Understanding Circadian Clock May Be Key to Combatting Obesity

Understanding how the circadian clock, as well as key clock proteins, affect the formation and accumulation of adipose tissue could be another front in the battle against obesity, according to a paper recently published in Endocrine Reviews.

The review, by Oren Froy, of the Hebrew University of Jerusalem in Rehovot, Israel, and Marta Garaulet, of the University of Murcia, Spain, points out that obesity is a major risk factor for many illnesses, and that obesity – excess fat accumulation in white adipose tissue – has been related to irregular sleep/wake cycles. The central circadian clock is confined to the suprachiasmatic nuclei (SCN) in the anterior hypothalamus, but clock genes that are found in peripheral tissues like the liver and adipose tissue mediate activity of nuclear receptors, enzymes, hormones, and transporters involved in carbohydrate, lipid, and protein metabolism. “Knockouts or mutations in clock genes that lead to disruption of cellular rhythmicity have provided evidence to the tight link between the circadian clock and metabolism,” the authors write.

Animal studies have shown that mice with mutated Clock genes are obese and develop a metabolic syndrome of hyperleptinemia, hyperlipidemia, hepatic steatosis, and hyperglycemia; mice with deleted Bmal1 genes were obese, and Bmal1 deletion led to changes in the expression of hypothalamic neuropeptides that regulate appetite; circadian changes in hepatic Cry1/2 expression led to mice being more vulnerable to high-fat diet-induced obesity that correlated with increased insulin secretion. “Consistent with these findings, genetic polymorphisms in human clock genes have been associated with metabolic alteration,” the authors write.

The authors of the review also detail some behaviors that explain the connections between chronodisruption (chronic desynchronization of 24-hour rhythms), such as how meal timing can affect weight gain. Mouse studies showed that changing feeding time led to an increase in weight gain, and in humans, unusual eating times disrupt the circadian system, which can produce adverse health effects. The authors write that the timing of food intake might have a significant role in obesity, weight loss, and glucose metabolism. “For example,” the authors write, “mice with adipocyte-specific deletion of Bmal1 fed a high-fat diet during the light period gained significantly more weight compared to mice fed during the dark period. Thus, disruption of the adipocyte clock leads to obesity without an overall increase in daily caloric intake when mice are fed during the inactive phase.”

The review covers many more topics in this area, but the authors note that despite the immense knowledge of how the internal clock affects health, there is still a big gap in this knowledge and clinical practice. “Currently, large-scale epidemiological studies are repeatedly demonstrating that the alteration of the circadian system has an impact on health and is associated with several adipose tissue-related metabolic illnesses, such as obesity, metabolic syndrome, or diabetes. Nevertheless, the success in translating this knowledge to the clinical practice is still limited,” the authors write.

Looking ahead, the authors write that further research is needed into synchronizing these molecular clocks in the different types of adipose tissues with the rest of the body. Understanding the connections among these genetic variants and obesity may help researchers design individual therapies for obesity. “The current knowledge of the presence of an internal clock in the different adipose tissue types, white, brown, and beige, and its connection with key elements in metabolism may help us to achieve a better understanding of adipose tissue function, and to design novel strategies to combat obesity,” the authors conclude.

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