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Hypothalamic Control of Circadian Homeostasis and Hormone Regulation: History
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Contributor: O. Hecmarie Meléndez-Fernández ,
Jennifer A. Liu
, Randy J. Nelson

Hypothalamic hormone release functions through a cascade system induced by input received from higher brain centers responding to environmental information. These hormones travel through the hypothalamic-hypophyseal portal system to the pituitary to produce or inhibit hormones that are then transported throughout the body to interact with target organs.

  • circadian rhythms
  • hormonal rhythms
  • SCN
  • sleep

1. Food Intake

Food intake is another biological process important in maintaining a healthy metabolism, from nutrient intake to optimal energy expenditure. The hypothalamus regulates appetitive behavior, food intake, and energy expenditure through hormonal release and afferent autonomic nerves [1]. The ventromedial hypothalamus (VMH) is primarily involved in satiety by receiving inputs from hormones in the bloodstream and arcuate nucleus (ARC), along with neurotransmitters, neuropeptide Y (NPY), Agouti-related peptide (AgRP), and pro-opiomelanocotin (POMC) [2]. Leptin is a hormone involved in satiety, produced in adipose tissue, and its dysregulation or dysfunction may lead to overeating. These hormones function as signals to the brain as the proportional value of fat storage relative to blood secretion levels [3]. Other hormones directly involved in food intake, include ghrelin, which directly induces food consumption through stimulating GHS-R1a in the VMH, and through an indirect orexigenic pathway from AgRP and NPY from the ARC inhibiting anorexigenic signals [4], and hypocretins/orexins, that mediate energy storage after food intake [5].

2. Sleep

Sleep is an integral biological process that affects several biological functions, including cognition, development, energy conservation, immune modulation, and others [6]. Sleep is characterized by altered brain wave activity, and reduced body movement and responsiveness to the environment [7]. The hypothalamus is one of the main brain regions responsible for playing a central role in sleep-wake regulation. The preoptic area of the hypothalamus functions by promoting sleep onset and maintenance by inhibiting arousal systems baseline, and contains inhibitory neuromodulator/transmitters galanin and gamma-aminobutyric acid (GABA) [8]. Sleep control systems are also implicated in bi-directional pathways with the SCN of the anterior hypothalamus, involved in entrainment and regulation of circadian rhythms. Notably, hypothalamic SCN oscillators, circadian rhythms, and sleep regulation have been recently implicated in playing a role in food intake, metabolism, hormone release, and temperature, suggesting its broad importance in homeostatic physiological regulation [9].

3. SCN-Mediated Hormonal Release and Function

The SCN mediates the timing of most circadian rhythms, including the daily release of many hormones associated with metabolism. In common with other circadian regulated processes, precise timing is critical. Thus, changes in environmental signals that influence circadian clock function can ultimately influence endocrine function in maladaptive ways. Interactions with peripheral clocks in the liver and pancreas, for example, that are entrained to meal timing are also critical for optimal metabolic function. As already discussed, intrahypothalamic signaling mediates the temporal output of the SCN. In the next sections researchers provide examples of key hormones under circadian clock control and provide the current understanding on how they communicate with the SCN.

3.1. Melatonin

Perhaps the best known SCN-mediated endocrine response is pineal-melatonin production and secretion. Melatonin, sometimes referred to as a “sleep hormone”, at least in humans [10][11] and various diurnal species [12][13][14][15], promotes sleep. More accurately, it is a “dark” hormone, which signals night length (scotoperiod). Upon the onset of darkness (night), the SCN release of GABAergic inputs to the PVN are halted, and the paraventricular nucleus (PVN) sends projections to the intermediolateral cell column of the spinal cord [16]. From here, preganglionic noradrenergic (NEergic) neurons project to the superior cervical ganglion, which subsequently innervate the pineal gland. NE released from these fibers then promotes the biosynthesis of melatonin [17][18]. Melatonin release peaks near the middle of the night and decreases by morning [19]. Although the SCN regulates the timing of pineal melatonin release, melatonin also feeds back to the SCN, through melatonin receptor 1 (MT1) [20] and through melatonin receptor 2 (MT2) [21] signaling, to decrease neuronal firing or induce a circadian phase shift [22][23], respectively. In this context, melatonin signaling is sustained throughout much of the night and inhibited by light exposure [24][25][26].
Melatonin is not only a primary endocrine clock output, but also serves as a neuroendocrine synchronizer of molecular rhythms, both centrally and peripherally [27][28][29][30][31][32]. In rodents, melatonin induces rhythmic expression of Per1, Bmal1, Clock, and Cry in the pituitary [33][34]; pinealectomy of Syrian hamsters abolishes the rhythmicity of Per1 mRNA expression in the pituitary without affecting its expression in the SCN or VMH [35]. Rat pinealectomy, however, leads to long-term (after three months) desynchrony of Per1 and Per2 expression, and decreased Rev-erbα amplitude in the SCN [36], suggesting that long-term loss of endogenous melatonin weakens circadian rhythmicity. Clinical studies support this hypothesis [37][38][39].
As a result of its feedback to the SCN, melatonin also plays a role in circadian entrainment [40]. Studies in humans and other mammals have demonstrated that exogenous melatonin can phase shift [41] and entrain the circadian clock of blind subjects [37][38][39]. The role of melatonin in promoting sleep itself, however, is a source of debate in the field, due to some of the data acquired from studies using nocturnal rodents. A core argument against the role of melatonin in sleep promotion results from the observation that, in these animals, melatonin is associated with wakefulness. Notwithstanding, some studies suggest that melatonin functions as a sleep-promoting signal [42][43], and it induces sedation and lowers core body temperature [44][45]. Indeed, a review of the literature suggests that administration of melatonin agonists may help in reducing sleep latency and promote sleep in patients with insomnia; however, additional clinical trials are necessary before approval for broad clinical use [46][47]. Additionally, melatonin receptors are broadly distributed (not unique to the CNS), so administration of exogenous melatonin may cause off-target effects and/or interact with other drugs, such as observed with nifedipine, an anti-hypertensive [48], although more recent data suggest protective effects [49][50].
In the periphery, melatonin has been reported to play a role in blood pressure regulation in experimental and clinical settings [31][48]. Its actions are receptor-specific; MT1 activation mediates vasoconstriction in both cerebral and peripheral arteries [51][52][53][54][55], and vasodilation via MT2 [56][57]. Other work in this field presents promising data regarding the role of melatonin in regulating blood pressure, in vascular protection after ischemic injury, and other vascular injuries [49][50][58][59][60]. Finally, in adipose tissue, melatonin synchronizes metabolic and hormonal function [61] by regulating Per2, Clock and REV-ERBα, of which REV-ERBα is a documented requirement for daily balanced metabolism of carbohydrates and lipids [62].
Various additional possible roles for melatonin have emerged. For instance, melatonin plays a role in T cell activation [63], and overall immune function [64][65][66][67][68][69][70], reviewed in [64][65]. It has been widely proposed as an antioxidant [71][72][73][74], particularly in the context of recovery from ischemia/reperfusion injury [49][71].
A more nuanced role for melatonin has been proposed for the aged. Specifically, given the association between decreased melatonin production in the early stages of Alzheimer’s disease (AD), the role of melatonin in sleep promotion (in humans), and the function of sleep in clearing the brain from metabolites and toxins, melatonin has been proposed as a promising therapeutic for those at risk [75]. Moreover, a preclinical study analyzing the relationship between sleep and the accumulation of Aβ, determined that sleep deprivation or orexin administration increases Aβ in interstitial fluid, suggesting a role for sleep and wakefulness-regulating molecular players in AD pathology [76]. Further, in the context of AD, and considering its antioxidant capacity, melatonin has also been proposed as an ‘anti-aging’ agent, as it is capable of stimulating antioxidant enzymes and re-establishing the mitochondrial membrane integrity [77]. Further pre-clinical and clinical research is required to fully understand the interconnectedness of these pathways and the molecular mechanisms that mediate their effects.
Despite the mounting literature on the systemic effects of melatonin, more work is required to fully understand (1) endogenous versus exogenous melatonin effects, (2) its central versus peripheral effects, (3) differential effects on diurnal versus nocturnal species, and (4) sex differences in response to its administration.

3.2. Glucocorticoids

Glucocorticoids (GC) are steroid hormones produced by the adrenal cortex, and are involved in several physiological processes, such as metabolism [78], immune response [79], cardiovascular function [80][81], and reproduction [82]. As many homeostatic drivers of physiology, the production of GC is driven by circadian rhythms and is tightly regulated. Neuronal activity in the SCN stimulates the PVN to initiate the release of corticotropin-releasing hormone, which then signals to the anterior pituitary to release adrenocorticotrophin, which, in turn, communicates to the adrenal cortex to release GC. Over time, GC feed back to the hypothalamus and pituitary to block secretion of their precursors, and consequently, their production. There is no GC feedback directly to the SCN [83]; however, the arcuate nucleus serves as the “stress sensor”, providing feedback to the PVN about corticosterone levels, and thus, modulating its release [84]. As a result, GC are released at specific times of the day, and in response to specific events (e.g., corticosterone release as a result of restraint), and display cyclic decreases and increases in their circulating concentrations. Cortisol secretion, for instance, begins prior to awakening, rises in the morning, peaking around the time of awakening [85][86]; elevated GC increase glucose availability in anticipation of the increase in energy demands associated with wakefulness [87]. In rodents and other nocturnal animals, the cycle of corticosterone secretion is reversed, with the peak observed around dusk, but coinciding with the beginning of their active phase [88].
The GC play an important role in overall animal physiology, particularly in the stress response. During times of stress, the release of GC and epinephrine suppresses energy storage and shifts towards usage of adipose and liver stores [89][90]. Thus, GC released as part of the stress response may also shut down cellular processes that require ample energy resources, such as humoral immune responses, digestion, growth, and reproduction [89][91].

This entry is adapted from the peer-reviewed paper 10.3390/ijms24043392

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