Nesfatin/nucleobindin 2 (NUCB2) is expressed in the appetite-control hypothalamic nuclei and brainstem nuclei. Nesfatin/NUCB2 expression in the paraventricular nucleus of the hypothalamus was modulated by starvation and refeeding. Intracerebroventricular administration of nesfatin-1 dose-dependently inhibited food intake for 6 hours in male Wistar and leptin resistant, Zucker fatty rats. Intraperitoneal administration of nesfatin-1 and its mid-segment (M30) dosedependentlyinhibited food intake for 3 hours in male ICR mice. Intraperitoneal administration of M30 also decreased foodintake in leptin-resistant, genetically obese (ob/ob), diabetic (db/db) mice and mice fed a 45% high fat diet for 28 days. Intraperitoneal administration of M30 increased proopiomelanocortin and cocaine- and amphetamine- related peptide mRNA expression in the nucleus of the solitary tract of mice. In addition, intranasal administration of nesfatin-1 significantly inhibited food intake for 6 hours in male Wistar rats. We summarize recent observations about nesfatin-1, and attempt to present future direction of nesfatin-1 research for developing a new anti-obesity treatment.

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While there is no doubt that total thyroidectomy is necessary for medullary thyroid carcinoma (MTC) in multiple endocrine neoplasia type 2A (MEN2A) patients, there is still controversy regarding the management of the parathyroid glands. Although most, but not all, endocrine surgeons leave normal-appearing parathyroid glands in situ during thyroid surgery for MEN2A, we have employed total parathyroidectomy with autotransplantation. Between 1994 and 2006, 12 MEN2A patients underwent therapeutic total or completion thyroidectomy and lymph nodes dissection at least in the central compartment for MTC. Total or completion parathyroidectomy with autotransplantation was performed concurrently with above-mentioned surgery. All patients were over 25 years old, and the median age was 48.5 years. There were 5 males and 7 females from 8 families. The average number of transplanted parathyroid glands was 3. Serum calcium and intact PTH levels have been maintained during the median follow up of 107 months in all patients except for one who of died of advanced MTC one year after surgery. Total parathyroidectomy with autotransplantation at the time of primary surgery for MTC, i.e. total thyroidectomy with bilateral central neck dissection, is a feasible approach for managing the risk of hyperparathyroidism.

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Primary aldosteronism (PA) is a secondary hypertension characterized by autonomous aldosterone hypersecretion from adrenocortical adenoma and/or hyperplasia. Recently it has been suggested that aldosterone excess is directly involved in the development of cardiovascular injury in PA independent of its hypertensive effect. The present study was designed to examine the relationship between aldosterone excess and endothelial dysfunction in PA patients. 25 PA patients were studied for vascular endothelial function by ultrasound measurement of flow-mediated vasodilation (FMD), and 10 PA patients were re-evaluated 3 months after surgical or medical treatment; 10 age-, gender-, and blood pressurematched hypertensive patients served as control subjects. Percent (%) FMD in PA patients (4.6±2.0%) was significantly (p < 0.0001) lower than that in the control subjects (7.9±2.0%). %FMD showed significant (p < 0.05) negative correlations with systolic blood pressure (SBP) (r=-0.48), brachial-ankle pulse wave velocity (r=-0.52), plasma aldosterone concentration (PAC) (r=-0.42), and aldosterone-renin ratio (ARR) (r=-0.42), while SBP showed a positive correlation with PAC (r=0.47). Percent FMD, SBP, PAC, and ARR significantly (p < 0.05) improved after surgical and medical treatment, although the changes of %FMD did not correlate with those of SBP, PAC or ARR. In conclusion, the present study has demonstrated that PA patients have endothelial dysfunction, which is related to aldosterone excess and raised blood pressure, and reversible after treatment, suggesting that aldosterone excess contributes to the development of endothelial dysfunction due to its hypertensive effect and/or its direct effect on the cardiovascular system.

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Patients with growth hormone (GH) deficiency (GHD) have a clinical feature of visceral adiposity and it has been reported that these patients have an increased active cortisol (F)/inactive cortisone (E) metabolite ratio. 11β hydroxysteroid dehydrogenase type 1 (11β-HSD1) is an enzyme expressed in liver and adipose tissue that acts principally as a reductase converting E to F. In the present study, we investigated the effects of GH or IGF-I on the activity of 11β- HSD1 in 3T3-L1 cell homogenates and its mRNA expression. First, we showed that 11β-HSD1 activity and mRNA levels were low in preadipocytes and increased throughout the process of adipogenesis. When fully differentiated adipocytes were treated with GH for various times, the activity of 11β-HSD1 was significantly decreased after 4 h and 8 h but was restored to basal levels after 24 h. After 8 h of GH stimulation, 11β-HSD1 mRNA levels were decreased compared with basal levels. IGF-I treatment of adipocytes resulted in rapid decreases in 11β-HSD1 activity as well as mRNA levels; however, IGF-I treatment for 24 h increased 11β-HSD1 activity. In long-term cultured adipocytes, GH or IGF-I showed only inhibitory effects on 11β-HSD1 activity. In conclusion, 11β-HSD1 activity was suppressed by GH or IGF-I in differentiated adipocytes, probably due to a reduction of 11β-HSD1 mRNA levels. These data suggest that under the conditions of low GH or IGF-I concentrations, 11β-HSD1 activity in adipose tissue is maintained at high levels, leading to an increase in active cortisol that induces adipogenesis and/or lipogenesis. Thus, visceral adiposity in patients with GHD might be related to increased 11β-HSD1 activity.

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We compared the effects of continuous subcutaneous insulin infusion (CSII) and multi-daily insulin injections therapy (MDI) on glicemic control and on lipid profile in type 1 and type 2 diabetic patients. We divided the patients in two groups: in the first one (n=32) CSII was administered, in the second one (n=32) MDI was administered. HbA_1C value was lower after 3, 6, 9, and 12 months with CSII compared to MDI. Fasting plasma glucose (FPG) value was lower with CSII after 3, 6, and 12 months compared to MDI. Post-prandial glucose (PPG) value was lower in the group with CSII after 3, 6, 9, and 12 months compared to MDI. A significant TC decrease was observed in the group treated with CSII at 9, and 12 months while a significant TC increase was observed with MDI at 6, and 12 months. A significant LDL-C decrease was obtained with CSII after 9, and 12 months while no significant changes were observed with MDI. A significant HDL-C increase was observed with CSII after 12 months. A significant Tg decrease was observed with CSII after 12 months while a significant Tg increase was observed with MDI at 6, and at 12 months. CSII therapy allows a faster and better achievement of the therapeutic target and also gives an improvement of the lipid profile.

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Somatostatin analogs and dopamine agonists are clinically used for medical therapy of functioning pituitary tumors, such as growth hormone- and prolactin-secreting tumors, however, their effects on ACTH-secreting tumors are controversial. This study was aimed to determine whether somatostatin receptor (SSTR) subtype (1-5) and dopamine receptor type 2 (D2R) are differentially expressed in pituitary tumors causing Cushing’s disease (CD), silent corticotroph adenoma (SCA), and non-functioning pituitary tumor (NFT). Tissue specimens were obtained from 35 pituitary tumors during transsphenoidal surgery. The steady-state mRNA levels of SSTR1-5 and D2R genes were determined by real-time reverse-transcription polymerase chain reaction. Both SSTR1 and 2 mRNA levels in SCA were greater than CD, while SSTR1 mRNA levels, but not SSTR2, in SCA were also greater than NFT. SSTR5 mRNA levels in CD were greater than SCA, but did not differ between NFT and SCA. SSTR4 mRNA expression was undetectable. D2R mRNA levels were markedly lower in CD and SCA than in NFT. The present study suggests that somatostatin analogs more selective for SSTR5 and for SSTR1 and/or 2may have the therapeutic potential for medical treatment of CD and SCA, respectively, whereas clinical application of dopamine agonists selective for D2R is very limited in either CD or SCA.

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Empty sella syndrome is frequently accompanied with pituitary dysfunction. Most of the patients with empty sella syndrome demonstrate primary pituitary or stalk dysfunction and few cases show hypothalamic dysfunction. A 71-year-old man manifested appetite loss, nausea and vomiting with hyponatremia and adrenal insufficiency. Hormonal evaluation and cranial MRI revealed a panhypopituitarism with empty sella. Intriguingly, while the response of ACTH to CRH administration was exaggerated, the response to insulin hypoglycemia was blunted. Serum PRL levels were normal. Further, decreased level of fT4, slightly elevated basal levels of TSH, and delayed response of TSH to TRH administration were observed. These findings strongly suggest that the panhypopituitarism is caused by hypothalamic dysfunction. The presence of autoantibodies to pituitary and cerebrum in the patient’s serum implies an autoimmune mechanism as a pathogenesis.

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We investigated the incidence of symptomatic vertebral fracture in patients who required long-term high-dose glucocorticoid (GC) treatment. The patients with collagen vascular diseases (aged 18 years or older) were registered to Chiba-Shimoshizu Rheumatic Cohort from 1986 to 2006. The study included the patients who were newly treated with the initial dose more than 20 mg prednisolone equivalent per day at least for more than 6 months. Among 700 patients (female/ male: 539/161, mean age: 46.7 years, mean initial GC dose: 39.9 mg/day), 167 patients (23.8%) had at least one symptomatic vertebral fracture. Age and daily GC dose were significantly higher in the symptomatic fracture group than the no symptomatic fracture group. Cox regression model demonstrated that the relative risk for symptomatic vertebral fracture is independently higher in female patients, and in patients with initial higher age, and in those patients with initial higher GC dose and GC dose-increase, but lower with cumulative higher GC dose. High-dose GC treatment causes significantly high prevalence of symptomatic vertebral fracture in patients with collagen vascular disease. Age, female, higher initial GC dose and GC dose-increase are the risk factors for the symptomatic vertebral fracture in those patients.

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The aims were assessing liver function tests (LFT) in women with congenital adrenal hyperplasia (CAH) on glucocorticoids. Sixty-one women with genetically verified CAH due to 21-hydroxylase deficiency, aged 18-63 years were compared to 61 controls. Serum alkaline phosphatase (ALP), alanine aminotransferase (ALT ), aspartate aminotransferase (AST) and gamma-glutamyl transpeptidase (GGT), anthropometry and fat mass (dual energy X-ray absorptiometry) were measured. ALT and GGT were higher in the entire patient group (p=0.01and 0.002); AST, GGT and ALP in patients ≥30 years (p=0.007-0.045); all LFT in salt-wasting (p<0.001-0.042); GGT in simple virilizing (p=0.008); ALT , GGT and ALP in Null/Null genotype (p=0.018-0.040); ALT and GGT in I2splice genotype (p<0.001 and 0.011). Using a recently proposed cut-off level for ALT (>0.317 μkat/L), 54% of patients vs 23% of controls had elevated levels (p=0.028). In patients, GGT and ALP correlated with waist circumference and with total body and trunk fat (r=0.274-0.406, p=0.001-0.043). However, ALT, GGT and ALP were increased even in non-obese patients (waist circumference ≤88 cm and body mass index <30 kg/m²) (p=0.012-0.045) mainly attributed to the patients ≥30 years who also demonstrated elevated insulin levels and HOMA-indices. In conclusion, compared with controls, women with CAH have higher LFT, in particular patients ≥30 years and those with severe forms, probably reflecting a higher lifetime glucocorticoid exposure. LFT were positively correlated to measurements of body fat. These women might have increased frequency of NAFLD. The finding of higher LFT also in non-obese patients suggests that not only central obesity but also glucocorticoids per se may influence.

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Ghrelin is known to promote neuronal defense and survival against ischemic injury by inhibiting apoptotic processes. In the present study, we investigated the role of prostate apoptosis response-4 (Par-4), a proapoptotic gene the expression of which is increased after ischemic injury, in ghrelin-mediated neuroprotection during middle cerebral artery occlusion (MCAO). Both ghrelin and des-acyl ghrelin protected cortical neurons from ischemic injury. Ghrelin receptor specific antagonist abolished the protective effects of ghrelin, whereas those of des-acyl ghrelin were preserved, suggesting the involvement of a receptor that is distinct from GHS-R1a. The expression of Par-4 was increased by MCAO, which was attenuated by ghrelin and des-acyl ghrelin treatments. Both ghrelin and des-acyl ghrelin increased the Bcl-2/Bax ratio, prevented cytochrome c release, and inhibited caspase-3 activation. Our data indicate that des-acyl ghrelin, as well as ghrelin, protect cortical neurons against ischemic injury through the inhibition of Par-4 expression and apoptotic molecules in mitochondrial pathway.

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Steroidogenic factor-1 [(SF-1/Ad4BP) (MIM184757)] is a nuclear receptor that regulates multiple genes involved in adrenal and gonadal development, steroidogenesis, reproduction, and other metabolic functions. Initially, mutations of SF-1/Ad4BP gene (NR5A1) in humans were identified in two 46, XY female patients with adrenal insufficiency and gonadal dysgenesis. However, recent studies have revealed that heterozygous mutations are more frequently found in 46, XY disorders of sex development (DSD) patients without adrenal failure than in 46, XY DSD patients with adrenal failure. We encountered a Japanese female patient of 46, XY DSD without adrenal failure and identified a novel mutation (V41G) of NR5A1. Functional analysis revealed that this mutant protein could not activate CYP19 promoter, indicating loss of function. In conclusion, we add a novel mutation of NR5A1 in 46, XY DSD patient without adrenal failure.

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Wnt signaling is an important regulator of bone homeostasis. The Wnt co-receptor, namely, low-density lipoprotein receptor-related protein 5 (LRP5), initiates Wnt signal transduction. Recently, we and several other groups have shown that there is a single nucleotide polymorphism (SNP) located in the exon 18 of the LRP5 gene that leads to an amino acid change (3989C > T, A1330V), and is associated with lumbar spine, femoral neck, and radial bone mineral density (BMD), and incidence of fracture. These data suggest that the A1330V variation in the LRP5 gene may affect the pathogenesis of osteoporosis. However, the functional basis of the A1330V variation remains unclear. In the present study, we analyzed the effect of the A1330V variation on Wnt activity. We also investigated the association between this LRP5 SNP and total body BMD using 739 postmenopausal women. LRP5 with the A1330V SNP were transiently coexpressed with Wnt3a in 293T cells and their activity was evaluated by the TCF-Lef reporter assay. In vitro, the TCF-Lef activity in presence of Wnt3a in cells expressing LRP5 and carrying the T allele (Valine at 1330 (V1330)) of exon 18 was significantly reduced as compared to the wild-type allele. The association between the A1330V SNP and total body BMD were replicated in 739 postmenopausal Japanese women (AA vs. VV; P = 0.0026). These data suggest that the V1330 variant in the LRP5 gene decreases Wnt activity, which in turn decreases the BMD.

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