Gi Hoon Son^a,1, Sooyoung Chung^a,1, Han Kyoung Choe^a, Hee-Dae Kim^a, Sun-Mee Baik^a, Hankyu Lee^a, Han-Woong Lee^b, Sukwoo Choi^a, Woong Sun^c, Hyun Kim^c, Sehyung Cho^d, Kun Ho Lee^a, and Kyungjin Kim<sup>a,2

a</sup>Department of Biological Sciences, Seoul National University, Seoul 151-742, Korea;
^bDepartment of Biochemistry, Yonsei University, Seoul 120-749, Korea;
^cDepartment of Anatomy, Korea University College of Medicine, Seoul 136-705, Korea; and
^dDepartment of Life and Nanopharmaceutical Science and Age-Related and Brain Diseases Research Center, Kyung Hee University, Seoul 130-701, Korea

¹G.H.S. and S. Chung contributed equally to this work.

Abstract
Glucocorticoid (GC) is an adrenal steroid with diverse physiological effects. It undergoes a robust daily oscillation, which has been thought to be driven by the master circadian clock in the suprachiasmatic nucleus of the hypothalamus via the hypothalamus-pituitary-adrenal axis. However, we show that the adrenal gland has its own clock and that the peripheral clockwork is tightly linked to steroidogenesis by the steroidogenic acute regulatory protein. Examination of mice with adrenal-specific knockdown of the canonical clock protein BMAL1 reveals that the adrenal clock machinery is required for circadian GC production. Furthermore, behavioral rhythmicity is drastically affected in these animals, together with altered expression of Period1, but not Period2, in several peripheral organs. We conclude that the adrenal peripheral clock plays an essential role in harmonizing the mammalian circadian timing system by generating a robust circadian GC rhythm.

adrenal gland, steroidogenic acute regulatory protein, BMAL1

²To whom correspondence should be addressed.

Author contributions: G.H.S., S. Chung, and K.K. designed research; G.H.S., S. Chung, H.K.C., H.-D.K., S.-M.B., H.L., H.-W.L., S. Choi, W.S., H.K., S. Cho, K.H.L., and K.K. performed research; G.H.S., S. Chung, H.K.C., H.-D.K., S.-M.B., H.L., H.-W.L., S. Choi, W.S., H.K., S. Cho, K.H.L., and K.K. analyzed data; and G.H.S., S. Chung, and K.K. wrote the paper.