The hypothalamic clock and its control of glucose homeostasis.
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Animals↗
Biomedical subjects
A Kalsbeek
Publications and source records attributed to A Kalsbeek.
A network of (autonomic) clock outputs.
The circadian clock in the suprachiasmatic nuclei (SCN) is composed of thousands of oscillator neurons, each of which is dependent on the cell-autonomous action of a defined set of circadian clock genes. A major question is still how these individual oscillators are organized into a biological clock producing a coherent output that is able to time all the different daily changes in behavior and physiology. We investigated which anatomical connections and neurotransmitters are used by the biological clock to control the daily release pattern of a number of hormones. The picture that emerged shows projections contacting target neurons in the medial hypothalamus surrounding the SCN. The activity of these pre-autonomic and neuro-endocrine target neurons is controlled by differentially timed waves of, among others, vasopressin, GABA, and glutamate release from SCN terminals. Together our data indicate that, with regard to the timing of their main release period within the light-dark (LD) cycle, at least 4 subpopulations of SCN neurons should be discerned. The different subgroups do not necessarily follow the phenotypic differences among SCN neurons. Thus, different subgroups can be found within neuron populations containing the same neurotransmitter. Remarkably, a similar distinction of 4 differentially timed subpopulations of SCN neurons was recently also discovered in experiments determining the temporal patterns of rhythmicity in individual SCN neurons by way of the electrophysiology or clock gene expression. Moreover, the specialization of the SCN may go as far as a single body structure; i.e., the SCN seems to contain neurons that specifically target the liver, pineal, and adrenal.
Adrenal Glands↗
A network of (autonomic) clock outputs.
The circadian clock in the suprachiasmatic nuclei (SCN) is composed of thousands of oscillator neurons, each dependent on the cell-autonomous action of a defined set of circadian clock genes. A major question is still how these individual oscillators are organized into a biological clock that produces a coherent output capable of timing all the different daily changes in behavior and physiology. We investigated which anatomical connections and neurotransmitters are used by the biological clock to control the daily release pattern of a number of hormones. The picture that emerged shows projections contacting target neurons in the medial hypothalamus surrounding the SCN. The activity of these pre-autonomic and neuro-endocrine target neurons is controlled by differentially timed waves of vasopressin, GABA, and glutamate release from SCN terminals, among other factors. Together our data indicate that, with regard to the timing of their main release period within the LD cycle, at least four subpopulations of SCN neurons should be discernible. The different subgroups do not necessarily follow the phenotypic differences among SCN neurons. Thus, different subgroups can be found within neuron populations containing the same neurotransmitter. Remarkably, a similar distinction of four differentially timed subpopulations of SCN neurons was recently also discovered in experiments determining the temporal patterns of rhythmicity in individual SCN neurons by way of the electrophysiology or clock gene expression. Moreover, the specialization of the SCN may go as far as a single body structure, i.e., the SCN seems to contain neurons that specifically target the liver, pineal gland, and adrenal gland.
Animals↗
SCN outputs and the hypothalamic balance of life.
The circadian clock in the suprachiasmatic nucleus (SCN) is composed of thousands of oscillator neurons, each dependent on the cell-autonomous action of a defined set of circadian clock genes. Still, the major question remains how these individual oscillators are organized into a biological clock producing a coherent output able to time all the different daily changes in behavior and physiology. In the present review, the authors discuss the anatomical connections and neurotransmitters used by the SCN to control the daily rhythms in hormone release. The efferent SCN projections mainly target neurons in the medial hypothalamus surrounding the SCN. The activity of these preautonomic and neuroendocrine target neurons is controlled by differentially timed waves of, among others, vasopressin, GABA, and glutamate release from SCN terminals. Together, the data on the SCN control of neuroendocrine rhythms provide clear evidence not only that the SCN consists of phenotypically (i.e., according to neurotransmitter content) different subpopulations of neurons but also that subpopulations should be distinguished (within phenotypically similar groups of neurons) based on the acrophase of their (electrical) activity. Moreover, the specialization of the SCN may go as far as a single body structure, that is, the SCN seems to contain neurons that specifically target the liver, pineal, and adrenal.
Animals↗
In vivo evidence for a controlled offset of melatonin synthesis at dawn by the suprachiasmatic nucleus in the rat.
The daily rhythm of melatonin synthesis in the rat pineal gland is controlled by the central biological clock, located in the suprachiasmatic nucleus (SCN), via a multi-synaptic pathway involving, successively, neurones of the paraventricular nucleus of the hypothalamus (PVN), sympathetic preganglionic neurones of the intermediolateral cell column of the spinal cord, and norepinephrine containing sympathetic neurones of the superior cervical ganglion. Recently, we showed that, in the rat, the SCN uses a combination of daytime inhibitory and nighttime stimulatory signals toward the PVN-pineal pathway in order to control the daily rhythm of melatonin synthesis, GABA being responsible for the daytime inhibitory message and glutamate for the nighttime stimulation. The present study was initiated to further check this concept, and to investigate the involvement of the inhibitory SCN output in the early morning circadian decline of melatonin release, with the hypothesis that, at dawn, the increased release of GABA onto pre-autonomic PVN neurones results in a diminished norepinephrine stimulation of the pineal, and ultimately an arrest of melatonin release. First, we established that prolonged norepinephrine stimulation of the pineal gland was indeed sufficient to prevent the early morning decline of melatonin release. Blockade of GABA-ergic signaling in the PVN at dawn could not prevent the early morning decline of melatonin completely. Therefore, these results show that an increased GABAergic inhibition of the PVN neurones that control the sympathetic innervation of the pineal gland, at dawn, is not sufficient to explain the early morning decline of melatonin release.
Adrenergic alpha-Agonists↗
Hyper and hypothyroidism change the expression and diurnal variation of thyroid hormone receptor isoforms in rat liver without major changes in their zonal distribution.
We investigated the effect of hypothyroidism or hyperthyroidism on mRNA and protein expression, diurnal variation and zonal distribution of thyroid hormone receptor (TR) isoforms TRalpha1, TRalpha2 and TRbeta1 in rat liver. Hypothyroidism results in increased isoform mRNA and protein expression whereas hyperthyroidism shows a decreased TRalpha1 and TRalpha2 mRNA and protein expression. During hyperthyroidism no change is seen in TRbeta1 mRNA, but TRbeta1 protein is upregulated in the light period and downregulated in the dark period. Diurnal changes (measured at 13:30 and 19:30 h) in the TR isoform proteins are abolished in hypothyroidism and hyperthyroidism, with the exception of a reversal in diurnal changes of TRbeta1 in hyperthyroidism. Zonal distribution of the isoforms is not affected by hypo- or hyperthyroidism. We therefore conclude that thyroid hormone influences both the levels and the diurnal expression of its receptor isoforms but not the zonal distribution.
Animals↗
Diurnal variation in rat liver thyroid hormone receptor (TR)-alpha messenger ribonucleic acid (mRNA) is dependent on the biological clock in the suprachiasmatic nucleus, whereas diurnal variation of TR beta 1 mRNA is modified by food intake.
Previous studies have shown a diurnal variation of certain isoforms of thyroid hormone receptors (TR) in rat liver. The genesis of these diurnal changes is still unknown. To clarify whether the biological clock, located in the hypothalamic suprachiasmatic nucleus (SCN), is involved, we made selective SCN lesions. Rats with an SCN lesion lost their circadian rhythm of plasma corticosterone and TSH when compared with intact animals. TR alpha 1 and TR alpha 2 mRNA expression of control rats was higher in the light period than in the dark period; changes that were abolished in the rats with SCN lesions. In contrast, liver TR beta 1 mRNA of intact rats showed a diurnal variation that failed to reach statistical significance. To evaluate whether these effects could be explained indirectly by the disappearance of rhythmic feeding behavior in rats with SCN lesions, we performed a second experiment in which otherwise intact animals were subjected to a regular feeding (RF) schedule, with one meal every 4 h. When compared with rats with free access to food, RF only affected TR beta 1 mRNA expression and had no effect on the diurnal changes in TR alpha 1 and TR alpha 2. We conclude that liver TR beta 1 expression is most clearly affected by food intake. Diurnal changes in liver TR alpha 1 and TR alpha 2 are controlled by the biological clock in the SCN but not via changes in the daily rhythm of food intake. The findings may have physiological relevance for diurnal variation of T(3)-dependent gene expression, which is supported by a diurnal variation in the expression of the 5'-deiodinase gene.
Animals↗
HIV-associated adipose redistribution syndrome as a selective autonomic neuropathy.
Abnormal body-fat distribution in HIV-1-associated adipose redistribution syndrome (HARS) remains unexplained at present. White adipose tissue is controlled by humoral factors and by neural regulation. Sympathetic innervation stimulates lipolysis, whereas parasympathetic innervation has an anabolic influence on white adipose tissue. Results of neuroanatomical studies showed a clear somatotopy with respect to autonomic control of white adipose tissue by both the sympathetic and parasympathetic branch, with separate sets of autonomic neurons innervating either the subcutaneous or the visceral fat compartment. Thus, the CNS is likely to be a key player in regulation of body-fat distribution. We propose that HARS is mediated by effects of antiretroviral treatment on the CNS and could indicate a change in autonomic balance resulting in redistribution of adipose tissue.
Adipose Tissue↗
White adipose tissue: getting nervous.
Neuroendocrine research has altered the traditional perspective of white adipose tissue (WAT) as a passive store of triglycerides. In addition to fatty acids, WAT produces many hormones and can therefore be designated as a traditional endocrine gland actively participating in the integrative physiology of fuel and energy metabolism, eating behaviour and the regulation of hormone secretion and sensitivity. WAT is controlled by humoral factors, para- and intracrine factors and by neural regulation. Sympathetic nerve fibres innervate WAT and stimulate lipolysis, leading to the release of glycerol and free fatty acids. In addition, recent research in rats has clearly shown a functional parasympathetic innervation of WAT. There appears to be a distinct somatotopy within the parasympathetic nuclei: separate sets of autonomic neurones in the brain stem innervate either the visceral or the subcutaneous fat compartment. We therefore propose that the central nervous system (CNS) plays a major role in the hitherto unexplained regulation of body fat distribution. Parasympathectomy induces insulin resistance with respect to glucose and fatty acid uptake in the innervated fat depot and has selective effects on local hormone synthesis. Thus, the CNS is involved not only in the regulation of hormone production by WAT, but also in its hormone sensitivity. The developments in this research area are likely to increase our insights in the pathogenesis of metabolic disorders such as hypertriglyceridemia, diabetes mellitus type 2 and lipodystrophy syndromes.
Adaptation, Physiological↗
The diurnal modulation of hormonal responses in the rat varies with different stimuli.
The circadian clock, located in the suprachiasmatic nuclei (SCN) of the hypothalamus not only controls the basal daily temporal organization of many neuroendocrine functions, but also its responsiveness. We studied the time-of-day influence on plasma changes in adrenocorticotropic hormone (ACTH), corticosterone, glucagon and leptin concentrations elicited by an insulin-induced hypoglycaemic event. Male Wistar rats were exposed to an insulin challenge at six different times during the light/dark cycle. The time-of-day of exposure markedly affected the responses of all four hormones studied. Generally, the magnitude of the different hormone responses correlated with their basal daily release pattern (i.e. the responses of ACTH and corticosterone were largest around lights off, and glucagon and leptin responses were most pronounced during the dark period). With regard to the hormones of the hypothalamic-pituitary-adrenal axis, the presently reported time-of-day dependent modulation is completely opposite to that previously reported for novelty or restraint. Therefore, these findings provide further support for the existence of at least two different neural pathways that are able to activate the hypothalamic-pituitary-adrenal axis, and provide different substrates for modulation by the biological clock. This observation warrants a thorough examination of possible functional explanations for the observed differences.
Adrenocorticotropic Hormone↗
The biological clock tunes the organs of the body: timing by hormones and the autonomic nervous system.
The biological clock, the suprachiasmatic nucleus (SCN), is essential for our daily well-being. It prepares us for the upcoming period of activity by an anticipatory rise in heart rate, glucose and cortisol. At the same time the 'hormone of the darkness', melatonin, decreases. Thus, the time-of-day message penetrates into all tissues, interestingly not only by means of hormones but also by a direct neuronal influence of the SCN on the organs of the body. The axis between the SCN and the paraventricular nucleus of the hypothalamus (PVN) is crucial for the organization/synchronization of the neuroendocrine and autonomic nervous system with the time of day. This SCN-neuroendocrine PVN axis takes care of a timely hormonal secretion. At the same time, the SCN-autonomic PVN axis fine-tunes the organs by means of the autonomic nervous system for the reception of these hormones. Finally, the similar organization of the projections of the human SCN as compared with that in the rodent brain suggests that these basic principles of neuroendocrine autonomic interaction may also be true in the human. The physiological data collected in humans thus far seem to support this hypothesis, while pathological changes in the SCN of humans suffering from depression or hypertension indicate a role for the SCN in the etiology of these diseases.
Animals↗
[Adipose tissue: an innervated endocrine gland].
Until recently, adipose tissue was considered to function as a passive store of triglycerides and therefore of calories. Fascinating research over the past ten years has altered this traditional perspective. Adipose tissue has been shown to produce hormones. Leptin was discovered in 1994; one of its main functions is to adapt the organism to starvation. Sympathetic nerve fibres were shown to innervate adipose tissue and to facilitate lipolysis leading to the release of glycerol and free fatty acids. In addition, parasympathetic innervation of adipose tissue was recently demonstrated, with anabolic effects. Different sets of autonomic neurons in the brain stem appear to innervate either the abdominal or the subcutaneous fat compartment. This may be the anatomical substrate for the hitherto unexplained regulation of body fat distribution (subcutaneous versus intra-abdominal). Moreover, fat distribution under physiological conditions (sex steroids, glucocorticoids) and pathological conditions (e.g., AIDS lipodystrophy, Cushing syndrome) might be mediated via the central nervous system. The developments in this research area have the potential to increase our insights into the pathogenesis of metabolic disorders such as hypertriglyceridaemia and type-2 diabetes mellitus.
Adipose Tissue↗
The stimulatory effect of vasopressin on the luteinizing hormone surge in ovariectomized, estradiol-treated rats is time-dependent.
The luteinizing hormone surge in the female rat is not only induced by the positive feedback of estradiol, but also by circadian signals originating in the suprachiasmatic nucleus (SCN). In a previous study we showed that administration of vasopressin, an SCN transmitter present in preoptic projections, induced an LH surge in animals bearing complete lesions of the SCN. This strongly suggests vasopressin as a stimulatory circadian signal for the timing of the LH surge. In the present study we investigated during which time window vasopressin may act in the medial preoptic area to stimulate LH secretion in SCN-intact female rats. Vasopressin or a specific V1a receptor antagonist was administered into the MPO by a reverse microdialysis technique during different time windows, and plasma LH concentrations were measured. Vasopressin stimulated the LH surge in 30% of the animals, when administered during the second half of the light period, but during the first half of the light period no effects were observed. Administration of the V1a receptor antagonist, however, did not affect the LH surge. These data confirm our previous results that vasopressin is a stimulatory factor for the LH surge also in SCN-intact animals, and indicate that a certain time window is available for such stimulation. We hypothesize that vasopressin in the SCN-intact animal may act as a circadian signal during a specific time window to induce the LH surge. The time window is the result of other SCN regulatory systems that are involved in the preparation of the LH surge.
Animals↗
Hypothalamic integration of central and peripheral clocks.
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Animals↗
Role for the pineal and melatonin in glucose homeostasis: pinealectomy increases night-time glucose concentrations.
The effects of melatonin on glucose metabolism are far from understood. In rats, the biological clock generates a 24-h rhythm in plasma glucose concentrations, with declining concentrations in the dark period. We hypothesized that, in the rat, melatonin enhances the dark signal of the biological clock, decreasing glucose concentrations in the dark period. We measured 24-h rhythms of plasma concentrations of glucose and insulin in pinealectomized rats fed ad libitum and subjected to a scheduled feeding regimen with six meals equally distributed over the light/dark cycle and compared them with previous data of intact rats. Pinealectomy dampened the amplitude of the 24-h rhythm in plasma glucose concentrations in rats fed ad libitum, and abolished it completely in rats subjected to the scheduled feeding regimen, while plasma insulin concentrations did not change under both conditions. Pinealectomy abolished the nocturnal decline in plasma glucose concentrations irrespective of whether rats were fed ad libitum or subjected to the scheduled feeding regimen. Melatonin replacement restored 24-h mean plasma glucose concentrations in pinealectomized rats that were subjected to the scheduled feeding regimen but, interestingly, it did not restore the 24-h rhythm. Melatonin treatment also resulted in higher meal-induced insulin responses, probably mediated via an increased sensitivity of the beta-cells. Taken together, our data demonstrate that the pineal hormone, melatonin, influences both glucose metabolism and insulin secretion from the pancreatic beta-cell. The present study also demonstrates that removal of the pineal gland cannot be compensated by mimicking plasma melatonin concentrations only.
Animals↗
The suprachiasmatic nucleus generates the diurnal changes in plasma leptin levels.
At present it is not clear which factors are responsible for the diurnal pattern of plasma leptin levels, although the timing of food intake and circulating hormones such as glucocorticoids and insulin have both been proposed as independent determinants. In this study we show that ablation of the biological clock by thermal lesions of the hypothalamic suprachiasmatic nucleus (SCN) completely eliminates the diurnal pattern of plasma leptin levels. By contrast, removal of the diurnal corticosterone signal by adrenalectomy and corticosterone replacement did not affect diurnal plasma leptin levels. More importantly, removal of the nocturnal feeding signal by submitting the animals to a regular feeding schedule of six meals per day did not abolish the diurnal plasma leptin levels. However, both SCN lesions and the regular feeding schedule did cause an increase in the 24-h mean plasma leptin levels. As neither rhythmic feeding, insulin, or corticosterone signals can completely explain the diurnal plasma leptin rhythm, we conclude that biological clock control of the sympathetic input to the adipocyte is essential for regulation of the daily rhythm in leptin release.
Adipocytes↗
Control of the estradiol-induced prolactin surge by the suprachiasmatic nucleus.
In the present study we investigated how the suprachiasmatic nucleus (SCN) controls the E(2)-induced PRL surge in female rats. First, the role of vasopressin (VP), a SCN transmitter present in medial preoptic area (MPO) projections and rhythmically released by SCN neurons, as a circadian signal for the E(2)-induced PRL surge was investigated. Using a reverse microdialysis technique, VP was administered in the MPO during the PRL surge, resulting in a suppression of the surge. VP administration before the surge did not affect PRL secretion. Also, administration of a V1a receptor antagonist before the surge was ineffective. Second, lesions of the SCN were made that resulted in constant basal PRL levels, suggesting that with removal of the SCN a stimulatory factor for PRL secretion disappeared. Indeed, the PRL secretory response to blockade of pituitary dopamine receptors was significantly reduced in SCN-lesioned animals. These data suggest that the afternoon decrease of VP release in the MPO by SCN terminals enables the PRL surge to occur, and may thus be a circadian signal for the PRL surge. Simultaneously the SCN is involved in the regulation of the secretory capacity of the pituitary, possibly via specific PRL-releasing factors.
Animals↗
A daily rhythm in glucose tolerance: a role for the suprachiasmatic nucleus.
The suprachiasmatic nucleus (SCN), the biological clock, is responsible for a 24-h rhythm in plasma glucose concentrations, with the highest concentrations toward the beginning of the activity period. To investigate whether the SCN is also responsible for daily fluctuations in glucose uptake and to examine how these fluctuations relate to the rhythm in plasma glucose concentrations, SCN-intact rats and SCN-lesioned rats were injected intravenously with a glucose bolus at different time points. We found an increase in glucose uptake toward the beginning of the activity period, followed by a gradual reduction in glucose uptake toward the end of the activity period. The daily variation in glucose tolerance seemed not to be caused by fluctuations in insulin responses of the pancreas but by a daily variation in insulin sensitivity. Lesioning the SCN resulted in the disappearance of the daily fluctuation in glucose uptake and insulin sensitivity. Interestingly, SCN-lesioned rats showed an enhancement in glucose tolerance that could not be explained by higher insulin responses or enhanced insulin sensitivity. Therefore, these findings suggest a role for the SCN in insulin-independent glucose uptake. The present results further show that the daily rhythm in glucose tolerance follows the same pattern as the daily rhythm in plasma glucose concentrations. We hypothesized that the biological clock prepares the individual for the upcoming activity period by two separate mechanisms: increasing plasma glucose concentrations and making tissue more tolerant to glucose.
Animals↗