Males and females exhibit many gender-based differences. In addition to the obvious anatomical and hormonal differences, there are also metabolic differences. One that is clinically important is the difference in the production of enzymes involved in drug metabolism. Metabolism is also regulated by the circadian clock. Bur et al. found that the differences between male and female mice in the transcription and activity of several liver enzymes were reduced in mice double homozygous for cryptochrome 1 and 2 (Cry−/−). For example, daily male-specific variations in the mRNA from the Elovl3 gene, which encodes an enzyme involved in fatty acid biosynthesis, was eliminated in Cry−/− males, and transcripts for the female-specific cytochrome p450 gene Cyp2b9 were increased in the Cry−/− males. Gender-specific differences in liver function are controlled by growth hormone (GH). GH production fluctuates over the day; in mice, a sustained period of low GH between peaks of secretion is required for expression of male-specific liver genes. GH stimulates the production of major urinary proteins (MUPs) and also controls body size, so these two parameters were used as the readout of GH activity. Cry−/− males exhibited a more pronounced decrease in body size than did female Cry−/− mice, and Cry−/−males also showed a substantial decrease in MUP production, which was not observed in the female Cry−/− mice. Random blood testing revealed that Cry−/− males exhibited an overall increased abundance of GH in the circulation and a relatively decreased range of GH in the pituitary, which are both consistent with a shorter duration of the low-GH period in the Cry−/− males. Administration of GH at 12-hour intervals or infusion of a somatostatin agonist (to stimulate endogenous GH release) to the Cry−/− male mice for a week restored the masculine liver gene expression profile and MUP production. Thus, the circadian clock contributes to sexual dimorphism in liver metabolism through effects on GH pulsatility. Interestingly, the circadian clock becomes less robust with age, and changes in drug metabolism also occur with age. The authors compared young and old male mice and found that the liver gene pattern was feminized in the old male mice, which suggests that changes in the circadian clock may underlie age-related differences in drug metabolism.
I. M. Bur, A. M. Cohen-Solal, D. Carmignac, P.-Y. Abecassis, N. Chauvet, A. O. Martin, G. T. J. van der Horst, I. C. A. F. Robinson, P. Maurel, P. Mollard, X. Bonnefont, The circadian clock components CRY1 and CRY2 are necessary to sustain sex dimorphism in mouse liver metabolism. J. Biol. Chem. 284, 9066–9073 (2009). [Abstract] [Full Text]