Prevention of Type-2 Diabetes: The Circadian System as a Novel Target for Long-Term Maintenance of Weight Loss

Obesity is a worldwide health problem and the major reason for the dramatic recent increase in type-2 diabetes prevalence. Weight loss in an attempt to combat obesity almost invariably results in weight regain to one’s original weight preceding the weight loss1. The reasons for the failure to achieve long-term weight maintenance following weight loss are, however, poorly understood. While recent studies have implicated the circadian system as a central mechanism in weight control and obesity development, its contribution to maintaining body weight after initial weight loss has not been studied. The Bass laboratory has pioneered experimental genetic strategies in mice to dissect the role of clock disruption in obesity and diabetes, and we propose the first effort to exploit these powerful systems to test the hypothesis that central circadian disruption contributes to weight regain following weight loss, and in so doing, to characterize how disrupted central circadian rhythms perturb weight maintenance and metabolic integrity when either a low- or high-energy diet is once more made available following calorie restriction (CR)-induced weight loss. To this aim, we will utilize mice that we have generated in which we can chemogenetically induce long-term silencing of the central pacemaker, i.e. the suprachiasmatic nucleus (SCN), which will also allow us to gain mechanistic insight into downstream contributions of hormones signaling from periphery to brain to impact glucose homeostasis, and the contribution of brown adipose tissue (BAT) thermogenic activity to weight recidivism. This will provide a greater understanding of how to achieve successful weight loss and thereby prevent the leading cause of the type-2 diabetes epidemic.