Peripheral circadian misalignment: contributor to systemic insulin resistance and potential intervention to improve bariatric surgical outcomes

Abstract

Thirteen percent of the world's population suffers from obesity and 39% from being overweight, which correlates with an increase in numerous secondary metabolic complications, such as Type 2 diabetes mellitus. Bariatric surgery is the most effective treatment for severe obesity and results in significant weight loss and the amelioration of obesity-related comorbidities through changes in enteroendocrine activity, caloric intake, and alterations in gut microbiota composition. The circadian system has recently been found to be a critical regulatory component in the control of metabolism and, thus, may potentially play an important role in inappropriate weight gain. Indeed, some behaviors and lifestyle factors associated with an increased risk of obesity are also risk factors for misalignment in the circadian clock system and for the metabolic syndrome. It is thus possible that alterations in peripheral circadian clocks in metabolically relevant tissues are a contributor to the current obesity epidemic. As such, it is plausible that postsurgical alterations in central circadian alignment, as well as peripheral gene expression in metabolic tissues may represent another mechanism for the beneficial effects of bariatric surgery. Bariatric surgery may represent an opportunity to identify changes in the circadian expression of clock genes that have been altered by environmental factors, allowing for a better understanding of the mechanism of action of surgery. These studies could also reveal an overlooked target for behavioral intervention to improve metabolic outcomes following bariatric surgery.

Fig. 1.

Circadian disruptors negatively impact peripheral circadian clocks. Continuous access to calorie-dense foods, increasingly sedentary lifestyles, inadvertent light pollution, and living conditions under a constant ambient temperature all contribute to circadian disruption and the obesity epidemic. That these disruptors act to desynchronize the suprachiasmatic nucleus (SCN; central clock) from peripheral clocks, or directly affect the peripheral clocks, are novel risk factors as a result of modern society. Thus, circadian disruptors act on multiple metabolic tissues through external cues and promote the development of obesity and its associated comorbidities.