Obesity and the circadian clock

Mammals have developed an endogenous circadian clock located in the suprachiasmatic nuclei (SCN) of the anterior hypothalamus that responds to the environmental light-dark cycle. The SCN clock receives light information from the retina and transmits synchronization cues to peripheral clocks in the liver, heart, etc., regulating cellular and physiological functions. The circadian clock also regulates metabolism and energy homeostasis in peripheral tissues by mediating the expression and/or activity of certain metabolic enzymes, hormones, and transport systems. Pronounced biological rhythms extend life span, as longevity was increased in older hamsters given fetal suprachiasmatic nuclei implants that restored higher amplitude rhythms. Destruction of the SCN results eventually in the absence of bodily rhythms. Disruption of circadian rhythms leads to hormone imbalance, psychological and sleep disorders, cancer proneness, and malignant growth. Recent data suggest that disruption of circadian rhythms in the SCN and peripheral tissues leads to manifestations of the metabolic syndrome and hyperphagia. Indeed, shift work and sleep deprivation in humans have been shown to be associated with increased adiposity. Similarly, homozygous Clock (a key gene of the biological clock) mutant mice have a greatly attenuated diurnal feeding rhythm, are hyperphagic and obese, and develop a metabolic syndrome. Bmal1^-/- (a key gene of the biological clock) knockout mice, similarly to Clock mutant mice, exhibited suppressed diurnal variations in glucose and triglycerides as well as abolished gluconeogenesis. In addition, high-fat diet disrupts circadian rhythms. Interestingly, Bmal1^-/- knockout mice have reduced life span. Thus, disruption in circadian rhythms leads to obesity and reduced life expectancy, whereas resetting of circadian rhythms leads to well-being and increased longevity.