The Circadian Clock Components CRY1 and CRY2 Are Necessary to Sustain Sex Dimorphism in Mouse Liver Metabolism

Abstract

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.Phenotypic differences between males and females of a given species exist from invertebrates to humans and cover various features including disease susceptibility and life span, for example. Although the anatomical and hormonal differences between sexes are well described, few genetic determinants are known to account for sexual dimorphism in mammals. Recent genome-wide studies on various mouse tissues showed that major differences in gene expression between males and females involve drug metabolism (1, 2), and among somatic organs, the sex-biased transcriptional activity is particularly high in the liver (3-5). These observations may provide insight into why many drugs exhibit a faster clearance in women as compared with men (6) but also underscore the importance of considering sex issues in studies on liver metabolism.Interestingly, liver activity also fluctuates along the light-dark cycle and is a noticeable target of circadian timekeeping (7-9). Both systemic cues and a circadian clock within hepatocytes are involved in daily oscillations of liver metabolism (10, 11). However, because most of these studies were focused on males exclusively, the possible interaction between circadian oscillators and sex dimorphism of hepatic activity is not documented.This prompted us to investigate whether circadian cogwheels could also be involved in the sexual dimorphism observed at the hepatic level. Indeed, several daily output parameters differ between sexes in a number of species, including humans (12)(13)(14), which may reflect the ability of the suprachiasmatic nuclei (SCN), 3 where the central pacemaker resides, to sense s...

High-fat diet-induced hyperinsulinemia and tissue-specific insulin resistance inCry-deficient mice

“…Food timing is known to have profound influences on obesity and metabolic dysfunction (3,22). However, although Cry1/2 Ϫ/Ϫ mice display arrhythmic feeding when fed standard chow, they remain lighter than controls and only develop obesity under HFD challenge (7). This highlights the importance of diet under conditions of circadian disruption, such as that seen with shift-working individuals.…”

“…Brd mice (7,10). To close this gap, the current study characterizes the response of Cry1/2 Ϫ/Ϫ mice to diet-induced obesity, providing mechanistic insight into the physiological anomalies seen under these conditions.…”

Sex and circadian modulatory effects on rat liver as assessed by transcriptome analyses

“…GCL is composed of a catalytic (GCLC) expressions of Gclc and Gclm were circadian-regulated in both sexes. In mice, the circadian clock components, Cry1 and Cry2, are suggested as a prerequisite for sustaining sex dimorphism in the liver metabolism (Bur et al, 2009). In human beings, sex dependency of circadian pharmacology has been observed in a Phase III clinical trial for chronomodulated therapy of metastatic colorectal cancer (Giacchetti et al, sexual dimorphism and the circadian timing system are generally interconnected in both humans and rodents.…”

“…Moreover, we have previously reported that the circadian rhythms of hepatic P450 activities in rats are obvious in males but not in females (Furukawa et al, 1999c). In mice, the circadian clock components, Cryptochrome 1 and 2 (Cry1 and Cry2), are suggested as a prerequisite for sustaining sex dimorphism in the liver metabolism (Bur et al, 2009). Furthermore, sex dependency of circadian pharmacology has been observed in a Phase III clinical trial for chronomodulated therapy of metastatic colorectal cancer (Giacchetti et al, 2006).…”

Circadian clock-dependent and -independent rhythmic proteomes implement distinct diurnal functions in mouse liver

“…Cry1/Cry2 double KO mice (53) in the C57BL/6J genetic background are described in ref. 54. Unless noted otherwise, mice were maintained under standard animal housing conditions with free access to food and water and in 12-h LD cycles.…”