Anke J. Borgers

Hypothalamic Neuropeptide Y (NPY) Controls Hepatic VLDL-Triglyceride Secretion in Rats via the Sympathetic Nervous System

Excessive secretion of triglyceride-rich very low-density lipoproteins (VLDL-TG) contributes to diabetic dyslipidemia. Earlier studies have indicated a possible role for the hypothalamus and autonomic nervous system in the regulation of VLDL-TG. In the current study, we investigated whether the autonomic nervous system and hypothalamic neuropeptide Y (NPY) release during fasting regulates hepatic VLDL-TG secretion. We report that, in fasted rats, an intact hypothalamic arcuate nucleus and hepatic sympathetic innervation are necessary to maintain VLDL-TG secretion. Furthermore, the hepatic sympathetic innervation is necessary to mediate the stimulatory effect of intracerebroventricular administration of NPY on VLDL-TG secretion. Since the intracerebroventricular administration of NPY increases VLDL-TG secretion by the liver without affecting lipolysis, its effect on lipid metabolism appears to be selective to the liver. Together, our findings indicate that the increased release of NPY during fasting stimulates the sympathetic nervous system to maintain VLDL-TG secretion at a postprandial level.

Thyroid hormone transporters and deiodinases in the developing human hypothalamus

OBJECTIVE Thyroid hormone (TH) signaling in brain cells is dependent on transport of TH across the plasma membrane followed by intracellular deiodination and binding to the nuclear TH receptors. The aim of this study is to investigate the expression of the specific TH transporters monocarboxylate transporter 8 (MCT8 (SLC16A2)), MCT10, organic anion transporting polypeptide 1C1 (OATP1C1 (SLCO1C1)), and the types 2 and 3 deiodinases (D2 and D3) in the developing human hypothalamus. DESIGN Fifteen postmortem brain samples of fetuses and young children ranging between 17 weeks of gestation and 29 months of postnatal age including one child (28 months) with central congenital hypothyroidism were studied. METHODS Sections of the different hypothalami were stained with polyclonal rabbit antisera against MCT8, MCT10, OATP1C1, D2, and D3. RESULTS We found MCT8 and D3 but not D2 protein expression to be present in our earliest sample of 17 weeks of gestation, indicating triiodothyronine degradation, but not production at this time of development. At term, expression of TH transporters and D2 decreased and D3 expression increased, suggesting decreased TH signaling just before birth. The child with central congenital hypothyroidism showed higher MCT8 and D2 expression compared with the other children of similar age. CONCLUSIONS This study reports the developmental timing of expression of components crucial for central TH signaling in the human hypothalamus. In general, during fetal hypothalamic development, the coordinated expression of D2 and D3 in combination with the different TH transporters suggests that proper TH concentrations are regulated to prevent untimely maturation of brain cells.

Compression of the optic chiasm is associated with permanent shorter sleep duration in patients with pituitary insufficiency

Objective  Patients with pituitary insufficiency often experience some degree of impaired sleep. Sleep–wake rhythm is regulated to a large extent by the suprachiasmatic nucleus (SCN). Because the SCN is located just superior to the optic chiasm, we hypothesized that a history of compression of the optic chiasm (CC) due to a tumour with suprasellar extension is associated with altered sleep patterns in patients with pituitary insufficiency.

Arginine vasopressin immunoreactivity is decreased in the hypothalamic suprachiasmatic nucleus of subjects with suprasellar tumors

Suprasellar tumors with compression of the optic chiasm are associated with an impaired sleep–wake rhythm. We hypothesized that this reflects a disorder of the biological clock of the human brain, the suprachiasmatic nucleus (SCN), which is located just above the optic chiasm. In order to test this hypothesis, we investigated the expression of two key neuropeptides of the SCN, that is, arginine vasopressin (AVP) and vasoactive intestinal peptide (VIP), as assessed by quantitative immunocytochemistry in post‐mortem hypothalamic tissue of patients with a suprasellar tumor inducing permanent visual field defects. Post‐mortem hypothalamic tissue of 5 patients with a suprasellar tumor inducing permanent visual field defects (acromegaly n = 2, nonfunctioning macro‐adenoma n = 1, macroprolactinoma n = 1, infundibular metastasis of a colorectal adenocarcinoma n = 1) and 15 age‐ and gender‐matched controls was obtained from the Netherlands Brain Bank. Total AVP immunoreactivity in the SCN was lower in patients with a suprasellar tumor than in controls (P = 0.03). By contrast, total VIP immunoreactivity was not different between patients and controls (P = 0.44). Suprasellar tumors leading to permanent visual field defects are associated with reduced AVP, but not VIP immunoreactivity, in the SCN. These findings raise the possibility that selective impairment of the SCN contributes to sleep–wake disturbances in these patients.

Imaging of serotonin transporters with [123I]FP-CIT SPECT in the human hypothalamus

BackgroundSerotonergic neurons in the rodent hypothalamus are implicated in key neuroendocrine and metabolic functions, including circadian rhythmicity. However, the assessment of the serotonergic system in the human hypothalamus in vivo is difficult as delineation of the hypothalamus is cumbersome with conventional region-of-interest analysis. In the present study, we aimed to develop a method to visualize serotonin transporters (SERT) in the hypothalamus. Additionally, we tested the hypothesis that hypothalamic SERT binding ratios are different between patients with hypothalamic impairment (HI), pituitary insufficiency (PI), and control subjects (C).MethodsSERT availability was determined in 17 subjects (6 HI, 5 PI, and 6 healthy controls), 2 h after injection of 123I-N-ω-fluoropropyl-2β-carboxymethoxy-3β-(4-iodophenyl) nortropane ([123I]FP-CIT), using single-photon emission computed tomography (performed on a brain-dedicated system) fused with individual magnetic resonance imaging (MRI) scans of the brain. The hypothalamus (representing specific SERT binding) and cerebellum (representing nonspecific binding) were manually delineated on each MRI to assess [123I]FP-CIT binding and specific-to-nonspecific binding ratios.ResultsIn each healthy subject, [123I]FP-CIT binding was higher in the hypothalamus than in the cerebellum, and the mean hypothalamic binding ratio of SERT was 0.29 ± 0.23. We found no difference in hypothalamic binding ratios between HI, PI, and control subjects (HI 0.16 ± 0.24, PI 0.45 ± 0.39, C 0.29 ± 0.23, p value 0.281).ConclusionsWe were able to demonstrate SERT binding in the human hypothalamus in vivo. However, we did not find altered hypothalamic SERT binding in patients with hypothalamic impairment.Trial registrationNetherlands Trial Register: NTR2520

Medical History of Optic Chiasm Compression in Patients With Pituitary Insufficiency Affects Skin Temperature and Its Relation to Sleep

The hypothalamus is crucially involved in the circadian timing of the sleep-wake rhythm, yet also accommodates the most important thermoregulatory neuronal network. We have shown before that adults with pituitary insufficiency and history of chiasm compression due to a tumor with suprasellar extension fall asleep later and sleep shorter than those without such history and presumed hypothalamic involvement. To solidify the hypothesized link between vigilance and thermoregulation by the hypothalamus, we aimed to test the hypothesis that the presumed hypothalamic impairment in these patients also affects skin temperature and its association with sleep onset. In a case-control study of 50 patients (54.7 ± 14.5 yrs of age, 30 males) with pituitary insufficiency, 33 of whom had a history of chiasm compression, ambulatory distal and proximal skin temperatures were assessed continuously for 24 h. Sleep parameters were assessed via questionnaire. Group differences in mean skin temperature, calculated over the wake and sleep periods separately, and group differences in the strength of association between pre-sleep skin temperature and sleep onset latency were compared. Results showed that patients with a medical history of chiasm compression had lower proximal skin temperature during the day (34.1°C ± .7°C vs. 34.6°C ± .7°C, p = .045). Additionally, the typical association between sleep onset latency and pre-sleep distal-to-proximal skin temperature gradient was absent in these patients (r = −.01, p = .96), whereas it was unimpaired in those without chiasm compression (r = −.61, p = .02). Thus, patients with history of chiasm compression show impaired skin temperature regulation in association with disturbed sleep. The findings support the hypothesis that a medical history of chiasm compression affects hypothalamic regulation of both vigilance and temperature, possibly by chronically affecting relevant nuclei, including the ventrolateral preoptic area and anterior hypothalamic preoptic area. (Corresponding Author: n.romeijn@nin.knaw.nl)

Decreased serotonin transporter immunoreactivity in the human hypothalamic infundibular nucleus of overweight subjects

Context: That serotonin plays a role in the regulation of feeding behavior and energy metabolism has been known for a long time. Serotonin transporters (SERT) play a crucial role in serotonin signaling by regulating its availability in the synaptic cleft. The neuroanatomy underlying serotonergic signaling in humans is largely unknown, and until now, SERT immunoreactivity in relation to body weight has not been investigated. Objective: To clarify the distribution of SERT immunoreactivity throughout the human hypothalamus and to compare SERT immunoreactivity in the infundibular nucleus (IFN), the human equivalent of the arcuate nucleus, in lean and overweight subjects. Design: First, we investigated the distribution of serotonin transporters (SERT) over the rostro-caudal axis of six post-mortem hypothalami by means of immunohistochemistry. Second, we estimated SERT immunoreactivity in the IFN of lean and overweight subjects. Lastly, double-labeling of SERT with Neuropeptide Y (NPY) and melanocortin cell populations was performed to further identify cells showing basket-like SERT staining. Results: SERT-immunoreactivity was ubiquitously expressed in fibers throughout the hypothalamus and was the strongest in the IFN. Immunoreactivity in the IFN was lower in overweight subjects (p = 0.036). Basket-like staining in the IFN was highly suggestive of synaptic innervation. A very small minority of cells showed SERT double labeling with NPY, agouti-related protein and α–melanocyte stimulating hormone. Conclusions: SERT is ubiquitously expressed in the human hypothalamus. Strong SERT immunoreactivity, was observed in the IFN a region important for appetite regulation, in combination with lower SERT immunoreactivity in the IFN of overweight and obese subjects, may point toward a role for hypothalamic SERT in human obesity.

A history of cranial radiotherapy is associated with a higher visceral to subcutaneous fat ratio in men with pituitary insufficiency

OBJECTIVE Endocrine deficiencies, like GH and estrogen deficiencies, are likely candidates to explain increased visceral to subcutaneous fat ratio in patients with pituitary insufficiency. However, recent reports pointed to cranial radiotherapy (CRT) as an additional determinant of an unfavorable fat distribution. Therefore, we determined the effect of CRT on abdominal fat distribution in men with treated pituitary insufficiency. DESIGN Cross-sectional study. METHODS Thirty-five consecutive male subjects (16 men with and 19 men without CRT aged 62±12 and 56±14 years respectively, P=0.175) visiting our Endocrine Outpatient Clinic for pituitary insufficiency were invited to participate in this study. A standardized single-slice abdominal CT scan at the level of fourth lumbar vertebra was performed to determine visceral fat area, subcutaneous fat area, and visceral to subcutaneous fat ratio. In addition, we assessed body mass index, total fat percentage with bioelectrical impedance analysis, resting energy expenditure with indirect calorimetry, calorie intake using a diary, and serum hormone concentrations. RESULTS Subjects with CRT had a smaller subcutaneous fat area (225.1 (71.1-480.7) vs 269.0 (133.2-59.9) cm(2), P=0.022) and a higher visceral to subcutaneous fat ratio (0.79 (0.39-1.55) vs 0.63 (0.23-0.88), P=0.001) than subjects without CRT. Both the groups were comparable for body mass index, waist-hip ratio, resting energy expenditure, and calorie intake. Importantly, serum hormone concentrations were similar. CONCLUSION In men treated for pituitary insufficiency, previous CRT is associated with a higher visceral to subcutaneous fat ratio.

Hypothalaam Neuropeptide Y (NPY) reguleert hepatische VLDL-triglyceriden secretie in ratten via het sympathisch zenuwstelsel

SamenvattingPatiënten met type 2 diabetes hebben een verhoogde leversecretie van triglyceriden in VLDL-partikels (VLDL-TG).1 VLDL-TG-secretie wordt onder andere gereguleerd door circulerende metabolieten (vrije vetzuren) en hormonen, zoals insuline. Recent onderzoek liet daarnaast ook een rol zien voor de hersenen en het autonome zenuwstelsel bij de regulatie van VLDL-TG-secretie.