Prolonged breastfeeding protects from obesity by hypothalamic action of hepatic FGF21.

Early-life determinants are thought to be a major factor in the rapid increase of obesity. However, while maternal nutrition has been extensively studied, the effects of breastfeeding by the infant on the reprogramming of energy balance in childhood and throughout adulthood remain largely unknown. Here we show that delayed weaning in rat pups protects them against diet-induced obesity in adulthood, through enhanced brown adipose tissue thermogenesis and energy expenditure. In-depth metabolic phenotyping in this rat model as well as in transgenic mice reveals that the effects of prolonged suckling are mediated by increased hepatic fibroblast growth factor 21 (FGF21) production and tanycyte-controlled access to the hypothalamus in adulthood. Specifically, FGF21 activates GABA-containing neurons expressing dopamine receptor 2 in the lateral hypothalamic area and zona incerta. Prolonged breastfeeding thus constitutes a protective mechanism against obesity by affecting long-lasting physiological changes in liver-to-hypothalamus communication and hypothalamic metabolic regulation.

Circulating LEAP-2 is associated with puberty in girls.

BACKGROUND/OBJECTIVES: Liver-expressed antimicrobial peptide 2 (LEAP-2) was recently identified as an endogenous non-competitive allosteric antagonist of the growth hormone secretagogue receptor 1a (GHSR1a). LEAP-2 blunts ghrelin-induced feeding and its plasma levels are modulated in response to nutritional status in humans. Despite the relevant role of ghrelin in childhood, puberty, and childhood obesity, the potential implication of LEAP-2 in these aspects remains totally unknown. We aimed to investigate the regulation of circulating plasma LEAP-2 in childhood and adolescent either lean or obese. METHODS AND RESULTS: Plasma levels of LEAP-2 were analyzed in a cross-sectional study with lean and obese children and adolescents (n = 150). Circulating LEAP-2 levels were significantly higher in girls than in boys independently of whether they were obese or lean. In addition, LEAP-2 was significantly increased (p < 0.001) in pubertal than in prepubertal girls, while no changes were found in boys between both developmental stages. Moreover, in girls LEAP-2 was positively correlated with insulin, IGF-1, HOMA-IR and triglycerides and negatively with ghrelin. In boys, LEAP-2 was positively correlated with leptin and negatively with vitamin D levels. CONCLUSION: This study reveals a sexual dimorphism in LEAP-2 levels in children and adolescents. These changes and the higher levels during puberty imply that LEAP-2 may contribute to some of the biological adaptations occurring during pubertal development in terms of food intake, energy balance, growth rate, and puberty onset. Future studies assessing LEAP-2 levels in longitudinal studies and its implications in growth rate, puberty onset, and reproductive hormones will help to understand the relevance of this hormone in this stage of life.

[Evaluation of food habits and physical activity in Galician students]. / Evaluación de los hábitos de alimentación y actividad física en escolares gallegos.

INTRODUCTION: Introduction: obesity causes millions of deaths each year. Its high prevalence in children and adolescents from southern European countries, including Spain, is associated with the new food preferences and decreased physical activity. Objective: to evaluate diet quality and physical activity in Galician schoolchildren in order to assess if modifying the current intervention strategies in lifestyles is required. Methods: in the present study, 662 students from the south of Galicia were studied (9-17 years). Body mass index (BMI) was calculated as adiposity indicator. The dietary pattern was evaluated through the Kidmed test and physical activity with PAQ-C. The sample was stratified by BMI according to Cole international standards. Data were analysed with the SPPS software. Results: fifty-six per cent of children are at high risk of overnutrition or need to improve their nutrition. The average adherence to the Mediterranean diet was low (7.64 ± 2.28), worsening with age and adiposity significantly. The average level of physical activity was moderate (3.02 ± 0.74) and it was lower in girls and adolescents; 58% showed a low-moderate level of physical activity. Quality diet was positively correlated with physical activity and negatively with BMI. Conclusions: Galician students showed a diet and physical activity risky pattern according to international/national recommendations. After several years of awareness campaigns and lifestyle interventions, improving their diet and increasing physical activity is still necessary.

INTRODUCCIÓN: Introducción: la obesidad causa millones de muertes anuales. Su elevada prevalencia en niños y adolescentes de países del sur de Europa, entre ellos España, se asocia con las nuevas preferencias alimentarias y la disminución de actividad física. Objetivos: evaluar la calidad de la dieta y la práctica de actividad física en escolares gallegos para valorar la necesidad de modificar las estrategias actuales de intervención en estilos de vida. Métodos: se estudiaron 662 niños de Galicia (9-17 años). Se calculó su índice de masa corporal (IMC) como indicador de adiposidad. El patrón alimentario se evaluó con el cuestionario Kidmed y la actividad física con el PAQ-C. Se estratificó la muestra en función del IMC de acuerdo con los estándares internacionales de Cole. Los datos se analizan con el paquete SPSS. Resultados: el 56% de los escolares están en riesgo elevado de malnutrición por exceso o necesitan mejorar su alimentación. La adherencia media al patrón alimentario mediterráneo fue baja (7,64 ± 2,28), empeorando significativamente con la edad y la adiposidad. El nivel de actividad física medio fue moderado (3,02 ± 0,74), significativamente menor en niñas y adolescentes. El 58% mostraron un nivel bajo-moderado de actividad física. La calidad de la dieta se correlacionó positivamente con la actividad física y negativamente con el IMC. Conclusiones: los escolares gallegos presentaron un patrón alimentario y de actividad física de riesgo en relación con las recomendaciones nacionales/internacionales. Tras varios años de campañas de concienciación e intervenciones sobre estilos de vida, continúa siendo necesario mejorar la dieta y aumentar la práctica física-deportiva.

Hypothalamic dopamine signaling regulates brown fat thermogenesis.

Dopamine signaling is a crucial part of the brain reward system and can affect feeding behavior. Dopamine receptors are also expressed in the hypothalamus, which is known to control energy metabolism in peripheral tissues. Here we show that pharmacological or chemogenetic stimulation of dopamine receptor 2 (D2R) expressing cells in the lateral hypothalamic area (LHA) and the zona incerta (ZI) decreases body weight and stimulates brown fat activity in rodents in a feeding-independent manner. LHA/ZI D2R stimulation requires an intact sympathetic nervous system and orexin system to exert its action and involves inhibition of PI3K in the LHA/ZI. We further demonstrate that, as early as 3 months after onset of treatment, patients treated with the D2R agonist cabergoline experience an increase in energy expenditure that persists for one year, leading to total body weight and fat loss through a prolactin-independent mechanism. Our results may provide a mechanistic explanation for how clinically used D2R agonists act in the CNS to regulate energy balance.

ANGPTL-4 is Associated with Obesity and Lipid Profile in Children and Adolescents.

Angiopoietin-like protein 4 (ANGPTL-4) regulates lipidic metabolism and affects energy homeostasis. However, its function in children with obesity remains unknown. We investigated plasma ANGPTL-4 levels in children and its relationship with body mass index (BMI) and different lipidic parameters such as free fatty acids (FFA). Plasma ANGPTL-4 levels were analyzed in two different cohorts. In the first cohort (n = 150, age 3-17 years), which included children with normal weight or obesity, we performed a cross-sectional study. In the second cohort, which included only children with obesity (n = 20, age 5-18 years) followed up for two years after an intervention for weight loss, in which we performed a longitudinal study measuring ANGPTL-4 before and after BMI-loss. In the cross-sectional study, circulating ANGPTL-4 levels were lower in children with obesity than in those with normal weight. Moreover, ANGPTL-4 presented a negative correlation with BMI, waist circumference, weight, insulin, homeostasis model assessment of insulin resistance index (HOMA index), triglycerides, and leptin, and a positive correlation with FFA and vitamin-D. In the longitudinal study, the percent change in plasma ANGPTL-4 was correlated with the percent change in FFA, total-cholesterol and high-density lipoprotein cholesterol. This study reveals a significant association of ANGPTL-4 with pediatric obesity and plasma lipid profile.

Circulating Pro-Uroguanylin Levels In Children And Their Relation To Obesity, Sex And Puberty.

Uroguanylin is a 16 amino acid peptide that constitutes a key component of the gut- brain axis with special relevance in body weight regulation. In childhood and adolescence, periods of life with notable metabolic changes; limited data exist, with measurements of pro-uroguanylin in adolescence but not in prepubertal children. This study investigates pro-uroguanylin circulating levels in children with obesity and its relationship with obesity, sex and pubertal development. We analyzed circulating prouroguanylin levels in 117 children (62) and adolescents (55), including 73 with obesity and 44 with normal weight. The pro-uroguanylin concentration is higher in lean girls during pre-puberty versus lean boys (1111 vs 635, p < 0.001). During puberty, pro-uroguanylin levels are higher in lean males with respect to lean females (1060 vs 698, p < 0.01). In girls, a negative correlation exists between pro-uroguanylin and age, Tanner stage, weight, height, BMI (body mass index), waist circumference and plasma levels of leptin and testosterone; a positive correlation was found between pro-uroguanylin and free triiodothyronine. In boys, a positive correlation was found between pro-uroguanylin and BMI and waist circumference and a negative correlation was found with high density lipoprotein-cholesterol. We conclude that a sexual dimorphism exists in circulating pro-uroguanylin levels with respect to BMI. Uroguanylin presents also an opposed circulating pattern during puberty in both sexes.

Plasma ANGPTL-4 is Associated with Obesity and Glucose Tolerance: Cross-Sectional and Longitudinal Findings.

SCOPE: Angiopoietin-like protein 4 (ANGPTL-4) regulates plasma lipoprotein levels, but its relevance in human obesity and type 2 diabetes (T2D) is largely unknown. We aim to investigate the regulation of circulating ANGPTL-4 levels in obesity, T2D, and after changes in body weight. METHODS AND RESULTS: Circulating ANGPTL-4 levels were measured in two different cohorts. First, in a cross-sectional study, we evaluated ANGPTL-4 levels in lean and obese patients with normoglycemia or with altered glucose tolerance (AGT; n = 282). Second, in a longitudinal intervention study, 51 obese participants were evaluated. A hypocaloric diet was prescribed, with follow-up 2 years later. ANGPTL-4 levels were significantly increased in obese patients with AGT compared to lean participants. Moreover, ANGPTL-4 was positively correlated with BMI, waist circumference, fat mass, HbA1c, HOMA-IR, fasting triglycerides, and with inflammatory markers. Participants gaining weight after the follow-up showed increased ANGPTL-4 levels in parallel to increased BMI, fat mass, and fasting glucose, while ANGPTL-4 levels were reduced in participants losing weight. CONCLUSION: Our data support a relevant role of ANGPTL-4 in human obesity and its involvement in long-term body weight changes.

25-Hydroxyvitamin D levels of children are inversely related to adiposity assessed by body mass index.

Vitamin D deficiency is associated with wide range of pathologies. Some evidences have shown that low vitamin D circulating levels in children and adolescent are related to fat mass and obesity. The objectives of the present study were to characterize vitamin D status in children and adolescents and to determine if serum 25-hydroxyvitamin D (25(OH)D) concentration is related to adiposity assessed by body mass index (BMI). Serum 25(OH)D levels were measured by LIAISON method in 471 children and adolescents (2 to 18 years age) and analyzed according to gender, pubertal period, age, and BMI. An overall prevalence of 25(OH)D insufficiency and deficiency was present in the 67.1%. Lower 25(OH)D levels were found in females (25.56 ± 14.03 vs 29.71 ± 17.10 ng ml-1; P = 0.004) and pubertal children (25.52 ± 13.97 vs 29.21 ± 16.83 ng ml-1; P = 0.011). In addition, an inverse relation of BMI and age on 25(OH)D concentrations was observed in children. In conclusion, low vitamin D status was highly prevalent among children and adolescents. Of note, a non-lineal regression model showed that 39.6% of vitamin D levels variability was explained by BMI. These results indicate that adiposity assessed by BMI impacts vitamin D status.

Pharmacological inhibition of cannabinoid receptor 1 stimulates gastric release of nesfatin-1 via the mTOR pathway.

AIM: To determine whether Nucb2/nesfatin1 production is regulated by the cannabinoid system through the intracellular mTOR pathway in the stomach. METHODS: Sprague Dawley rats were treated with vehicle, rimonabant, rapamycin or rapamycin+rimonabant. Gastric tissue obtained from the animals was used for biochemical assays: Nucb2 mRNA measurement by real time PCR, gastric Nucb2/nesfatin protein content by western blot, and gastric explants to obtain gastric secretomes. Nucb2/nesfatin levels were measured in gastric secretomes and plasma using enzyme-linked immunosorbent assay. RESULTS: The inhibition of cannabinoid receptor 1 (CB1) by the peripheral injection of an inverse agonist, namely rimonabant, decreases food intake and increases the gastric secretion and circulating levels of Nucb2/nesfatin-1. In addition, rimonabant treatment activates mTOR pathway in the stomach as showed by the increase in pmTOR/mTOR expression in gastric tissue obtained from rimonabant treated animals. These effects were confirmed by the use of a CB1 antagonist, AM281. When the intracellular pathway mTOR/S6k was inactivated by chronic treatment with rapamycin, rimonabant treatment was no longer able to stimulate the gastric secretion of Nucb2/nesfatin-1. CONCLUSION: The peripheral cannabinoid system regulates food intake through a mechanism that implies gastric production and release of Nucb2/Nesfatin-1, which is mediated by the mTOR/S6k pathway.

Regulation of Growth Hormone by the Splanchnic Area.

The regulation of growth hormone (GH) was traditionally thought to be under the control of two main hypothalamic neuropeptides; GH-releasing hormone and somatostatin. In 1999, with the isolation of ghrelin, as a gastric-derived peptide with potent GH-releasing activity, concept of regulation of the somatotropic axis completely changed. In addition to its GH-releasing activity, ghrelin exhibited the capacity to modulate food intake and body weight. The role of this splanchnic factor in regulating GH as a nexus of energy balance control and GH are explored in this chapter. From a physiological standpoint, a novel mechanism of GH regulation mediated by ghrelin exists, implicating the peripheral modulation of the cannabinoid receptor.

Uroguanylin Action in the Brain Reduces Weight Gain in Obese Mice via Different Efferent Autonomic Pathways.

The gut-brain axis is of great importance in the control of energy homeostasis. The identification of uroguanylin (UGN), a peptide released in the intestines that is regulated by nutritional status and anorectic actions, as the endogenous ligand for the guanylyl cyclase 2C receptor has revealed a new system in the regulation of energy balance. We show that chronic central infusion of UGN reduces weight gain and adiposity in diet-induced obese mice. These effects were independent of food intake and involved specific efferent autonomic pathways. On one hand, brain UGN induces brown adipose tissue thermogenesis, as well as browning and lipid mobilization in white adipose tissue through stimulation of the sympathetic nervous system. On the other hand, brain UGN augments fecal output through the vagus nerve. These findings are of relevance as they suggest that the beneficial metabolic actions of UGN through the sympathetic nervous system do not involve nondesirable gastrointestinal adverse effects, such as diarrhea. The present work provides mechanistic insights into how UGN influences energy homeostasis and suggests that UGN action in the brain represents a feasible pharmacological target in the treatment of obesity.

Circulating Betatrophin Levels Are Increased in Anorexia and Decreased in Morbidly Obese Women.

CONTEXT: Betatrophin is produced primarily by liver and adipose tissue and has been recently reported as a novel hormone promoting ß-cell proliferation and ß-cell mass and improving glucose tolerance. OBJECTIVE: Because it is markedly regulated by nutritional status, we hypothesized that circulating betatrophin levels might be affected by pathophysiological conditions altering body weight. SETTING AND PATIENTS: We analyzed circulating betatrophin levels in 149 female patients, including 99 with extreme body mass index (30 anorexia nervosa, 24 obese, 45 morbid obese, and 50 healthy eating/weight controls). OUTCOME MEASUREMENTS: Serum betatrophin levels and its correlations with different anthropometric and biochemical parameters were measured. RESULTS: Plasma betatrophin levels were significantly elevated in anorexic patients, whereas its levels were reduced in morbidly obese women when compared with normal-weight women. Plasma betatrophin correlated negatively with weight, body mass index, fat percentage, glucose, insulin, and homeostatic model assessment index and positively correlated with high-density lipoprotein. CONCLUSIONS: These results suggest that metabolic status is an important regulator of circulating betatrophin levels.

Peripheral signals mediate the beneficial effects of gastric surgery in obesity.

Obesity is nowadays a public health problem both in the industrialized world and developing countries. The different treatments to fight against obesity are not very successful with the exception of gastric surgery. The mechanism behind the achievement of this procedure remains unclear although the modifications in the pattern of gastrointestinal hormones production appear to be responsible for the beneficial effect. The gastrointestinal tract has emerged in the last time as an endocrine organ in charge of response to the different stimulus related to nutritional status by the modulation of more than 30 signals acting at central level to modulate food intake and body weight. The production of some of these gastric derived signals has been proved to be altered in obesity (ghrelin, CCK, and GLP-1). In fact, bariatric surgery modifies the production of both gastrointestinal and adipose tissue peripheral signals beyond the gut microbiota composition. Through this paper the main peripheral signals altered in obesity will be reviewed together with their modifications after bariatric surgery.

Regulation of NUCB2/nesfatin-1 production in rat's stomach and adipose tissue is dependent on age, testosterone levels and lactating status.

Nesfatin-1, which is derived from the NEFA/nucleobindin 2 (NUCB2) precursor, was recently identified as an anorexigenic peptide that is produced in several tissues including the hypothalamus. Currently, no data exist regarding the regulation of NUCB2/nesfatin-1 production in peripheral tissues, such as gastric mucosa and adipose tissue, through different periods of development. The aim of the present work was to study the variations on circulating levels, mRNA expression and tissue content in gastric mucosa and adipose tissue of NUCB2/nesfatin-1 with age and specially in two clue periods of maturation, weaning and puberty. The weaning period affected NUCB2/nesfatin-1 production in gastric tissue. The testosterone changes associated with the initiation of puberty regulated NUCB2/nesfatin-1 production via adipose tissue and gastric NUCB2/nesfatin-1 production. In conclusion, the production of NUCB2/nesfatin-1 by the stomach and adipose tissue fluctuates with age to regulate energy homeostasis during different states of development.

The gastric CB1 receptor modulates ghrelin production through the mTOR pathway to regulate food intake.

Over the years, the knowledge regarding the relevance of the cannabinoid system to the regulation of metabolism has grown steadily. A central interaction between the cannabinoid system and ghrelin has been suggested to regulate food intake. Although the stomach is the main source of ghrelin and CB1 receptor expression in the stomach has been described, little information is available regarding the possible interaction between the gastric cannabinoid and ghrelin systems in the integrated control of energy homeostasis. The main objective of the present work was to assess the functional interaction between these two systems in terms of food intake using a combination of in vivo and in vitro approaches. The present work demonstrates that the peripheral blockade of the CB1 receptor by rimonabant treatment decreased food intake but only in food-deprived animals. This anorexigenic effect is likely a consequence of decreases in gastric ghrelin secretion induced by the activation of the mTOR/S6K1 intracellular pathway in the stomach following treatment with rimonabant. In support of this supposition, animals in which the mTOR/S6K1 intracellular pathway was blocked by chronic rapamycin treatment, rimonabant had no effect on ghrelin secretion. Vagal communication may also be involved because rimonabant treatment was no longer effective when administered to animals that had undergone surgical vagotomy. In conclusion, to the best of our knowledge, the present work is the first to describe a CB1 receptor-mediated mechanism that influences gastric ghrelin secretion and food intake through the mTOR pathway.

Histopathological effects of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) in the gills, intestine and liver of turbot (Psetta maxima).

Polybrominated diphenyl ethers (PBDEs) have become ubiquitous environmental pollutants because of their widespread use as flame retardants in various consumer products (plastics, textiles, electronic appliances and building materials) and their long half-life. BDE-47 (2,2',4,4'-tetrabromodiphenyl ether) is the major PBDE congener detected in the environment and in animal tissues. In the present study, the histopathological effects are examined of BDE-47 on the gills, intestine and liver tissues of juvenile turbot (Psetta maxima).The specimens were exposed to two concentrations of BDE-47 (0.03 and 0.3 µg/L) for a period of 15 days. The histological changes were detected microscopically and evaluated with quantitative or semi-quantitative analyses. At the doses of BDE-47 assayed, the most common gill injuries were lamellar fusion, blood congestion and hyperplasia and hypertrophy of the epithelial and mucous cells. In the intestine of fish exposed to BDE-47, the alterations detected were hyperplasia and hypertrophy of mucous cells. Hepatic lesions in the liver of fish exposed to BDE-47 were characterized by circulatory disturbances, irregular morphology of hepatocytes, cellular and nuclear hypertrophy, and nuclear vacuolation and pyknosis. As BDE-47 is present in food and other material related to aquaculture systems, our results indicate that exposure to this pollutant could have serious consequences on health in turbot and other cultured fish.