About 78 million American adults are classified as obese, with a body mass index greater than 30 kg/m2. Serious cardiometabolic health threats such as diabetes, heart disease, stroke, and cancer have been linked to obesity. Interestingly, excess weight gain and an increased risk for metabolic disorders are also observed within populations subjected to a disruption of their normal circadian rhythm (e.g., night-shift workers and patients with Night Eating Syndrome). Currently, the most successful treatment for severe obesity and diabetes is bariatric surgery. While it is known that the degree of success of bariatric surgery varies greatly from one individual to another, the exact reasons for the variance are unknown. Given that ~40% of the bariatric surgery population also have some degree of circadian disruption (CD), it is possible that disrupted circadian biology can influence the outcome of bariatric surgery. Investigating the important role that circadian rhythms play in normal and dysregulated aspects of metabolism marks a novel, integrative approach to better understanding obesity and diabetes. The proposed experiments will elucidate key circadian and metabolic connections by studying whether the deleterious metabolic consequences of environmental or genetic CD can be reversed by bariatric surgery. Specifically, this proposal utilizes our laboratory-developed rodent model of the increasingly popular bariatric surgery procedure known as vertical sleeve gastrectomy. Using this model, we will 1) investigate how environmental and genetic CD can affect the outcome of bariatric surgery, and 2) whether and how bariatric surgery ameliorates obesity-induced changes to circadian biology. By using repeating light shifts to mirror human "night-shift work" and time-restricted feeding to mirror patients with "Night Eating Syndrome," this proposal effectively models human CD in a context that allows for mechanistic studies. Furthermore, by utilizing the Clock mutant mouse that has both circadian and metabolic impairments, this proposal also examines genetic influence on bariatric surgery success. The goals of this proposal can be achieved through a unique research training plan which integrates the investigator's expertise in circadian rhythms with new techniques, concepts, and procedures in endocrinology, metabolism, and body weight regulation. The successful execution of these proposed experiments will have two important impacts. First, it will reveal clinically relevant information as to whether individuals with CD ar less responsive to bariatric surgery. Second, by combining molecular and behavioral aspects of circadian biology with the powerful impact of bariatric surgery on multiple metabolic systems, it will shed considerable light on the key mechanisms that link circadian rhythms to metabolic diseases. This will provide insight into both the etiology of metabolic diseases as they relate to circadian biology and also potential therapeutic strategies that could mimic crucial molecular and physiological effects of bariatric procedures by less invasive and more tailored means.
This proposal is expected to provide clinically relevant advances in the treatment of obesity, particularly within the severely obese and/or circadian disrupted population, as well as insights into the mechanistic biology controlling body weight regulation.