Why 13-lined ground squirrels are an amazing model for obesity discovery
In December 2023, Fauna Bio entered into a collaboration with Lilly for novel target discovery in obesity. In this collaboration, Fauna Bio will use their ConvergenceTM AI Platform to find novel therapeutic targets using proprietary ‘omics data from the 13-lined ground squirrel. The hibernating 13-lined ground squirrel is a natural animal model of extreme physiology of weight gain and weight loss. Each and every year of their life, this mammal doubles their body weight in fat accumulation by eating voraciously over just a few short months in the summer and then enters hibernation in an obese state during the fall. Extraordinarily, these mammals will inhibit all food intake at hibernation onset and naturally fast for the next six months while using up their stored fat as their primary energy source. In the spring, the animals will emerge from hibernation quite lean and devoid of body fat and will begin the cycle of fat accumulation over the summer once again.(link) While markedly obese pre-hibernation, these animals do not develop aspects of metabolic syndrome, are protected from cardiac damage and do not develop diabetes, while showing clear changes in obesity characteristics such as insulin resistance over the hibernation season. In addition to extreme changes in food intake, satiety, body weight and fat stores, 13-lined ground squirrels (and many other hibernators) have mechanisms to not only maintain, but rebuild skeletal muscle (link)(link) despite being motionless and fasting during the 6 months of hibernation of the year.
What most people do not realize is that hibernation is not a quiescent state. White the majority of the 6 month period of hibernation is characterized by extreme metabolic suppression, with animals maintaining a metabolic state of 1-3% of normal, with a heart rate of 5 beats per minute and almost completely lacking oxygen, this state of frozen animation is punctuated by frequent and rapid arousals (which occur roughly every 2 weeks) (link). During these arousal episodes, ground squirrels increase their metabolism 235x in just an hour. The closest human equivalent would be going from a dead sleep to biking the tour de france in an hour. There are very few other mammals that demonstrate such metabolic flexibility and it provides an extremely unique window into the ways that we can fundamentally alter our own mammalian metabolism.
These dramatic changes in metabolic rate are particularly relevant for patients that have lost a significant amount of weight, and as a consequence have reset their baseline metabolism to a much lower level. These patients are then much more likely to put the weight back on, or in some cases, put on even more weight than when they started dieting or other interventions. This is known as the “Biggest Loser Syndrome”. Fauna Bio has multiple animal and human datasets relevant to obesity, including modulation of body weight, fat mass, lean mass, body composition, metabolic rate, and alteration of food intake. We also collaborate with the University of Wisconsin, OshKosh to generate new proprietary datasets at critical timepoints for translating insights to human patients. Using Fauna’s comparative genomics data and our proprietary AI platform allows us to more rapidly find highly impactful drug targets, driving innovation and first-in-class therapeutics programs across a wide range of disease areas, including obesity.
By Katie Grabek and Bryan Burkey