Chun-Xia Yi

Organization of circadian functions: interaction with the body.

The hypothalamus integrates information from the brain and the body; this activity is essential for survival of the individual (adaptation to the environment) and the species (reproduction). As a result, countless functions are regulated by neuroendocrine and autonomic hypothalamic processes in concert with the appropriate behaviour that is mediated by neuronal influences on other brain areas. In the current chapter attention will be focussed on fundamental hypothalamic systems that control metabolism, circulation and the immune system. Herein a system is defined as a physiological and anatomical functional unit, responsible for the organisation of one of these functions. Interestingly probably because these systems are essential for survival, their function is highly dependent on each others performance and often shares same hypothalamic structures. The functioning of these systems is strongly influenced by (environmental) factors such as the time of the day, stress and sensory autonomic feedback and by circulating hormones. In order to get insight in the mechanisms of hypothalamic integration we have focussed on the influence of the biological clock; the suprachiasmatic nucleus (SCN) on processes that are organized by and in the hypothalamus. The SCN imposes its rhythm onto the body via three different routes of communication: 1.Via the secretion of hormones; 2. via the parasympathetic and 3.via the sympathetic autonomous nervous system. The SCN uses separate connections via either the sympathetic or via the parasympathetic system not only to prepare the body for the coming change in activity cycle but also to prepare the body and its organs for the hormones that are associated with such change. Up till now relatively little attention has been given to the question how peripheral information might be transmitted back to the SCN. Apart from light and melatonin little is known about other systems from the periphery that may provide information to the SCN. In this chapter attention will be paid to e.g. the role of the circumventricular organs in passing info to the SCN. Herein especially the role of the arcuate nucleus (ARC) will be highlighted. The ARC is crucial in the maintenance of energy homeostasis as an integrator of long- and short-term hunger and satiety signals. Receptors for metabolic hormones like insulin, leptin and ghrelin allow the ARC to sense information from the periphery and signal it to the central nervous system. Neuroanatomical tracing studies using injections of a retrograde and anterograde tracer into the ARC and SCN showed a reciprocal connection between the ARC and the SCN which is used to transmit feeding related signals to the SCN. The implications of multiple inputs and outputs of the SCN to the body will be discussed in relation with metabolic functions.

A major role for perifornical orexin neurons in the control of glucose metabolism in rats

OBJECTIVE The hypothalamic neuropeptide orexin influences (feeding) behavior as well as energy metabolism. Administration of exogenous orexin-A into the brain has been shown to increase both food intake and blood glucose levels. In the present study, we investigated the role of endogenous hypothalamic orexin release in glucose homeostasis in rats. RESEARCH DESIGN AND METHODS We investigated the effects of the hypothalamic orexin system on basal endogenous glucose production (EGP) as well as on hepatic and peripheral insulin sensitivity by changing orexinergic activity in the hypothalamus combined with hepatic sympathetic or parasympathetic denervation, two-step hyperinsulinemic-euglycemic clamps, immunohistochemistry, and RT-PCR studies. RESULTS Hypothalamic disinhibition of neuronal activity by the γ-aminobutyric acid receptor antagonist bicuculline (BIC) increased basal EGP, especially when BIC was administered in the perifornical area where orexin-containing neurons but not melanocortin-concentrating hormone–containing neurons were activated. The increased BIC-induced EGP was largely prevented by intracerebroventricular pretreatment with the orexin-1 receptor antagonist. Intracerebroventricular administration of orexin-A itself caused an increase in plasma glucose and prevented the daytime decrease of EGP. The stimulatory effect of intracerebroventricular orexin-A on EGP was prevented by hepatic sympathetic denervation. Plasma insulin clamped at two or six times the basal levels did not counteract the stimulatory effect of perifornical BIC on EGP, indicating hepatic insulin resistance. RT-PCR showed that stimulation of orexin neurons increased the expression of hepatic glucoregulatory enzymes. CONCLUSIONS Hypothalamic orexin plays an important role in EGP, most likely by changing the hypothalamic output to the autonomic nervous system. Disturbance of this pathway may result in unbalanced glucose homeostasis.

Interaction between hypothalamic dorsomedial nucleus and the suprachiasmatic nucleus determines intensity of food anticipatory behavior

Food anticipatory behavior (FAA) is induced by limiting access to food for a few hours daily. Animals anticipate this scheduled meal event even without the suprachiasmatic nucleus (SCN), the biological clock. Consequently, a food-entrained oscillator has been proposed to be responsible for meal time estimation. Recent studies suggested the dorsomedial hypothalamus (DMH) as the site for this food-entrained oscillator, which has led to considerable controversy in the literature. Herein we demonstrate by means of c-Fos immunohistochemistry that the neuronal activity of the suprachiasmatic nucleus (SCN), which signals the rest phase in nocturnal animals, is reduced when animals anticipate the scheduled food and, simultaneously, neuronal activity within the DMH increases. Using retrograde tracing and confocal analysis, we show that inhibition of SCN neuronal activity is the consequence of activation of GABA-containing neurons in the DMH that project to the SCN. Next, we show that DMH lesions result in a loss or diminution of FAA, simultaneous with increased activity in the SCN. A subsequent lesion of the SCN restored FAA. We conclude that in intact animals, FAA may only occur when the DMH inhibits the activity of the SCN, thus permitting locomotor activity. As a result, FAA originates from a neuronal network comprising an interaction between the DMH and SCN. Moreover, this study shows that the DMH–SCN interaction may serve as an intrahypothalamic system to gate activity instead of rest overriding circadian predetermined temporal patterns.

The role of the autonomic nervous liver innervation in the control of energy metabolism

Despite a longstanding research interest ever since the early work by Claude Bernard, the functional significance of autonomic liver innervation, either sympathetic or parasympathetic, is still ill defined. This scarcity of information not only holds for the brain control of hepatic metabolism, but also for the metabolic sensing function of the liver and the way in which this metabolic information from the liver affects the brain. Clinical information from the bedside suggests that successful human liver transplantation (implying a complete autonomic liver denervation) causes no life threatening metabolic derangements, at least in the absence of severe metabolic challenges such as hypoglycemia. However, from the benchside, data are accumulating that interference with the neuronal brain-liver connection does cause pronounced changes in liver metabolism. This review provides an extensive overview on how metabolic information is sensed by the liver, and how this information is processed via neuronal pathways to the brain. With this information the brain controls liver metabolism and that of other organs and tissues. We will pay special attention to the hypothalamic pathways involved in these liver-brain-liver circuits. At this stage, we still do not know the final destination and processing of the metabolic information that is transferred from the liver to the brain. On the other hand, in recent years, there has been a considerable increase in the understanding which brain areas are involved in the control of liver metabolism via its autonomic innervation. However, in view of the ever rising prevalence of type 2 diabetes, this potentially highly relevant knowledge is still by far too limited. Thus the autonomic innervation of the liver and its role in the control of metabolism needs our continued and devoted attention.

The hypothalamic clock and its control of glucose homeostasis

The everyday life of mammals, including humans, exhibits many behavioral, physiological and endocrine oscillations. The major timekeeping mechanism for these rhythms is contained in the central nervous system (CNS). The output of the CNS clock not only controls daily rhythms in sleep/wake (or feeding/fasting) behavior but also exerts a direct control over glucose metabolism. Here, we show how the biological clock plays an important role in determining early morning (fasting) plasma glucose concentrations by affecting hepatic glucose production and glucose uptake, as well as glucose tolerance, by determining feeding-induced insulin responses. Recently, large-scale genetic studies in humans provided the first evidence for the involvement of disrupted (clock gene) rhythms in the pathogenesis of type 2 diabetes.

Circadian disruption and SCN control of energy metabolism

In this review we first present the anatomical pathways used by the suprachiasmatic nuclei to enforce its rhythmicity onto the body, especially its energy homeostatic system. The experimental data show that by activating the orexin system at the start of the active phase, the biological clock not only ensures that we wake up on time, but also that our glucose metabolism and cardiovascular system are prepared for increased activity. The drawback of such a highly integrated system, however, becomes visible when our daily lives are not fully synchronized with the environment. Thus, in addition to increased physical activity and decreased intake of high‐energy food, also a well‐lighted and fully resonating biological clock may help to withstand the increasing “diabetogenic” pressure of todays 24/7 society.

Hypothalamic innate immune reaction in obesity

Findings from rodent and human studies show that the presence of inflammatory factors is positively correlated with obesity and the metabolic syndrome. Obesity-associated inflammatory responses take place not only in the periphery but also in the brain. The hypothalamus contains a range of resident glial cells including microglia, macrophages and astrocytes, which are embedded in highly heterogenic groups of neurons that control metabolic homeostasis. This complex neural–glia network can receive information directly from blood-borne factors, positioning it as a metabolic sensor. Following hypercaloric challenge, mediobasal hypothalamic microglia and astrocytes enter a reactive state, which persists during diet-induced obesity. In established mouse models of diet-induced obesity, the hypothalamic vasculature displays angiogenic alterations. Moreover, proopiomelanocortin neurons, which regulate food intake and energy expenditure, are impaired in the arcuate nucleus, where there is an increase in local inflammatory signals. The sum total of these events is a hypothalamic innate immune reactivity, which includes temporal and spatial changes to each cell population. Although the exact role of each participant of the neural–glial–vascular network is still under exploration, therapeutic targets for treating obesity should probably be linked to individual cell types and their specific signalling pathways to address each dysfunction with cell-selective compounds.

Glucocorticoid Signaling in the Arcuate Nucleus Modulates Hepatic Insulin Sensitivity

Glucocorticoid receptors are highly expressed in the hypothalamic paraventricular nucleus (PVN) and arcuate nucleus (ARC). As glucocorticoids have pronounced effects on neuropeptide Y (NPY) expression and as NPY neurons projecting from the ARC to the PVN are pivotal for balancing feeding behavior and glucose metabolism, we investigated the effect of glucocorticoid signaling in these areas on endogenous glucose production (EGP) and insulin sensitivity by local retrodialysis of the glucocorticoid receptor agonist dexamethasone into the ARC or the PVN, in combination with isotope dilution and hyperinsulinemic–euglycemic clamp techniques. Retrodialysis of dexamethasone for 90 min into the ARC or the PVN did not have significant effects on basal plasma glucose concentration. During the hyperinsulinemic–euglycemic clamp, retrodialysis of dexamethasone into the ARC largely prevented the suppressive effect of hyperinsulinemia on EGP. Antagonizing the NPY1 receptors by intracerebroventricular infusion of its antagonist largely blocked the hepatic insulin resistance induced by dexamethasone in the ARC. The dexamethasone-ARC–induced inhibition of hepatic insulin sensitivity was also prevented by hepatic sympathetic denervation. These data suggest that glucocorticoid signaling specifically in the ARC neurons modulates hepatic insulin responsiveness via NPY and the sympathetic system, which may add to our understanding of the metabolic impact of clinical conditions associated with hypercortisolism.

Hypothalamic astrocytes in obesity

Obesity is characterized by a chronic and low-grade inflammation in tissues including the hypothalamus. Hypothalamic inflammation is considered an early and determining factor for the onset of obesity, a factor that occurs even before body weight gain. Within the hypothalamus, microglia and astrocytes produce cytokines that drive inflammatory responses. Astrocytes are directly affected by nutrient excess and might play a unique role in promoting hypothalamic inflammatory responses in obesity. This article reviews evidence supporting the role of hypothalamic astrocytes in obesity, and suggests a new approach for neuroendocrine research designed to reveal pathogenesis and develop novel treatment strategies against obesity.

Inverse Agonistic Action of 3-Iodothyronamine at the Human Trace Amine-Associated Receptor 5

Objective Application of 3-iodothyronamine (3-T1AM) results in decreased body temperature and body weight in rodents. The trace amine-associated receptor (TAAR) 1, a family A G protein-coupled receptor, is a target of 3-T1AM. However, 3-T1AM effects still persist in mTaar1 knockout mice, which suggest so far unknown further receptor targets that are of physiological relevance. TAAR5 is a highly conserved TAAR subtype among mammals and we here tested TAAR5 as a potential 3-T1AM target. First, we investigated mouse Taar5 (mTaar5) expression in several brain regions of the mouse in comparison to mTaar1. Secondly, to unravel the full spectrum of signaling capacities, we examined the distinct Gs-, Gi/o-, G12/13-, Gq/11- and MAP kinase-mediated signaling pathways of mouse and human TAAR5 under ligand-independent conditions and after application of 3-T1AM. We found overlapping localization of mTaar1 and mTaar5 in the amygdala and ventromedial hypothalamus of the mouse brain. Second, the murine and human TAAR5 (hTAAR5) display significant basal activity in the Gq/11 pathway but show differences in the basal activity in Gs and MAP kinase signaling. In contrast to mTaar5, 3-T1AM application at hTAAR5 resulted in significant reduction in basal IP3 formation and MAP kinase signaling. In conclusion, our data suggest that the human TAAR5 is a target for 3-T1AM, exhibiting inhibitory effects on IP3 formation and MAP kinase signaling pathways, but does not mediate Gs signaling effects as observed for TAAR1. This study also indicates differences between TAAR5 orthologs with respect to their signaling profile. In consequence, 3-T1AM-mediated effects may differ between rodents and humans.