Diurnal glycogen metabolism drives rhythmic liver protein secretion [in vivo]

The liver secretes most circulating proteins, which are critical for inter-organ communication and systemic energy homeostasis. However, the regulatory mechanisms governing hepatic protein secretion are largely unknown. Using proteomics approaches in humans and mice, we here demonstrate that hepatic protein secretion follows a 24-hour rhythm which is modulated by the timing of food intake. Rhythmic variations in the expression of secretory pathway proteins, involved in protein glycosylation and folding in the endoplasmic reticulum and Golgi apparatus, mediate this process. We find that feeding rhythms and the circadian clock protein BMAL1 regulate diurnal hepatic protein secretion by driving glycogen breakdown which generates glycosylation substrates. Rhythmic secretion was attenuated in a mouse model of obesity and affected by genetic variants associated with glycogen storage disease and congenital disorders of glycosylation. Our study reveals a mechanistic link between glycogen-derived metabolites and the protein secretion pathway, thereby connecting nutrient intake with fundamental liver functions. Overall design: C57BL/6J mice (n=4 per treatment and timepoint) were exposed to 12-hour night-restricted feeding for four days before receiving a subcutaneous injection of CP-91149 (40 mg/kg; volume of 10 µl per g body weight) or vehicle at ZT0. Serum and liver tissues were collected at ZT3, ZT6, ZT9, ZT12, and ZT24.