Eric Fliers

The suprachiasmatic nucleus of the human brain in relation to sex, age and senile dementia.

The suprachiasmatic nucleus (SCN) is considered to be the endogenous clock of the brain, essential for the ovulation cycle and the temporal organization of sleep-wake patterns, among other things. Immunocytochemical staining with anti-vasopressin as a marker permitted a morphometric study of this nucleus in the human brain, which revealed that the shape of the SCN is sexually dimorphic. The shape of the SCN was elongated in women and more spherical in men. In both sexes a decrease in SCN volume and cell number was observed in senescence (80-100 years). The latter change was especially pronounced in patients with senile dementia of the Alzheimer type (SDAT). This suggests the presence of a structural defect in the SCN which underlies the general disturbance of biological rhythms in senescence and SDAT.

Selective parasympathetic innervation of subcutaneous and intra-abdominal fat — functional implications

The wealth of clinical epidemiological data on the association between intra-abdominal fat accumulation and morbidity sharply contrasts with the paucity of knowledge about the determinants of fat distribution, which cannot be explained merely in terms of humoral factors. If it comes to neuronal control, until now, adipose tissue was reported to be innervated by the sympathetic nervous system only, known for its catabolic effect. We hypothesized the presence of a parasympathetic input stimulating anabolic processes in adipose tissue. Intra-abdominal fat pads in rats were first sympathetically denervated and then injected with the retrograde transneuronal tracer pseudorabies virus (PRV). The resulting labeling of PRV in the vagal motor nuclei of the brain stem reveals that adipose tissue receives vagal input. Next, we assessed the physiological impact of these findings by combining a fat pad-specific vagotomy with a hyperinsulinemic euglycemic clamp and RT-PCR analysis. Insulin-mediated glucose and FFA uptake were reduced by 33% and 36%, respectively, whereas the activity of the catabolic enzyme hormone-sensitive lipase increased by 51%. Moreover, expression of resistin and leptin mRNA decreased, whereas adiponectin mRNA did not change. All these data indicate an anabolic role for the vagal input to adipose tissue. Finally, we demonstrate somatotopy within the central part of the autonomic nervous system, as intra-abdominal and subcutaneous fat pads appeared to be innervated by separate sympathetic and parasympathetic motor neurons. In conclusion, parasympathetic input to adipose tissue clearly modulates its insulin sensitivity and glucose and FFA metabolism in an anabolic way. The implications of these findings for the (patho)physiology of fat distribution are discussed.

Circadian rhythms in the hypothalamo-pituitary-adrenal (HPA) axis

The pronounced daily variation in the release of adrenal hormones has been at the heart of the deciphering and understanding of the circadian timing system. Indeed, the first demonstration of an endocrine day/night rhythm was provided by Pincus (1943), by showing a daily pattern of 17-keto-steroid excretion in the urine of 7 healthy males. Twenty years later the adrenal gland was one of the very first organs to show, in vitro, that circadian rhythmicity was maintained. In the seventies, experimental manipulation of the daily corticosterone rhythm served as evidence for the identification of respectively the light- and food-entrainable oscillator. Another 20 years later the hypothalamo-pituitary-adrenal (HPA)-axis was key in furthering our understanding of the way in which rhythmic signals generated by the central pacemaker in the hypothalamic suprachiasmatic nuclei (SCN) are forwarded to the rest of the brain and to the organism as a whole. To date, the adrenal gland is still of prime importance for understanding how the oscillations of clock genes in peripheral tissues result in functional rhythms of these tissues, whereas it has become even more evident that adrenal glucocorticoids are key in the resetting of the circadian system after a phase-shift. The HPA-axis thus still is an excellent model for studying the transmission of circadian information in the body.

The vasopressin and oxytocin neurons in the human supraoptic and paraventricular nucleus; changes with aging and in senile dementia

The neuropeptides vasopressin (AVP) and oxytocin (OXT) are supposed to be involved not only in peripheral functions (e.g. diuresis, labour and lactation) but also in central processes that are frequently disturbed during aging and senile dementia (e.g. fluid and electrolyte homeostasis and cognitive functions). A concomitant decrease in activity of the hypothalamo-neurohypophyseal system (HNS) with aging has been postulated in the literature, but has not yet been established. In order to investigate possible age-related changes in the human HNS, immunocytochemically identified AVP and OXT neurons in the paraventricular and supraoptic nucleus (PVN and SON) were analysed morphometrically in subjects from 10 to 93 years of age, including patients with senile dementia of the Alzheimer type (SDAT). Cell size was used as a parameter for peptide production. Mean profile area of OXT cells did not show any significant changes with increasing age. Mean profile area of AVP cells, however, showed an initial decrease up to the sixth decade of life, after which a gradual increase was observed. Size of AVP and OXT cell nuclei did not change significantly with aging. Observations in brains from patients with SDAT were within the range for their age group. The present results do not support degeneration or diminished function of the HNS in senescence or SDAT, as generally presumed in the literature, but suggest an activation of AVP cells after 80 years of age. The activation of AVP cells in senescence is in accordance with previous findings in the aged Wistar rat.

Estradiol Regulates Brown Adipose Tissue Thermogenesis via Hypothalamic AMPK

Summary 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.

Hypercoagulable State in Cushing's Syndrome: A Systematic Review

CONTEXT It has been debated whether an increased risk of venous thromboembolism (VTE) exists in patients with Cushings syndrome. OBJECTIVE We aimed to summarize published literature on the effects of endogenous hypercortisolism on coagulation and fibrinolysis, as well as on the clinical outcome of VTE. DATA SOURCES We searched the MEDLINE and EMBASE databases up to July 2008. Review of reference lists further identified candidate studies. STUDY SELECTION Two investigators independently performed study selection and data extraction. Eligible studies had to include Cushings syndrome patients and either evaluate hemostatic parameters in comparison with control persons or posttreatment levels or describe the occurrence of VTE. DATA EXTRACTION The Newcastle-Ottawa Scale was used to assess study quality. A scoring system divided studies into categories of low, medium and high quality. DATA SYNTHESIS Of 441 identified publications, 15 reports were included. They contained information on eight cross-sectionals, two intervention, and eight cohort studies. No high-quality studies were identified. Hypercoagulability was suggested by high levels of factor VIII, factor IX, and von Willebrand factor and by evidence of enhanced thrombin generation. A risk of 1.9 and 2.5% was reported for VTE not provoked by surgery, whereas risk of postoperative VTE varied between 0 and 5.6%, with one outlier of 20%. VTE was reported as the cause of death in 0-1.9% of Cushings syndrome patients. CONCLUSIONS Available studies suggest a high risk of venous thrombosis in patients with Cushings syndrome. Glucocorticoid-induced hypercoagulability as well as surgery and obesity almost certainly contribute to this thrombotic tendency.

Mutations in fibroblast growth factor receptor 1 cause Kallmann syndrome with a wide spectrum of reproductive phenotypes.

BACKGROUND Kallmanns syndrome (KS) is a clinically and genetically heterogeneous disorder consisting of idiopathic hypogonadotropic hypogonadism (IHH) and anosmia. Mutations in KAL1 causing the X-linked form of KS have been identified in 10% of all KS patients and consistently result in a severe reproductive phenotype. KAL1 gene encodes for anosmin-1, a key protein involved in olfactory and GnRH neuronal migration through a putative interaction with FGFR1. Heterozygous mutations in the FGFR1 gene accompanied by a high frequency of cleft palate and other facial dysmorphisms were recently identified in 8% of a large KS cohort, yet the reproductive phenotype of KS patients harboring FGFR1 mutations has not been described. RESULTS One hundred and fifty probands with KS (130 males and 20 females) were studied to determine the frequency and distribution of FGFR1 mutations and their detailed reproductive phenotypes. Fifteen heterozygous mutations in unrelated probands were identified. Twelve missense mutations (p.R78C, p.V102I, p.D224H, p.G237D, p.R254Q, p.V273M, p.E274G, p.Y339C, p.S346C, p.I538V, p.G703S and p.G703R) were distributed among the first, second and third immunoglobulin-like domains (D1-D3), as well as the tyrosine kinase domain (TKD). The mutations Y339C and S346C are located in exon 8B and code for the isoform FGFR1c. Additionally, two nonsense mutations (p.T585X and p.R622X) were documented in the TKD of the protein. A wide spectrum of reproductive function was observed among KS probands including: (1) a severe phenotype demonstrated by microphallus, cryptorchidism, no pubertal development, undetectable serum gonadotropins and low serum testosterone (T) and inhibin B; (2) partial pubertal development; (3) the fertile eunuch variant of IHH with normal testicular size and active spermatogenesis with a reversal of HH after T therapy. In addition, we found an even wider spectrum of reproductive function within pedigrees carrying an FGFR1 mutation ranging from IHH to delayed puberty to normal reproductive function (anosmia only or asymptomatic carriers). These observations strongly suggest a role for other genes that modify the phenotype of FGFR1 mutations. CONCLUSION KS patients and family members carrying an FGFR1 mutation present a broad spectrum of pubertal development in contrast to the almost uniform severe clinical phenotype described in KS subjects with a KAL1 mutation. Additionally, this report implicates the isoform FGFR1c in the pathogenesis of KS.

Beyond Low Plasma T3: Local Thyroid Hormone Metabolism during Inflammation and Infection

Decreased serum thyroid hormone concentrations in severely ill patients were first reported in the 1970s, but the functional meaning of the observed changes in thyroid hormone levels, together known as nonthyroidal illness syndrome (NTIS), remains enigmatic. Although the common view was that NTIS results in overall down-regulation of metabolism in order to save energy, recent work has shown a more complex picture. NTIS comprises marked variation in transcriptional and translational activity of genes involved in thyroid hormone metabolism, ranging from inhibition to activation, dependent on the organ or tissue studied. Illness-induced changes in each of these organs appear to be very different during acute or chronic inflammation, adding an additional level of complexity. Organ- and timing-specific changes in the activity of thyroid hormone deiodinating enzymes (deiodinase types 1, 2, and 3) highlight deiodinases as proactive players in the response to illness, whereas the granulocyte is a novel and potentially important cell type involved in NTIS during bacterial infection. Although acute NTIS can be seen as an adaptive response to support the immune response, NTIS may turn disadvantageous when critical illness enters a chronic phase necessitating prolonged life support. For instance, changes in thyroid hormone metabolism in muscle during critical illness may be relevant for the pathogenesis of myopathy associated with prolonged ventilator dependence. This review focuses on NTIS as a timing-related and organ-specific response to illness, occurring independently from the decrease in serum thyroid hormone levels and potentially relevant for disease progression.

Thyroid hormone modulates glucose production via a sympathetic pathway from the hypothalamic paraventricular nucleus to the liver

Thyrotoxicosis increases endogenous glucose production (EGP) and induces hepatic insulin resistance. We have recently shown that these alterations can be modulated by selective hepatic sympathetic and parasympathetic denervation, pointing to neurally mediated effects of thyroid hormone on glucose metabolism. Here, we investigated the effects of central triiodothyronine (T3) administration on EGP. We used stable isotope dilution to measure EGP before and after i.c.v. bolus infusion of T3 or vehicle in euthyroid rats. To study the role of hypothalamic preautonomic neurons, bilateral T3 microdialysis in the paraventricular nucleus (PVN) was performed for 2 h. Finally, we combined T3 microdialysis in the PVN with selective hepatic sympathetic denervation to delineate the involvement of the sympathetic nervous system in the observed metabolic alterations. T3 microdialysis in the PVN increased EGP by 11 ± 4% (P = 0.020), while EGP decreased by 5 ± 8% (ns) in vehicle-treated rats (T3 vs. Veh, P = 0.030). Plasma glucose increased by 29 ± 5% (P = 0.0001) after T3 microdialysis versus 8 ± 3% in vehicle-treated rats (T3 vs. Veh, P = 0.003). Similar effects were observed after i.c.v. T3 administration. Effects of PVN T3 microdialysis were independent of plasma T3, insulin, glucagon, and corticosterone. However, selective hepatic sympathectomy completely prevented the effect of T3 microdialysis on EGP. We conclude that stimulation of T3-sensitive neurons in the PVN of euthyroid rats increases EGP via sympathetic projections to the liver, independently of circulating glucoregulatory hormones. This represents a unique central pathway for modulation of hepatic glucose metabolism by thyroid hormone.

Lower striatal dopamine D2/3 receptor availability in obese compared with non-obese subjects

BackgroundObesity is a result of a relative excess in energy intake over energy expenditure. These processes are controlled by genetic, environmental, psychological and biological factors. One of the factors involved in the regulation of food intake and satiety is dopaminergic signalling. A small number of studies have reported that striatal dopamine D2/D3 receptor [D2/3R] availability is lower in morbidly obese subjects.MethodsTo confirm the role of D2/3R in obesity, we measured striatal D2/3R availability, using [123I]IBZM SPECT, in 15 obese women and 15 non-obese controls.ResultsStriatal D2/3R availability was 23% (p = 0.028) lower in obese compared with non-obese women.ConclusionThis study is an independent replication of the finding that severely obese subjects have lower striatal D2/3R availability. Our findings invigorate the evidence for lower striatal D2/3R availability in obesity and confirm the role of the striatal dopaminergic reward system in obesity.