FNDC5 expression and circulating irisin levels are modified by diet and hormonal conditions in hypothalamus, adipose tissue and muscle.

Irisin is processed from fibronectin type III domain-containing protein 5 (FNDC5). However, a controversy exists concerning irisin origin, regulation and function. To elucidate the relationship between serum irisin and FNDC5 mRNA expression levels, we evaluated plasma irisin levels and FNDC5 gene expression in the hypothalamus, gastrocnemius muscle and different depots of adipose tissue in models of altered metabolism. In normal rats, blood irisin levels diminished after 48-h fast and with leptin, insulin and alloxan treatments, and serum irisin concentrations increased in diabetic rats after insulin treatment and acute treatments of irisin increased blood insulin levels. No changes were observed during long-term experiments with different diets. We suggested that levels of circulating irisin are the result of the sum of the irisin produced by different depots of adipose tissue and skeletal muscle. This study shows for the first time that there are differences in FNDC5 expression depending on white adipose tissue depots. Moreover, a considerable decrease in visceral and epididymal adipose tissue depots correlated with increased FNDC5 mRNA expression levels, probably in an attempt to compensate the decrease that occurs in their mass. Hypothalamic FNDC5 expression did not change for any of the tested diets but increased with leptin, insulin and metformin treatments suggesting that the regulation of central and peripheral FNDC5/irisin expression and functions are different.

Testicular expression of the Lin28/let-7 system: Hormonal regulation and changes during postnatal maturation and after manipulations of puberty.

The Lin28/let-7 system, which includes the RNA-binding proteins, Lin28a/Lin28b, and let-7 miRNAs, has emerged as putative regulator of puberty and male gametogenesis; yet, its expression pattern and regulation in postnatal testis remain ill defined. We report herein expression profiles of Lin28 and let-7 members, and related mir-145 and mir-132, in rat testis during postnatal maturation and in models of altered puberty and hormonal deregulation. Neonatal expression of Lin28a and Lin28b was low and rose markedly during the infantile period; yet, expression patterns diverged thereafter, with persistently elevated levels only for Lin28b, which peaked at puberty. Let-7a, let-7b, mir-132 and mir-145 showed profiles opposite to Lin28b. In fact, let-7b and mir-145 were abundant in pachytene spermatocytes, but absent in elongating spermatids, where high expression of Lin28b was previously reported. Perturbation of puberty by neonatal estrogenization reverted the Lin28/let-7 expression ratio; expression changes were also detected in other models of delayed puberty, due to early photoperiod or nutritional manipulations. In addition, hypophysectomy or growth hormone (GH) deficiency revealed regulation of this system by gonadotropins and GH. Our data document the expression profiles of the Lin28/let-7 system in rat testis along postnatal/pubertal maturation, and their perturbation in models of pubertal and hormonal manipulation.

Importance of exercise in the control of metabolic and inflammatory parameters at the moment of onset in type 1 diabetic subjects.

The onset of type 1 diabetes coincides with the final phase of ß-cell destruction. In some cases, this period is characterized by the presence of a functional reserve of ß-cells, favouring an adequate metabolic control (honeymoon phase). Therefore, the extension of this situation could have evident benefits in subsequent diabetes management. We aimed to study the influence of regular physical activity before and after the onset of the disease. We did an observational study of 2 groups of type 1 diabetic patients from onset to a 2-year period. One group (n = 8) exercised regularly (5 or more hours/week) before onset and continued doing so with the same regularity. The second group (n = 11) either did not perform physical activity or did so sporadically. Circulating glycated haemoglobin (HbA1c), C-peptide, protein carbonyls and basal cytokine levels were determined at the beginning and at the end of the 1(st) and 2(nd) year. The more active group debuted with and maintained significantly lower HbA(1c) levels and insulin requirements compared to the more sedentary group. C-peptide levels were only significantly higher in the active group at the moment of onset compared to the sedentary group. In addition, determination of basal circulating cytokines revealed a large variability between individuals but no significant differences when comparing the groups. Altogether, the obtained results seem to indicate that physical activity allows a better control at the moment of onset regarding glycaemic control, residual endocrine pancreatic mass and subsequent insulin requirements.

Changes in hypothalamic expression of the Lin28/let-7 system and related microRNAs during postnatal maturation and after experimental manipulations of puberty.

Lin28 and Lin28b are related RNA-binding proteins that inhibit the maturation of miRNAs of the let-7 family and participate in the control of cellular stemness and early embryonic development. Considerable interest has arisen recently concerning other physiological roles of the Lin28/let-7 axis, including its potential involvement in the control of puberty, as suggested by genome-wide association studies and functional genomics. We report herein the expression profiles of Lin28 and let-7 members in the rat hypothalamus during postnatal maturation and in selected models of altered puberty. The expression patterns of c-Myc (upstream positive regulator of Lin28), mir-145 (negative regulator of c-Myc), and mir-132 and mir-9 (putative miRNA repressors of Lin28, predicted by bioinformatic algorithms) were also explored. In male and female rats, Lin28, Lin28b, and c-Myc mRNAs displayed very high hypothalamic expression during the neonatal period, markedly decreased during the infantile-to-juvenile transition and reached minimal levels before/around puberty. A similar puberty-related decline was observed for Lin28b in monkey hypothalamus but not in the rat cortex, suggesting species conservation and tissue specificity. Conversely, let-7a, let-7b, mir-132, and mir-145, but not mir-9, showed opposite expression profiles. Perturbation of brain sex differentiation and puberty, by neonatal treatment with estrogen or androgen, altered the expression ratios of Lin28/let-7 at the time of puberty. Changes in the c-Myc/Lin28b/let-7 pathway were also detected in models of delayed puberty linked to early photoperiod manipulation and, to a lesser extent, postnatal underfeeding or chronic subnutrition. Altogether, our data are the first to document dramatic changes in the expression of the Lin28/let-7 axis in the rat hypothalamus during the postnatal maturation and after different manipulations that disturb puberty, thus suggesting the potential involvement of developmental changes in hypothalamic Lin28/let-7 expression in the mechanisms permitting/leading to puberty onset.

Sexual dimorphism on growth hormone secretion after oral glucose administration.

Sexual dimorphism of GH secretion is unclear in humans. There is evidence that oral glucose (OG) administration initially decreases and subsequently stimulates GH secretion. Our aim was to study fasting GH concentrations and their response to OG administration in obese and healthy women and men, in order to elucidate the mechanism of sexual dimorphism of GH secretion and the possible contribution of ghrelin. We selected 33 women and 11 men as obese and healthy subjects. After an overnight fast, 75 g of oral glucose were administered; glucose, insulin, ghrelin, and PYY1-36 were obtained at baseline and during 300 min. Fasting GH (µg/l) was higher in women than men; 1.3 ± 0.3 vs. 0.2 ± 0.1, p=0.009, for women and men, respectively. The area under the curve between 0 and 150 min (AUC) of GH (µg/l · min) was higher in women than men; 98.2 ± 25.9 vs. 41.5 ± 28.6, p=0.002, for women and men, respectively. The AUC of total ghrelin (pg/ml · min, mean ± SEM) between 0 and 150 min was borderline and significantly higher in women than men; 128 562.3 ± 8 335.9 vs. 98 839.1 ± 7 668.6, p=0.069, for women and men, respectively. Several initial time points were higher in women than men. Glucose, insulin, and PYY1-36 were similar in women and men after OG. There were significant correlations between indices of post-oral glucose GH and ghrelin secretion. Fasting and initial GH secretion is higher in women than men, in contrast to peak and late GH secretion, which is similar in both cases. Sexual dimorphism in the regulation of GH secretion probably involves ghrelin.

Growth hormone, ghrelin and peptide YY secretion after oral glucose administration in healthy and obese women.

The mechanism of the altered GH secretion in obesity is unclear. There is evidence that oral glucose (OG) administration initially decreases and subsequently stimulates GH secretion. Ghrelin is a peptide that displays strong growth hormone-releasing activity. Its physiological importance on GH regulation is unclear. Our aim was to study fasting GH concentrations and their response to OG administration in relation with ghrelin secretion in obese and healthy women, in order to elucidate the hypothetical participation of ghrelin on post-oral glucose GH secretion. 36 women were included in the study. After an overnight fast, 75 g of oral glucose was administered; glucose, insulin, ghrelin, and PYY (1-36) were obtained at baseline and during 300 min. The area under the curve between 0 and 300 min (AUC) of GH µ/l·min) was lower in obese patients than in controls; 262.5±57.5 vs. 534.9±95.6, p=0.01, for obese and controls respectively. GH peak (µg/l) was lower in obese patients than in controls; 3.7±0.7 vs. 7.1±1.0, p=0.012, for obese and controls, respectively. The AUC of total ghrelin (pg/ml·min) was lower in obese patients than in controls; 233,032±12,641 vs. 333,697±29,877, p=0.004, for the obese patients and controls respectively. PYY (1-36) was similar in obese and healthy women after OG. There were significant correlations between the different indices of post-oral glucose GH and ghrelin secretion. These data suggest that ghrelin is a physiological regulator of GH in the post-oral glucose state, and the decreased ghrelin secretion could be one of the mechanisms responsible for the altered GH secretion in obesity.

Influence of ghrelin and growth hormone deficiency on AMP-activated protein kinase and hypothalamic lipid metabolism.

Current evidence demonstrates that the stomach-derived hormone ghrelin, a potent growth hormone (GH) secretagogue, promotes feeding through a mechanism involving the short-term activation of hypothalamic AMP-activated protein kinase (AMPK), which in turn results in decreased hypothalamic levels of malonyl-CoA and increased carnitine palmitoyltransferase 1 (CPT1) activity. Despite this evidence, no data have been reported about the effect of chronic, central ghrelin administration on hypothalamic fatty acid metabolism. In the present study, we examined the differences in hypothalamic fatty acid metabolism in the presence and absence of GH, by using a model for the study of GH-deficiency, namely the spontaneous dwarf rat and the effect of long-term central ghrelin treatment and starvation on hypothalamic fatty acid metabolism in this animal model. Our data showed that GH-deficiency induces reductions in both de novo lipogenesis and beta-oxidation pathways in the hypothalamus. Thus, dwarf rats display reductions in fatty acid synthase (FAS) mRNA expression both in the ventromedial nucleus of the hypothalamus (VMH) and whole hypothalamus, as well as in FAS protein and activity. CPT1 activity was also reduced. In addition, in the present study, we show that chronic ghrelin treatment does not promote AMPK-induced changes in the overall fluxes of hypothalamic fatty acid metabolism in normal rats and that this effect is independent of GH status. By contrast, we demonstrated that both chronic ghrelin and fasting decreased FAS mRNA expression in the VMH of normal rats but not dwarf rats, suggesting GH status dependency. Overall, these results suggest that ghrelin plays a dual time-dependent role in modulating hypothalamic lipid metabolism. Understanding the molecular mechanism underlying the interplay between GH and ghrelin on hypothalamic lipid metabolism will allow new strategies for the design and development of suitable drugs for the treatment of GH-deficiency, obesity and its comorbidities.

Cutaneous lesions associated to multiple endocrine neoplasia syndrome type 1.

BACKGROUND: Multiple endocrine neoplasia type 1 (MEN1) is a genetic disease that predisposes to endocrine tumour development. Some cutaneous lesions (angiofibromas, collagenomas, melanosis guttaca, lipomas, melanomas, 'cafe au lait macules') have been associated to this syndrome. We compare the prevalence of cutaneous lesion in affected patients with their non-carrier relatives. PATIENTS AND METHOD: We studied 9 patients with MEN1 and 20 non-carrier, first-degree relatives. Genetic screening was realized in all of them. Patients were examined by dermatologist, and biopsy was performed when necessary. RESULTS: Patients with MEN1 presented hyperparathyroidism (100%), neuroendocrine tumours of pancreas (66%) and pituitary adenomas (44%); their relatives were free of endocrine features of MEN1. The studied cutaneous lesions were more prevalent in affected patients than in non-carriers (55.5% vs. 25%; P = 0.029). Odds ratio of developing cutaneous lesions in MEN1 patients was 6.6 (95% confidence interval, 1.09-40.43). The frequency of angiofibromas was lower (22.2%) than the reported in other studies (43-88%), and we did not find any collagenoma. CONCLUSIONS: MEN1 is associated to some cutaneous lesions and could be useful for detecting MEN1 carriers in an affected family. Cutaneous lesions should be assessed in MEN1 patients.

Introducción, definición y medida del exceso de peso en adolescentes / No disponible

No disponible

Comorbilidades del exceso ponderal en el adolescente / No disponible

No disponible

Atypical thymic carcinoid in multiple endocrine neoplasia type 1 syndrome.

An asymptomatic, non-smoker patient carrier of a multiple endocrine neoplasia syndrome type 1 (MEN1) mutation was diagnosed with invasive atypical thymic carcinoid tumor. After surgical treatment the tumor reappeared albeit without metastasis. Thymic carcinoid is a well-known cause of mortality in MEN1, and usually metastatic disease is present at diagnosis. Male sex, smoking, and previous hyperparathyroidism probably play a role in the pathogenesis of this neoplasia.

Effect of acute ghrelin administration on glycaemia and insulin levels in obese patients.

OBJECTIVES: Ghrelin is a 28-amino-acid peptide, predominantly produced by the stomach. There are several studies that suggest the importance of ghrelin in obesity. However, the pancreatic endocrine response to ghrelin in obesity is unclear at present. The aim of this study was to clarify whether ghrelin administration influences glucose and insulin levels in obese patients. PATIENTS AND METHODS: Six obese female patients (31 +/- 3.4 year) with a BMI of 36.1 +/- 7.7 kg/m(2) were studied. Three tests were done: placebo, ghrelin (1 microg/kg, intravenously) and growth hormone-releasing hormone (GHRH; 1 microg/kg, iv) plus ghrelin (1 microg/kg, iv). Blood samples were taken at appropriate intervals for determination of glucose and insulin. Statistical analyses were performed by Wilcoxon and Mann-Whitney tests. RESULTS: Glucose (mean peak, mmol/l) level after placebo administration was 4.9 +/- 0.2. Glucose level after the administration of ghrelin was 5.1 +/- 0.2, not significantly different from the response after placebo (p = NS). Glucose level after the administration of ghrelin plus GHRH was 5.1 +/- 0.2, not significantly different from placebo (p = NS). Insulin (mean peak, mU/l) level after placebo administration was 16.1 +/- 6.1. Insulin level after the administration of ghrelin was 12.3 +/- 1.6, not significantly different from placebo (p = NS). Insulin level after the administration of ghrelin plus GHRH was 11.1 +/- 2.7, not significantly different from the response after placebo (p = NS). CONCLUSIONS: In female obese patients, we did not find significant differences in glucose or insulin levels following ghrelin or GHRH plus ghrelin administration.

Incidentalomas hipofisarios / Pituitary incidentalomas

Los incidentalomas hipofisarios (IH) son lesiones ocupantes de espacio localizadas en la zona selar que se identifican casualmente cuando se realiza una prueba de imagen craneal (tomografía computarizada o resonancia magnética) para el estudio de otra enfermedad no relacionada. En estudios de autopsias no seleccionadas se ha estimado que hasta el 10% de los varones y las mujeres presentan tumores hipofisarios no sospechados en vida. El diagnóstico diferencial de las lesiones ocupantes de espacio en la zona selar incluye una amplia gama de afecciones. Los microadenomas hipofisarios y las lesiones quísticas son las causas más frecuentes de IH en los estudios de autopsia. Existen pocos datos de la evolución natural de los IH, si bien se cree que muy pocos aumentan de tamaño de forma significativa durante el seguimiento. Es necesario determinar el protocolo de estudio y seguimiento del paciente con un IH, teniendo en cuenta la relación coste-beneficio del estudio

Pituitary incidentalomas (PI) are defined as pituitary masses that are incidentally found when cranial computed tomography (CT) or magnetic resonance imaging (MRI) scans are performed to study an unrelated condition. In studies of unselected autopsies it has been estimated that up to 10% of men and women harbour pituitary tumors that were not suspected while the individuals were alive. The differential diagnosis of PI is wide, but pituitary microadenomas and cystic lesions are the most common causes of PI in autopsy series. There are few data about the natural course of PI but it is thought that significant mass enlargement is not usual during follow-up. The optimal management strategy for patients with PI, taking into account the cost-benefit ratio, remains to be determined

Acromegalia que simula un neuroblastoma / Acromegaly simulating a neuroblastoma

La endocrinología es una especialidad que carece, en gran medida, de técnicas diagnósticas específicas. El endocrinólogo se caracteriza por su capacidad para interpretar datos hormonales basales y tras estímulos. Presentamos el caso de un paciente que, en función de los datos histológicos y radiológicos, había sido diagnosticado de secreción ectópica de prolactina por un neuroblastoma olfatorio y en el cual la revisión de los datos clínicos y, especialmente, el estudio hormonal, condujo al diagnóstico correcto de macroadenoma hipofisario secretor de hormona de crecimiento (GH) y prolactina. En resumen, en ocasiones los adenomas hipofisarios secretores de GH y prolactina pueden simular otras neoplasias, especialmente cuando las determinaciones hormonales no se interpretan adecuadamente (AU)

Endocrinology is a specialty that, to a large extent, lacks specific diagnostic tools. Endocrinologists are characterized by their ability to interpret basal and stimulated hormonal data. We describe the case of a male patient initially diagnosed as suffering from an olfactory neuroblastoma with ectopic prolactin secretion, based on histological and radiological studies. After a review of all the clinical and hormonal results, the tumor was finally diagnosed as a growth hormone (GH)- and prolactin-secreting pituitary macroadenoma. In summary, pituitary adenomas that secrete GH and prolactin can sometimes simulate other tumors, especially when hormonal results are not interpreted correctly (AU)

Acromegaly due to a growth hormone-releasing hormone-secreting intracranial gangliocytoma.

In more than 95% of cases acromegaly is due to GH hypersecretion by a pituitary adenoma. GHRH hypersecretion accounts for about 0.5% of cases of acromegaly. Intracranial GHRH-secreting tumors are extremely rare and only a few well-documented cases have been reported. The clinical features of acromegaly due to intracranial GHRH-secreting tumor are indistinguishable from those of other patients with "classical acromegaly". In cases of intrasellar gangliocytomas, not even radiological findings help to make the correct diagnosis, which can only be made with the hystological study. We present the case of a woman with acromegaly; the magnetic resonance demonstrated a 2x1.8x1.2 cm mass in the jugum sphenoidalis region, associated with a partial empty sella. There was a partial response to high-dose lanreotide therapy, so surgical treatment was decided, although only part of the tumor could be removed. Histopathological diagnosis was consistent with gangliocytoma, and immunostaining in the ganglionic cells was positive for GHRH. After surgery, hormone hypersecretion persisted, so medical treatment was reintroduced. In summary, we report a well-documented case of an intracranial GHRH-secreting gangliocytoma, an exceedingly rare cause of acromegaly. Clinical and biochemical data did not allow to make the correct diagnosis, which was only made on the pathological study. This case underscores that acromegaly can be due to causes other than a GH-secreting adenoma, and underlines that finding an image not typical of a pituitary adenoma should raise the suspicion that an unusual cause subsides the acromegaly.

[Neuroendocrine disturbances in obesity]. / Alteraciones neuroendocrinas en la obesidad.

Obesity is associated with different disturbances in endocrine function. Both spontaneous growth hormone (GH) secretion and its response to several stimuli have shown to be reduced in obese patients. The GH responses to GH-releasing hormone and other challenges by pyridostigmine suggest that the reduction in GH secretion is related to an increased somatostatinergic tone. Other experiments point to a down-regulation of somatostatin receptors in the somatotroph cell. Ghrelin administration is followed by a massive GH release, but the possibility that ghrelin or GHRH deficiency are the cause of GH deficiency in obesity is unlikely. The increase in free fatty acids in obesity might be related to GH reduction, since acipimox administration is able to reverse GH secretion. In women, abdominal obesity is associated with hyperandrogenism and low sex hormone-binding globulin levels. Obese men have low testosterone and gonadotrophin concentrations, specially in cases of morbid obesity. An increase in hypothalamic-pituitary-adrenal axis activity and some resistance to dexamethasone suppression have been described in abdominal obesity. This effect may be due to neuroendocrine alterations related to a genetic origin. Adrenal hyperfunction may favour cardiovascular and metabolic complications. There are no disturbances in thyroid function. Sometimes a reduction in prolactin response to several stimuli has been reported. This effect may be due to hyperinsulinaemia or to disturbances in the dopaminergic tone.

Guía de Práctica Clínica para el Manejo del Sobrepeso y la Obesidad en Personas Adultas / Clinical Practice Guideline for the Management of Overweight and Obesity in Adults

La obesidad es una enfermedad crónica multifactorial de gran trascendencia sociosanitaria y económica y constituye un problema de salud pública. Causa o empeora un gran número de problemas relacionados con la salud: diabetes, enfermedad coronaria, hipertensión y determinados tumores. Se asocia con mayor riesgo de mortalidad cardiovascular, mayor prevalencia de alteraciones psicopatológicas, incremento del coste sanitario y disminución de la esperanza de vida. Actualmente en España, la prevalencia de exceso de peso afecta aproximadamente al 50% de la población. La Sociedad Española de Endocrinología y Nutrición (SEEN) ha elaborado una Guía de Práctica Clínica sobre el diagnóstico, la evaluación y el tratamiento del sobrepeso y de la obesidad en adultos estructurada en dos partes: 1) Definición y clasificación, epidemiología, etiopatogenia, complicaciones, beneficios de la reducción ponderal y evaluación del enfermo con sobrepeso u obesidad; 2) identificación de enfermos con riesgo de obesidad subsidiarios de tratamiento, objetivos de tratamiento y estrategias terapéuticas disponibles para conseguirlos, indicándose además, el grado de recomendación basado en la evidencia científica sobre cada uno de estos aspectos. Aun siendo la obesidad una enfermedad que debiera implicar no sólo a personal sanitario, sino también a autoridades políticas, agentes sociales, educadores e industria alimentaria entre otros, la SEEN ha querido desarrollar esta guía dados los evidentes aspectos endocrinológicos y metabólicos de este trastorno. Esta guía establece recomendaciones basadas en la evidencia científica para ayudar a tomar decisiones sobre el diagnóstico, la evaluación y el tratamiento del exceso ponderal en adultos y posibilitar una atención más homogénea y de calidad (AU)

Obesity is a chronic, multifactor disease with sizeable socio sanitary and economic consequences and is an issue in public health, mostly in developing countries. It causes or exacerbates a large number of health problems: diabetes, coronary heart disease, hypertension, and the incidence of certain cancers. It has been linked to a greater risk of cardiovascular mortality, a higher prevalence of psychopathology disorders and social maladjustment with a higher health care cost and shorter life-expectancy. In Spain, nowadays, the prevalence of overweight and obesity is nearly 50% of population. SEEN has developed a Clinical Practice Guide on diagnosis, evaluation and treatment of overweight and obesity in adult people with two sections: 1) Definition and classification of adult obesity, its epidemiology, etiopathogeny, complications, benefits of weight reduction and clinical evaluation of patients with overweight or obesity, and 2) Identification of patients with obesity risk subsidiary to weight reduction treatment, therapy goals and therapeutical strategies available to achieve them indicating as well the degree of recommendation based upon scientific evidence on each aspect. Although obesity is a disease which is supposed to involve not only medical but also political authorities, social agents, educators and food industry among others, SEEN decided to develop this Guide taking into account the evident endocrinological and metabolical aspects of this disorder. The Guide contains scientific evidencebased recommendations intended to help doctors making decisions on diagnose, evaluations and treatment of adult overweight so that a more homogeneous attendance with settled quality can be achieved (AU)