UC San Diego

Circadian rhythms are the endogenous 24-hour cycle that coordinates physiology with time of day. The molecular feedback loop that regulates circadian rhythms also regulates the secretion of many hormones, including growth hormone (GH). GH is secreted in a sexually dimorphic pattern, which drives sexually dimorphic expression of many genes in the liver, including the Major Urinary Protein (MUP) pheromone family in mice, and the drug-metabolizing Cytochrome p450 (Cyp) family. Interestingly, some MUPs and Cyps are expressed in a circadian pattern, indicating that their expression is regulated not only by the GH axis, but also by circadian clock genes. Thus, we sought to establish the role of a core circadian clock gene, Bmal1, in regulating the GH axis and sexually dimorphic hepatic genes. Bmal1 knockout (KO) male mice have decreased MUP expression and feminized GH pulse patterns. Surprisingly, Bmal1 KO males have dysregulated, but not feminized, Cyp expression, indicating that feminization of the GH pulses is not responsible for the disruption. To determine if Bmal1 is acting in the liver to regulate hepatic gene expression, we specifically deleted Bmal1 from hepatocytes with an Albumin Cre; Bmal1flox/flox (Bmal1 liver KO) mouse. The males have decreased MUP expression, and similar Cyp expression to the full-body Bmal1 KO, indicating that Bmal1 acts in the liver to regulate MUPs and Cyps. Together, our study indicates that Bmal1 plays a vital role in regulating both the GH axis and sex-specific hepatic gene expression.