism to assimilate nutrients, to mobilize
these nutrients for various functions, and to dis-
card metabolic waste at specific times of the
24-hour day (3, 4). Whereas circadian rhythms
generally refer to ~24-hour oscillations that occur
in the absence of external timing cues, daily or
diurnal rhythms apparent during normal living
conditions emerge from interactions between
the internal circadian clock and timing cues,
which include light and food. Accordingly, a
consistent daily pattern of eating and fasting
maintains normal circadian physiology, where-
as frequent disruptions in daily activity-rest and
eating-fasting rhythms (as occurs in shiftwork)
(5) or genetic disruption of circadian clock in
rodents predisposes to metabolic diseases (6).
Certain diet regimens (e.g., the frequent eating
of energy-dense food) and aging can dampen
these daily oscillations and predispose one to
metabolic diseases. Therefore, understanding the
diurnal physiology of metabolism at a mech-
anistic level could potentially reveal lifestyle and
therapeutic interventions for preventing and
treating metabolic diseases.
Cell-autonomous circadian oscillator
In animals, the core mechanism that gives rise
to circadian oscillations is a cell-autonomous
transcriptional-translational feedback loop (T TFL)
present in most cells. The transcription factors
CLOCK (or NPAS2) and BMAL1 bind as heterodimers to cis-acting E boxes in the promoters
of their own repressors—Cryptochrome (Cry1
and Cry2) and Period (Per-1, -2, and -3)—and
of the nuclear hormone receptors Rev-erb (-a
and -b), and Ror (-a, -b, and -g). ROR and REV-ERB drive rhythmic Bmal1 gene expression by
respectively acting so as to activate and repress
its expression through RRE elements present
in its promoter (Fig. 1) (7). REV and ROR proteins also affect the expression of Cry1, delaying its expression several hours relative to
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