INSIGHTS | PERSPECTIVES1164 4 SEPTEMBER 2020 • VOL 369 ISSUE 6508 sciencemag.org SCIENCEPHYSIOLOGYSexual dimorphism in body clocks
Sexual dimorphism in chronobiology has implications for the health of our 24-hour society
By Seán T. Anderson and Garret A. FitzGeraldC
ircadian rhythms, or the body clock,
confer temporal structure on hu-
man behavior and physiology to
align homeostatic processes with an-
ticipated changes in the environment.
Disruption of these rhythms can influ-
ence health and well-being. Chronobiological
research has often failed to consider how
this temporal organization may be affected
by sex. The few studies that do consider how
these rhythms differ between sexes suggest a
dimorphism that warrants further investiga-
tion. Recent findings from both humans and
animal models illustrate how the systems
that generate circadian rhythms diverge be-
tween the sexes, which has potential conse-
quences for health and resilience to changes
in sleep pattern.
Circadian rhythms are generated centrally
by a transcription-translation feedback loop
in the suprachiasmatic nucleus (SCN) of the
hypothalamus. The proteins brain and mus-
cle ARNT-like 1 (BMAL1) and circadian loco-
motor output cycles kaput (CLOCK) form the
positive arm of the molecular clock. This het-
erodimer promotes the expression of its own
repressors period 1 (PER1) and PER2 and
cryptochrome 1 (CRY1) and CRY2. Inhibition
of the BMAL1-CLOCK heterodimer in turn
suppresses PER1/2 and CRY1/2, allowing
BMAL1 and CLOCK expression levels to rise
once again. This cycle takes roughly 24 hours,
forming the core molecular clock. Photic
(light) input to the SCN can also induce the
expression of PER1/2 and CRY1/2 and repre-
sents the main stimulus that entrains the cir-
cadian rhythm to the day-night cycle.
Estrogen and androgen receptors are
expressed in a sexually dimorphic pattern
along the central neuronal circuitry regulat-
ing circadian rhythms and show rhythmic
expression in peripheral tissues ( 1 ) (see the
figure). Early studies of hamsters placed into
constant darkness observed shorter free-run-
ning periods among females, indicating that
their core molecular clock machinery oscil-
lates faster than that of males ( 2 ). Females
also showed significantly earlier onset of
activity and responded differently to stimuli
that shift the intrinsic timing of the circa-dian clock. It was subsequently reported that
in female mice, behavioral rhythms were
more consolidated, had higher amplitudes
(difference between the peak and the mean
24-hour activity level), and peaked earlier in
the day than in males.
Recently, large-scale collections of remote
sensing data have enabled the observation of
natural activity patterns in humans. A study
of 91,105 participants in the UK Biobank re-
vealed that males were more likely to have
low-amplitude behavioral rhythms than fe-
males ( 3 ). This can be due to increased ac-
tivity at night or decreased activity in the
daytime, reflecting the conservation of more
robust oscillations in activity rhythms among
females. Females also spend more time
asleep, spend more of their time in slow-wave
(deep) sleep, and are more resilient to noctur-
nal disturbances than males ( 4 ).
A study of chronotype, or day-night pref-
erence, in more than 53,000 individuals
highlighted how age and sex both substan-
tially affect the timing of circadian rhythms
( 5 ). Whereas children are typically morn-
ing types regardless of sex, after puberty
males tend to be more evening oriented
than females, mirroring the findings in
animal models. The hormonal changes as-
sociated with menopause add extra com-
plexity to the aging process for females;
chronotypes converge during middle age as
both sexes become more morning oriented.
New efforts to study rhythmic changes out-
side the laboratory are characterizing the
“chronobiome”—a phenotype incorporating
the in-depth assessment of thousands of
time-of-day signals across diverse physio-
logical readouts that will clarify the array of
sexually dimorphic rhythms in humans ( 6 ).
Forced desynchrony protocols, in which
the sleep-wake cycle is desynchronized from
endogenous circadian rhythms, have also
been used to examine how key parameters
of circadian rhythmicity differ between the
sexes. One such study found that females had
higher-amplitude rhythms in their perfor-
mance on cognitive tests that assess working
memory, attention, effort, mood, and sleepi-
ness ( 7 ). Together with a higher-amplitude
rhythm in the sleep-promoting hormone
melatonin, this increased amplitude in cog-
nitive processing resulted in females experi-
encing a greater deficit during the biological
night compared with their peak functioning
time. Although higher amplitudes (peaks-to-trough ratio) are typically beneficial because
they allow for greater compartmentalization
of different homeostatic processes, in this ex-
ample a higher amplitude may be detrimen-
tal when females must be awake at night.
The expansion of sequencing efforts has
revealed how sexual dimorphism in chrono-
biology extends into oscillations of the tran-
scriptome, metabolome, and microbiome.
In a study of transcriptional and metabolic
rhythmicity in mice, 71% of liver transcripts
showed conserved rhythmicity between
males and females, 9% of genes showed
rhythmicity only in males, and 16% of genes
showed rhythmicity only in females ( 8 ). A
further 4% were rhythmically expressed in
both sexes but differed in their phase or am-
plitude, including several core clock genes
that showed higher-amplitude oscillations in
females. Only 55% of liver metabolites and
29% of serum metabolites had conserved
oscillations between sexes. Germ-free mice,
which have no gut microbiota, had dimin-
ished sexual dimorphism in their gene ex-
pression and circadian rhythms. Female mice
have greater diurnal oscillations in their total
bacterial load, and genetic disruption of the
host clock machinery affects gut microbiota
differentially in male and female mice ( 9 ).
Thus, the gut microbiota can contribute to
the orchestration of circadian rhythms dur-
ing development and adulthood; this contri-
bution is likely to differ between the sexes.
A clinical study comparing the metabolic
response to misalignment between sexes
tracked energy consumption and expendi-
ture during 8 days on a normal schedule
and then for 8 days featuring a 12-hour
phase shift, achieved through an 8-hour
wake opportunity followed by a 4-hour
sleep opportunity on the fourth day ( 10 ).
Circadian misalignment increased the hun-
ger hormone ghrelin and decreased the sa-
tiety hormone leptin in females, which was
accompanied by decreased feelings of full-
ness. Female participants’ carbohydrate oxi-
dation rate and respiratory quotients also
dropped after misalignment, whereas their
energy expenditure and lipid oxidation rate
increased. Conversely, males showed an in-
crease in leptin and no change in ghrelin af-
ter the phase shift. They reported increased
cravings for energy-dense foods, which is
inconsistent with their hormone changes,
and showed no difference in energy utiliza-
tion. This switch in energy utilization mayInstitute for Translational Medicine and Therapeutics,
Perelman School of Medicine, University of Pennsylvania,
Philadelphia, PA, USA. Email: [email protected]Published by AAAS