A Novel Link Between Circadian Clocks and Adipose Tissue Energy Metabolism

Abstract

Many behaviors and physiological processes are influenced by internal recurrent daily rhythms, which likely represent an adaptation to the Earth’s rotation around the Sun and the recurrent 24-h light-dark cycles in the external environment. These circadian rhythms are an important regulator of many key biological processes that influence cellular metabolic pathways and organ function (1,2). The results from a series of studies have demonstrated the importance of normal circadian action for maintaining health in people and the disruption of circadian rhythm, which can have adverse effects on metabolic function. For example, experimentally induced sleep restriction and/or circadian misalignment, generated by inducing recurrent 28-h sleep-wake cycles, decrease insulin sensitivity and glucose tolerance (3–6). Data from epidemiological studies suggest that long-term alteration in sleep pattern increases the risk of obesity and metabolic diseases. The prevalence of obesity, hypertension, hypertriglyceridemia, and the metabolic syndrome are greater in shift workers than day workers, and short sleep duration is associated with an increased risk of obesity and diabetes (7,8). Circadian rhythms are generated by a transcriptional autoregulatory feedback loop that involves core clock genes. CLOCK (circadian locomotor output cycles protein kaput) and BMAL1 (brain and muscle ARNT-like 1) proteins form a heterodimer complex that binds to E-boxes, which drive the transcription of Period (PER1, 2, and 3) and Cryptochrome (CRY1 and 2), which in turn produce a negative feedback loop by suppressing CLOCK:BMAL1-mediated transcriptional activity (1,2). In mammals, neurons in the hypothalamic suprachiasmatic nucleus act as a master pacemaker and synchronize the daily oscillations in peripheral tissues throughout the …