Brown Bears activates a Satiety Hormone Cholecystokinin (CCK) pathway in adipose tissue during hibernation

The brown bear (Ursus arctos) hibernates to survive cold winters without access to food. It builds enormous subcutaneous fat stores during summer and relies on it for energy during winter. Remarkably, the weight loss during winter occurs without muscle loss despite inactivity. Studying brown bear biology can therefore provide insights for improving human health in obesity and weight loss treatments. We here investigate subcutaneous adipose tissue biopsies obtained during summer and winter from free-living brown bears. During winter, a signature of genes involved in food intake and digestion is upregulated. Among these are several regulators of satiety, substrate transport and lipid metabolism. Interestingly, in humans these genes are enriched in distinct metabolic organs including, brain, intestine, stomach, liver and even salivary glands. We focused on the satiety brain/intestinal hormone cholecystokinin (CCK), which we demonstrate is produced in adipocytes, accompanied by an upregulation of the CCK receptor CCKBR. Importantly, CCK was undetectable in the circulation during winter and presence of sensory neurons suggest a neuronal feedback mechanism within the adipose tissue. Using RNA sequencing, we predict additionally 537 secreted proteins to be seasonally regulated, 37 of which could be confirmed with plasma proteomics. In conclusion, we propose that brown bears have developed a strategy of healthy fat burning and satiety regulation through an adipose tissue-contained mechanism which includes digestion factors and satiety mediators to provide safe energy turnover during hibernation-dependent weight loss.