The circadian clock components CRY1 and CRY2 are necessary to sustain sex dimorphism in mouse liver metabolism.
In mammals, males and females exhibit anatomical, hormonal, and metabolic differences. A major example of such sex dimorphism in mouse involves hepatic drug metabolism, which is also a noticeable target of circadian timekeeping. However, whether the circadian clock itself contributes to sex-biased metabolism has remained unknown, although several daily output parameters differ between sexes in a number of species, including humans. Here we show that dimorphic liver metabolism is altered when the circadian regulators Cryptochromes, Cry1 and Cry2, are inactivated. Indeed, double mutant Cry1(-/-) Cry2(-/-) male mice that lack a functional circadian clock express a number of sex-specific liver products, including several cytochrome P450 enzymes, at levels close to those measured in females. In addition, body growth of Cry-deficient mice is impaired, also in a sex-biased manner, and this phenotype goes along with an altered pattern of circulating growth hormone (GH) in mutant males, specifically. It is noteworthy that hormonal injections able to mimic male GH pulses reversed the feminized gene expression profile in the liver of Cry1(-/-) Cry2(-/-) males. Altogether, our observations suggest that the 24-h clock paces the dimorphic ultradian pulsatility of GH that is responsible for sex-dependent liver activity. We thus conclude that circadian timing, sex dimorphism, and liver metabolism are finely interconnected.
Bur
Isabelle M
IM
CNRS, UMR 5203, Institut de Génomique Fonctionnelle and INSERM, U661 and Université Montpellier, 34094 Montpellier, France.
Cohen-Solal
Anne M
AM
Carmignac
Danielle
D
Abecassis
Pierre-Yves
PY
Chauvet
Norbert
N
Martin
Agnès O
AO
van der Horst
Gijsbertus T J
GT
Robinson
Iain C A F
IC
Maurel
Patrick
P
Mollard
Patrice
P
Bonnefont
Xavier
X
D000818:Animals; D040761:Biomimetic Materials / Q000494:pharmacology; D002940:Circadian Rhythm / Q000502:physiology*; D056931:Cryptochromes; D005260:Female; D005420:Flavoproteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D013006:Growth Hormone / Q000031:analogs & derivatives / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D010641:Phenotype; D012727:Sex Characteristics; D013739:Testosterone / Q000378:metabolism
C538963:CRY1 protein, human; C538966:CRY2 protein, human; C538964:Cry1 protein, mouse; C538967:Cry2 protein, mouse; D056931:Cryptochromes; D005420:Flavoproteins; D013739:Testosterone; D013006:Growth Hormone