The response to prolonged fasting in hypothalamic serotonin transporter availability is blunted in obesity.

BACKGROUND AND AIMS: Serotonergic and dopaminergic systems in the brain are essential for homeostatic and reward-associated regulation of food intake and systemic energy metabolism. It is largely unknown how fasting influences these systems or if such effects are altered in humans with obesity. We therefore aimed to evaluate the effects of fasting on hypothalamic/thalamic serotonin transporter (SERT) and striatal dopamine transporter (DAT) availability in lean subjects and subjects with obesity. METHODS: In this randomized controlled cross-over trial, we assessed the effects of 12 vs 24 h of fasting on SERT and DAT availability in the hypothalamus/thalamus and striatum, respectively, using SPECT imaging in 10 lean men and 10 men with obesity. RESULTS: As compared with the 12-h fast, a 24-h fast increased hypothalamic SERT availability in lean men, but not in men with obesity. We observed high inter-individual variation in the effects of fasting on thalamic SERT and striatal DAT, with no differences between lean men and those with obesity. In all subjects, fasting-induced increases in circulating free fatty acid (FFA) concentrations were associated with an increase in hypothalamic SERT availability and a decrease in striatal DAT availability. Multiple regression analysis showed that changes in plasma insulin and FFAs together accounted for 44% of the observed variation in striatal DAT availability. CONCLUSION: Lean men respond to prolonged fasting by increasing hypothalamic SERT availability, whereas this response is absent in men with obesity. Inter-individual differences in the adaptations of the cerebral serotonergic and dopaminergic systems to fasting may, in part, be explained by changes in peripheral metabolic signals of fasting, including FFAs and insulin.

Hypothalamic neuropeptides and neurocircuitries in Prader Willi syndrome.

Prader-Willi Syndrome (PWS) is a rare and incurable congenital neurodevelopmental disorder, resulting from the absence of expression of a group of genes on the paternally acquired chromosome 15q11-q13. Phenotypical characteristics of PWS include infantile hypotonia, short stature, incomplete pubertal development, hyperphagia and morbid obesity. Hypothalamic dysfunction in controlling body weight and food intake is a hallmark of PWS. Neuroimaging studies have demonstrated that PWS subjects have abnormal neurocircuitry engaged in the hedonic and physiological control of feeding behavior. This is translated into diminished production of hypothalamic effector peptides which are responsible for the coordination of energy homeostasis and satiety. So far, studies with animal models for PWS and with human post-mortem hypothalamic specimens demonstrated changes particularly in the infundibular and the paraventricular nuclei of the hypothalamus, both in orexigenic and anorexigenic neural populations. Moreover, many PWS patients have a severe endocrine dysfunction, e.g. central hypogonadism and/or growth hormone deficiency, which may contribute to the development of increased fat mass, especially if left untreated. Additionally, the role of non-neuronal cells, such as astrocytes and microglia in the hypothalamic dysregulation in PWS is yet to be determined. Notably, microglial activation is persistently present in non-genetic obesity. To what extent microglia, and other glial cells, are affected in PWS is poorly understood. The elucidation of the hypothalamic dysfunction in PWS could prove to be a key feature of rational therapeutic management in this syndrome. This review aims to examine the evidence for hypothalamic dysfunction, both at the neuropeptidergic and circuitry levels, and its correlation with the pathophysiology of PWS.

Downregulation of Type 3 Deiodinase in the Hypothalamus During Inflammation.

Background: Inflammation is associated with marked changes in cellular thyroid hormone (TH) metabolism in triiodothyronine (T3) target organs. In the hypothalamus, type 2 deiodinase (D2), the main T3 producing enzyme, increases upon inflammation, leading to an increase in local T3 availability, which in turn decreases thyrotropin releasing hormone expression in the paraventricular nucleus. Type 3 deiodinase (D3), the T3 inactivating enzyme, decreases during inflammation, which might also contribute to the increased T3 availability in the hypothalamus. While it is known that D2 is regulated by nuclear factor κB (NF-κB) during inflammation, the underlying mechanisms of D3 regulation are unknown. Therefore, the aim of the present study was to investigate inflammation-induced D3 regulation using in vivo and in vitro models. Methods: Mice were injected with a sublethal dose of bacterial endotoxin (lipopolysaccharide [LPS]) to induce a systemic acute-phase response. A human neuroblastoma (SK-N-AS) cell line was used to test the involvement of the thyroid hormone receptor alpha 1 (TRα1) as well as the activator protein-1 (AP-1) and NF-κB inflammatory pathways in the inflammation-induced decrease of D3. Results: D3 expression in the hypothalamus was decreased 24 hours after LPS injection in mice. This decrease was similar in mice lacking the TRα. Incubation of SK-N-AS cells with LPS robustly decreased both D3 mRNA expression and activity. This led to increased intracellular T3 concentrations. The D3 decrease was prevented when NF-κB or AP-1 was inhibited. TRα1 mRNA expression decreased in SK-N-AS cells incubated with LPS, but knockdown of the TRα in SK-N-AS cells did not prevent the LPS-induced D3 decrease. Conclusions: We conclude that the inflammation-induced D3 decrease in the hypothalamus is mediated by the inflammatory pathways NF-κB and AP-1, but not TRα1. Furthermore, the observed decrease modulates intracellular T3 concentrations. Our results suggest a concerted action of inflammatory modulators to regulate both hypothalamic D2 and D3 activities to increase the local TH concentrations.

Mutations in IRS4 are associated with central hypothyroidism.

BACKGROUND: Four genetic causes of isolated congenital central hypothyroidism (CeH) have been identified, but many cases remain unexplained. We hypothesised the existence of other genetic causes of CeH with a Mendelian inheritance pattern. METHODS: We performed exome sequencing in two families with unexplained isolated CeH and subsequently Sanger sequenced unrelated idiopathic CeH cases. We performed clinical and biochemical characterisation of the probands and carriers identified by family screening. We investigated IRS4 mRNA expression in human hypothalamus and pituitary tissue, and measured serum thyroid hormones and Trh and Tshb mRNA expression in hypothalamus and pituitary tissue of Irs4 knockout mice. RESULTS: We found mutations in the insulin receptor substrate 4 (IRS4) gene in two pairs of brothers with CeH (one nonsense, one frameshift). Sequencing of IRS4 in 12 unrelated CeH cases negative for variants in known genes yielded three frameshift mutations (two novel) in three patients and one male sibling. All male carriers (n=8) had CeH with plasma free thyroxine concentrations below the reference interval. MRI of the hypothalamus and pituitary showed no structural abnormalities (n=12). 24-hour thyroid-stimulating hormone (TSH) secretion profiles in two adult male patients showed decreased basal, pulsatile and total TSH secretion. IRS4 mRNA was expressed in human hypothalamic nuclei, including the paraventricular nucleus, and in the pituitary gland. Female knockout mice showed decreased pituitary Tshb mRNA levels but had unchanged serum thyroid hormone concentrations. CONCLUSIONS: Mutations in IRS4 are associated with isolated CeH in male carriers. As IRS4 is involved in leptin signalling, the phenotype may be related to disrupted leptin signalling.

Mutations in TBL1X Are Associated With Central Hypothyroidism.

CONTEXT: Isolated congenital central hypothyroidism (CeH) can result from mutations in TRHR, TSHB, and IGSF1, but its etiology often remains unexplained. We identified a missense mutation in the transducin ß-like protein 1, X-linked (TBL1X) gene in three relatives diagnosed with isolated CeH. TBL1X is part of the thyroid hormone receptor-corepressor complex. OBJECTIVE: The objectives of the study were the identification of TBL1X mutations in patients with unexplained isolated CeH, Sanger sequencing of relatives of affected individuals, and clinical and biochemical characterization; in vitro investigation of functional consequences of mutations; and mRNA expression in, and immunostaining of, human hypothalami and pituitary glands. DESIGN: This was an observational study. SETTING: The study was conducted at university medical centers. PATIENTS: Nineteen individuals with and seven without a mutation participated in the study. MAIN OUTCOME MEASURES: Outcome measures included sequencing results, clinical and biochemical characteristics of mutation carriers, and results of in vitro functional and expression studies. RESULTS: Sanger sequencing yielded five additional mutations. All patients (n = 8; six males) were previously diagnosed with CeH (free T4 [FT4] concentration below the reference interval, normal thyrotropin). Eleven relatives (two males) also carried mutations. One female had CeH, whereas 10 others had low-normal FT4 concentrations. As a group, adult mutation carriers had 20%-25% lower FT4 concentrations than controls. Twelve of 19 evaluated carriers had hearing loss. Mutations are located in the highly conserved WD40-repeat domain of the protein, influencing its expression and thermal stability. TBL1X mRNA and protein are expressed in the human hypothalamus and pituitary. CONCLUSIONS: TBL1X mutations are associated with CeH and hearing loss. FT4 concentrations in mutation carriers vary from low-normal to values compatible with CeH.

Feeding during the resting phase causes profound changes in physiology and desynchronization between liver and muscle rhythms of rats.

Shiftworkers run an increased risk of developing metabolic disorders, presumably as a result of disturbed circadian physiology. Eating at a time-of-day that is normally dedicated to resting and fasting, may contribute to this association. The hypothalamus is the key brain area that integrates different inputs, including environmental time information from the central biological clock in the suprachiasmatic nuclei, with peripheral information on energy status to maintain energy homeostasis. The orexin system within the lateral hypothalamus is an important output of the suprachiasmatic nuclei involved in the control of sleep/wake behavior and glucose homeostasis, among other functions. In this study, we tested the hypothesis that feeding during the rest period disturbs the orexin system as a possible underlying contributor to metabolic health problems. Male Wistar rats were exposed to an 8-week protocol in which food was available ad libitum for 24-h, for 12-h during the light phase (i.e., unnatural feeding time) or for 12-h during the dark phase (i.e., restricted feeding, but at the natural time-of-day). Animals forced to eat at an unnatural time, i.e., during the light period, showed no changes in orexin and orexin-receptor gene expression in the hypothalamus, but the rhythmic expression of clock genes in the lateral hypothalamus was absent in these animals. Light fed animals did show adverse changes in whole-body physiology and internal desynchronization of muscle and liver clock and metabolic gene expression. Eating at the 'wrong' time-of-day thus causes internal desynchronization at different levels, which in the long run may disrupt body physiology.

Effects of Intracerebroventricular Administration of Neuropeptide Y on Metabolic Gene Expression and Energy Metabolism in Male Rats.

Neuropeptide Y (NPY) is an important neurotransmitter in the control of energy metabolism. Several studies have shown that obesity is associated with increased levels of NPY in the hypothalamus. We hypothesized that the central release of NPY has coordinated and integrated effects on energy metabolism in different tissues, resulting in increased energy storage and decreased energy expenditure (EE). We first investigated the acute effects of an intracerebroventricular (ICV) infusion of NPY on gene expression in liver, brown adipose tissue, soleus muscle, and sc and epididymal white adipose tissue (WAT). We found increased expression of genes involved in gluconeogenesis and triglyceride secretion in the liver already 2-hour after the start of the NPY administration. In brown adipose tissue, the expression of thermogenic genes was decreased. In sc WAT, the expression of genes involved in lipogenesis was increased, whereas in soleus muscle, the expression of lipolytic genes was decreased after ICV NPY. These findings indicate that the ICV infusion of NPY acutely and simultaneously increases lipogenesis and decreases lipolysis in different tissues. Subsequently, we investigated the acute effects of ICV NPY on locomotor activity, respiratory exchange ratio, EE, and body temperature. The ICV infusion of NPY increased locomotor activity, body temperature, and EE as well as respiratory exchange ratio. Together, these results show that an acutely increased central availability of NPY results in a shift of metabolism towards lipid storage and an increased use of carbohydrates, while at the same time increasing activity, EE, and body temperature.

Autonomic regulation of hepatic glucose production.

Glucose produced by the liver is a major energy source for the brain. Considering its critical dependence on glucose, it seems only natural that the brain is capable of monitoring and controlling glucose homeostasis. In addition to neuroendocrine pathways, the brain uses the autonomic nervous system to communicate with peripheral organs. Within the brain, the hypothalamus is the key region to integrate signals on energy status, including signals from lipid, glucose, and hormone sensing cells, with afferent neural signals from the internal and external milieu. In turn, the hypothalamus regulates metabolism in peripheral organs, including the liver, not only via the anterior pituitary gland but also via multiple neuropeptidergic pathways in the hypothalamus that have been identified as regulators of hepatic glucose metabolism. These pathways comprise preautonomic neurons projecting to nuclei in the brain stem and spinal cord, which relay signals from the hypothalamus to the liver via the autonomic nervous system. The neuroendocrine and neuronal outputs of the hypothalamus are not separate entities. They appear to act as a single integrated regulatory system, far more subtle, and complex than when each is viewed in isolation. Consequently, hypothalamic regulation should be viewed as a summation of both neuroendocrine and neural influences. As a result, our endocrine-based understanding of diseases such as diabetes and obesity should be expanded by integration of neural inputs into our concept of the pathophysiological process.

Effects of adrenalectomy on daily gene expression rhythms in the rat suprachiasmatic and paraventricular hypothalamic nuclei and in white adipose tissue.

It is assumed that in mammals the circadian rhythms of peripheral clocks are synchronized to the environment via neural, humoral and/or behavioral outputs of the central pacemaker in the suprachiasmatic nucleus of the hypothalamus (SCN). With regard to the humoral outputs, the daily rhythm of the adrenal hormone corticosterone is considered as an important candidate. To examine whether adrenal hormones are necessary for the maintenance of daily rhythms in gene expression in white adipose tissue (WAT), we used RT-PCR to check rhythmic as well as 24 h mean gene expression in WAT from adrenalectomized (ADX) and sham-operated rats. In addition, we investigated the effect of adrenalectomy on gene expression in the hypothalamic SCN and paraventricular nucleus (PVN). Adrenalectomy hardly affected daily rhythms of clock gene expression in WAT. On the other hand, >80% of the rhythmic metabolic/adipokine genes in WAT lost their daily rhythmicity in ADX rats. Likewise, in the hypothalamus adrenalectomy had no major effects on daily rhythms in gene expression, but it did change the expression level of some of the neuropeptide genes. Together, these data indicate that adrenal hormones are important for the maintenance of daily rhythms in metabolic/adipokine gene expression in WAT, without playing a major role in clock gene expression in either WAT or hypothalamus.

Hypothalamic control of hepatic lipid metabolism via the autonomic nervous system.

Our body is well designed to store energy in times of nutrient excess, and release energy in times of food deprivation. This adaptation to the external environment is achieved by humoral factors and the autonomic nervous system. Claude Bernard, in the 19th century, showed the importance of the autonomic nervous system in the control of glucose metabolism. In the 20th century, the discovery of insulin and the development of techniques to measure hormone concentrations shifted the focus from the neural control of metabolism to the secretion of hormones, thus functionally "decapitating" the body. Just before the end of the 20th century, starting with the discovery of leptin in 1994, the control of energy metabolism went back to our heads. Since the start of 21st century, numerous studies have reported the involvement of hypothalamic pathways in the control of hepatic insulin sensitivity and glucose production. The autonomic nervous system is, therefore, acknowledged to be one of the important determinants of liver metabolism and a possible treatment target. In this chapter, we review research to date on the hypothalamic control of hepatic lipid metabolism.

Estradiol regulates brown adipose tissue thermogenesis via hypothalamic AMPK.

Estrogens play a major role in the modulation of energy balance through central and peripheral actions. Here, we demonstrate that central action of estradiol (E2) inhibits AMP-activated protein kinase (AMPK) through estrogen receptor alpha (ERα) selectively in the ventromedial nucleus of the hypothalamus (VMH), leading to activation of thermogenesis in brown adipose tissue (BAT) through the sympathetic nervous system (SNS) in a feeding-independent manner. Genetic activation of AMPK in the VMH prevented E2-induced increase in BAT-mediated thermogenesis and weight loss. Notably, fluctuations in E2 levels during estrous cycle also modulate this integrated physiological network. Together, these findings demonstrate that E2 regulation of the VMH AMPK-SNS-BAT axis is an important determinant of energy balance and suggest that dysregulation in this axis may account for the common changes in energy homeostasis and obesity linked to dysfunction of the female gonadal axis.

Hormonal control of metabolism by the hypothalamus-autonomic nervous system-liver axis.

The hypothalamus has long been appreciated to be fundamental in the control and coordination of homeostatic activity. Historically, this has been viewed in terms of the extensive neuroendocrine control system resulting from processing of hypothalamic signals relayed to the pituitary. Through these actions, endocrine signals are integrated throughout the body, modulating a vast array of physiological processes. Our understanding of the responses to endocrine signals is crucial for the diagnosis and management of many pathological conditions. More recently, the control emanating from the hypothalamus over the autonomic nervous system has been increasingly recognized as a powerful additional modulator of peripheral tissues. However, the neuroendocrine and autonomic control pathways emanating from the hypothalamus are not separate processes. They appear to act as a single integrated regulatory system, far more subtle and complex than when each is viewed in isolation. Consequently, hypothalamic regulation should be viewed as a summation of both neuroendocrine and autonomic influences. The neural regulation is believed to be fine and rapid, whereas the hormonal regulation is more stable and widespread. In this chapter, we will focus on the hypothalamic control of hepatic glucose and lipid metabolism.

Selenite supplementation in euthyroid subjects with thyroid peroxidase antibodies.

CONTEXT: Euthyroid thyroid peroxidase (TPO-Ab)-positive subjects are at risk for progression to subclinical and overt autoimmune hypothyroidism. Previous studies have shown a decrease in TPO-Ab and improvement of quality-of-life (QoL) in L-T4-treated hypothyroid patients upon selenium supplementation. OBJECTIVES: To evaluate in euthyroid TPO-Ab-positive women without thyroid medication whether selenite decreases TPO-Ab and improves QoL. DESIGN: Randomized, placebo-controlled, double-blind study. PATIENTS AND METHODS: Euthyroid (TSH 0·5-5·0 mU/l, FT4 10-23 pm) women with TPO-Ab ≥ 100 kU/l were randomized to receive 200 mcg sodium selenite daily (n = 30) or placebo (n = 31) for 6 months. TSH, FT4, TPO-Ab, selenium (Se), selenoprotein P (SePP) and QoL were measured at baseline, 3, 6 and 9 months. RESULTS: There were no differences in baseline characteristics between the Se group and the placebo group. During selenite supplementation, serum Se and SePP did not change in the placebo group, but increased in the Se group. TPO-Ab and TSH did not change significantly in any group. TPO-Ab in the Se group were 895 (130-6800) at baseline, 1360 (60-7050) kU/l at 6 months, in the placebo group 1090 (120-9200) and 1130 (80-9900) kU/l, respectively (median values with range). TSH in the Se group was 2·1 (0·5-4·3) at baseline, 1·7 (0·0-5·3) mU/l at 6 months, in the placebo group 2·4 (0·7-4·4) and 2·5 (0·2-4·3) mU/l, respectively. QoL was not different between the groups. CONCLUSION: Six months selenite supplementation increased markers of selenium status but had no effect on serum TPO-Ab, TSH or quality-of-life in euthyroid TPO-Ab-positive women.

Brain areas and pathways in the regulation of glucose metabolism.

Glucose is the most important source of fuel for the brain and its concentration must be kept within strict boundaries to ensure the organism's optimal fitness. To maintain glucose homeostasis, an optimal balance between glucose uptake and glucose output is required. Besides managing acute changes in plasma glucose concentrations, the brain controls a daily rhythm in glucose concentrations. The various nuclei within the hypothalamus that are involved in the control of both these processes are well known. However, novel studies indicate an additional role for brain areas that are originally appreciated in other processes than glucose metabolism. Therefore, besides the classic hypothalamic pathways, we will review cortico-limbic brain areas and their role in glucose metabolism.

Central administration of an orexin receptor 1 antagonist prevents the stimulatory effect of Olanzapine on endogenous glucose production.

Atypical antipsychotic drugs such as Olanzapine (Olan) induce weight gain and metabolic changes associated with the development of type 2 diabetes. The mechanisms underlying these undesired side-effects are currently unknown. It has been shown that peripheral injections of Olan activate neurons in the lateral hypothalamus/perifornical area and that a large part of these neurons are orexin (Ox) A-positive. We investigated further the possible involvement of the central Ox system in the metabolic side-effects of Olan by comparing the hyperglycaemic effects of an intragastric (IG) Olan infusion between animals treated intracerebroventricularly (ICV) with an Ox-1 receptor antagonist (SB-408124) or vehicle. As observed in previous studies IG Olan caused an increase in blood glucose, endogenous glucose production and plasma glucagon levels. ICV pre-treatment with the Ox-1 receptor antagonist did not affect the Olan-induced hyperglycaemia or increased plasma glucagon concentrations, but the increased endogenous glucose production was blunted by the ICV SB-408124 treatment. From these results we conclude that the metabolic side-effects of Olan are partly mediated by the hypothalamic Ox system.

Intrahypothalamic estradiol regulates glucose metabolism via the sympathetic nervous system in female rats.

Long-term reduced hypothalamic estrogen signaling leads to increased food intake and decreased locomotor activity and energy expenditure, and ultimately results in obesity and insulin resistance. In the current study, we aimed to determine the acute obesity-independent effects of hypothalamic estrogen signaling on glucose metabolism. We studied endogenous glucose production (EGP) and insulin sensitivity during selective modulation of systemic or intrahypothalamic estradiol (E2) signaling in rats 1 week after ovariectomy (OVX). OVX caused a 17% decrease in plasma glucose, which was completely restored by systemic E2. Likewise, the administration of E2 by microdialysis, either in the hypothalamic paraventricular nucleus (PVN) or in the ventromedial nucleus (VMH), restored plasma glucose. The infusion of an E2 antagonist via reverse microdialysis into the PVN or VMH attenuated the effect of systemic E2 on plasma glucose. Furthermore, E2 administration in the VMH, but not in the PVN, increased EGP and induced hepatic insulin resistance. E2 administration in both the PVN and the VMH resulted in peripheral insulin resistance. Finally, sympathetic, but not parasympathetic, hepatic denervation blunted the effect of E2 in the VMH on both EGP and hepatic insulin sensitivity. In conclusion, intrahypothalamic estrogen regulates peripheral and hepatic insulin sensitivity via sympathetic signaling to the liver.

Melanocortin 4 receptor distribution in the human hypothalamus.

OBJECTIVE: The melanocortin 4 receptor (MC4R) is an essential regulator of energy homeostasis and metabolism, and MC4R mutations represent the most prevalent monogenetic cause of obesity in humans known to date. Hypothalamic MC4Rs in rodents are well characterized in neuroanatomical and functional terms, but their expression pattern in the human hypothalamus is unknown. DESIGN AND METHODS: To determine the topographic distribution and identity of cells expressing MC4R mRNA in the human hypothalamus, locked nucleic acid in situ hybridization was performed on nine human postmortem hypothalami. In addition, co-expression of MC4R with glial fibrillary acidic protein (GFAP), vasopressin/oxytocin (AVP/OXT), corticotropin-releasing hormone (CRH), neuropeptide Y (NPY), agouti-related protein (AgRP), and α-melanocyte stimulating hormone (α-MSH) was examined. RESULTS: Most intense MC4R mRNA expression was present in the paraventricular nucleus (PVN), the supraoptic nucleus (SON), and the nucleus basalis of Meynert. Most MC4R-positive cells in the SON also expressed AVP/OXT. Co-expression with AVP/OXT in the PVN was less abundant. We did not observe co-expression of MC4R mRNA and GFAP, CRH, NPY, AgRP, or α-MSH. However, fiber-like staining of NPY, AgRP, and α-MSH was found adjacent to MC4R-positive cells in the PVN. CONCLUSION: Expression of MC4R mRNA in the human hypothalamus is widespread and in close approximation to endogenous MC4R binding partners AgRP and α-MSH.

Action of specific thyroid hormone receptor α(1) and ß(1) antagonists in the central and peripheral regulation of thyroid hormone metabolism in the rat.

BACKGROUND: The iodine-containing drug amiodarone (Amio) and its noniodine containing analogue dronedarone (Dron) are potent antiarrhythmic drugs. Previous in vivo and in vitro studies have shown that the major metabolite of Amio, desethylamiodarone, acts as a thyroid hormone receptor (TR) α(1) and ß(1) antagonist, whereas the major metabolite of Dron debutyldronedarone acts as a selective TRα(1) antagonist. In the present study, Amio and Dron were used as tools to discriminate between TRα(1) or TRß(1) regulated genes in central and peripheral thyroid hormone metabolism. METHODS: Three groups of male rats received either Amio, Dron, or vehicle by daily intragastric administration for 2 weeks. We assessed the effects of treatment on triiodothyronine (T(3)) and thyroxine (T(4)) plasma and tissue concentrations, deiodinase type 1, 2, and 3 mRNA expressions and activities, and thyroid hormone transporters monocarboxylate transporter 8 (MCT8), monocarboxylate transporter 10 (MCT10), and organic anion transporter 1C1 (OATP1C1). RESULTS: Amio treatment decreased serum T(3), while serum T(4) and thyrotropin (TSH) increased compared to Dron-treated and control rats. At the central level of the hypothalamus-pituitary-thyroid axis, Amio treatment decreased hypothalamic thyrotropin releasing hormone (TRH) expression, while increasing pituitary TSHß and MCT10 mRNA expression. Amio decreased the pituitary D2 activity. By contrast, Dron treatment resulted in decreased hypothalamic TRH mRNA expression only. Upon Amio treatment, liver T(3) concentration decreased substantially compared to Dron and control rats (50%, p<0.01), but liver T(4) concentration was unaffected. In addition, liver D1, mRNA, and activity decreased, while the D3 activity and mRNA increased. Liver MCT8, MCT10, and OATP1C1 mRNA expression were similar between groups. CONCLUSION: Our results suggest an important role for TRα1 in the regulation of hypothalamic TRH mRNA expression, whereas TRß plays a dominant role in pituitary and liver thyroid hormone metabolism.

Orexins, feeding, and energy balance.

In this chapter, we give an overview of the current status of the role of orexins in feeding and energy homeostasis. Orexins, also known as hypocretins, initially were discovered in 1998 as hypothalamic regulators of food intake. A little later, their far more important function as regulators of sleep and arousal came to light. Despite their restricted distribution, orexin neurons have projections throughout the entire brain, with dense projections especially to the paraventricular nucleus of the thalamus, the arcuate nucleus of the hypothalamus, and the locus coeruleus and tuberomammillary nucleus. Its two receptors are orexin receptor 1 and orexin receptor 2. These receptors show a specific and localized distribution in a number of brain regions, and a variety of different actions has been demonstrated upon their binding. Our group showed that through the autonomic nervous system, the orexin system plays a key role in the control of glucose metabolism, but it has also been shown to stimulate sympathetic outflow, to increase body temperature, heart rate, blood pressure, and renal sympathetic nerve activity. The well-known effects of orexin on the control of food intake, arousal, and wakefulness appear to be more extensive than originally thought, with additional effects on the autonomic nervous system, that is, to increase body temperature and energy metabolism.