Abstract
The nearly ubiquitous expression of endogenous 24 h oscillations known as circadian rhythms regulate the timing of physiological functions in the body. These intrinsic rhythms are sensitive to external cues, known as zeitgebers, which entrain the internal biological processes to the daily environmental changes in light, temperature, and food availability. Light directly entrains the master clock, the suprachiasmatic nucleus (SCN) which lies in the hypothalamus of the brain and is responsible for synchronizing internal rhythms. However, recent evidence underscores the importance of other hypothalamic nuclei in regulating several essential rhythmic biological functions. These extra-SCN hypothalamic nuclei also express circadian rhythms, suggesting distinct regions that oscillate either semi-autonomously or independent of SCN innervation. Concurrently, the extra-SCN hypothalamic nuclei are also sensitized to fluctuations in nutrient and hormonal signals. Thus, food intake acts as another powerful entrainer for the hypothalamic oscillators’ mediation of energy homeostasis. Ablation studies and genetic mouse models with perturbed extra-SCN hypothalamic nuclei function reveal their critical downstream involvement in an array of functions including metabolism, thermogenesis, food consumption, thirst, mood and sleep. Large epidemiological studies of individuals whose internal circadian cycle is chronically disrupted reveal that disruption of our internal clock is associated with an increased risk of obesity and several neurological diseases and disorders. In this review, we discuss the profound role of the extra-SCN hypothalamic nuclei in rhythmically regulating and coordinating body wide functions.
Highlights
Most organisms on earth exhibit highly conserved 24 h rhythms in physiology and behavior
Circadian clocks throughout the body are synchronized in large part through the suprachiasmatic nucleus (SCN) of the hypothalamus, rhythmicity in other hypothalamic nuclei has proved to be a critical regulator of physiological rhythms such as the sleep–wake cycle and daily food intake
Rats express food-anticipatory activity (FAA) in constant darkness and even in the absence of a functional SCN [47]. These findings point to an elusive food-entrainable circadian oscillator (FEO) which is independent of the SCN [48]
Summary
Most organisms on earth exhibit highly conserved 24 h rhythms in physiology and behavior. Constant 24 h rotations of the earth punctuated by the rising and setting of the sun contribute to an organism’s circadian (i.e., 24 h) biology at the molecular, cellular, and behavioral levels This internal clock sensitizes, but enables an organism to anticipate daily fluctuations in its environment. Circadian clocks throughout the body are synchronized in large part through the suprachiasmatic nucleus (SCN) of the hypothalamus, rhythmicity in other hypothalamic nuclei has proved to be a critical regulator of physiological rhythms such as the sleep–wake cycle and daily food intake. A combination of ablation studies in rats and monkeys, along with clinical psychiatric observations carried out in the mid-1900s first implicated a circadian clock in the hypothalamic region [25,26] It was not until the discovery of the retinohypothalamic tract (RHT) in rats that the SCN was proven to be important for rhythmicity [27]. When explanted from the body into culture, these tissue clocks maintain rhythms, indicating their own autonomy [42]
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