Circadian rhythms and metabolic syndrome: from experimental genetics to human disease

Abstract

The incidence of the metabolic syndrome represents a spectrum of disorders that continue to increase across the industrialized world. Both genetic and environmental factors contribute to metabolic syndrome and recent evidence has emerged to suggest that alterations in circadian systems and sleep participate in the pathogenesis of the disease. In this review, we highlight studies at the intersection of clinical medicine and experimental genetics that pinpoint how perturbations of the internal clock system, and sleep, constitute risk factors for disorders including obesity, diabetes mellitus, cardiovascular disease, thrombosis and even inflammation. An exciting aspect of the field has been the integration of behavioral and physiological approaches, and the emerging insight into both neural and peripheral tissues in disease pathogenesis. Consideration of the cell and molecular links between disorders of circadian rhythms and sleep with metabolic syndrome has begun to open new opportunities for mechanism-based therapeutics.

Fig 1. The core molecular clock components

The mammalian circadian clock consists of a series of interlocking transcription/translation feedback loops. The positive limb of the clock is composed of the transcription factors CLOCK/NPAS2 and BMAL1, which heterodimerize and activate transcription of downstream clock target genes, including the period (Per1, 2, and 3) and cryptochrome (Cry1 and 2) genes, Rev-erba, Rora, and other clock-controlled genes. Upon translation, the PERs and CRYs heterodimerize, translocate back to the nucleus, and inhibit CLOCK/BMAL1. Multiple additional interlocking loops are shown and are described within the text.

Fig. 2. Synchronization of internal biological rhythms by external cues

Light is the predominant environmental cue that is received by the SCN; photic input is transmitted via the retinohypothalamic tract. In turn, the SCN maintains circadian synchrony of peripheral clocks, a process that involves transmission via both autonomic innervation and/or humoral signals. Circadian oscillators may also be entrained by food and hormones. Circadian synchrony and the entrainment process are reflected in the robustly rhythmic behavioral and physiological outputs such as feeding, sleep-wakefulness, hormone secretion, and metabolic homeostasis.

Fig. 3. Peripheral clock output

The core clock machinery has been identified in most peripheral tissues. In addition, rhythmic gene expression appears to be regulated in a tissue-specific manner, enabling each tissue to appropriately calibrate local physiological processes within the appropriate overall temporal schedule. However, circadian disruption either within or amongst individual tissues may lead to organ dysfunction. Indeed, recent studies suggest that peripheral clock alteration is involved in body weight gain as well as abnormalities in glucose homeostasis and blood pressure regulation, thereby contributing to the development of the metabolic syndrome. These alterations may be initiated by disruptions in circadian behavioral and/or environmental factors such as high-fat diet. Circadian and physiological systems are interconnected through reciprocal feedback loops within each tissue locale.