Endocannabinoid-related molecules predict the metabolic efficacy of GLP-1 receptor agonism in humans with obesity.

OBJECTIVE: N-acylethanolamines (NAEs) include endocannabinoid (EC) and EC-related molecules that impact the anti-obesity and anti-diabetic efficacy of glucagon-like peptide-1 receptor agonists (GLP-1RA) in animal studies. However, the clinical relevance of these findings remains to be determined. Here, we tested whether GLP-1RA treatment affects circulating NAE levels and whether NAEs may predict the efficacy of GLP-1RA treatment in humans with obesity undergoing weight loss maintenance. MATERIALS AND METHODS: We profiled plasma levels of NAEs in participants with obesity undergoing weight loss maintenance with (n = 23)/or without (n = 20) treatment with the GLP-1RA liraglutide. NAE levels were measured at three different time points: before the start of the study, at the end of the diet-induced weight loss, and after 52-weeks treatment. Linear regression analyses were used to investigate whether pharmacological responses could be predicted by NAEs levels. RESULTS: Liraglutide treatment reduced plasma concentrations of the NAE and oleoyl-ethanolamide (OEA), without altering arachidonoyl-ethanolamide (AEA) levels and palmitoyl-ethanolamide (PEA) levels. High pre-treatment levels of OEA were predictive of superior compound-mediated effects on fasting insulin and triglyceride levels. High pre-treatment PEA and AEA levels were also predictive of superior Liraglutide-mediated effects on triglyceride levels. CONCLUSIONS: Our data suggests that specific NAEs such as OEA and AEA are promising biomarkers of GLP-1RA metabolic efficacy in humans with obesity during weight loss maintenance. Plasma profiling of EC-related molecules may be a promising strategy to tailor GLP-1R-based therapies to individual needs in obesity and diabetes management.

New insights on the role of the endocannabinoid system in the regulation of energy balance.

Within the past 15 years, the endocannabinoid system (ECS) has emerged as a lipid signaling system critically involved in the regulation of energy balance, as it exerts a regulatory control on every aspect related to the search, the intake, the metabolism and the storage of calories. An overactive endocannabinoid cannabinoid type 1 (CB1) receptor signaling promotes the development of obesity, insulin resistance and dyslipidemia, representing a valuable pharmacotherapeutic target for obesity and metabolic disorders. However, because of the psychiatric side effects, the first generation of brain-penetrant CB1 receptor blockers developed as antiobesity treatment were removed from the European market in late 2008. Since then, recent studies have identified new mechanisms of action of the ECS in energy balance and metabolism, as well as novel ways of targeting the system that may be efficacious for the treatment of obesity and metabolic disorders. These aspects will be especially highlighted in this review.

The corticotrophin-releasing factor/urocortin system regulates white fat browning in mice through paracrine mechanisms.

OBJECTIVES: The corticotrophin-releasing factor (CRF)/urocortin system is expressed in the adipose tissue of mammals, but its functional role in this tissue remains unknown. METHODS: Pharmacological manipulation of the activity of CRF receptors, CRF1 and CRF2, was performed in 3T3L1 white pre-adipocytes and T37i brown pre-adipocytes during in vitro differentiation. The expression of genes of the CRF/urocortin system and of markers of white and brown adipocytes was evaluated along with mitochondrial biogenesis and cellular oxygen consumption. Metabolic evaluation of corticosterone-deficient or supplemented Crhr1-null (Crhr1(-/-)) mice and their wild-type controls was performed along with gene expression analysis carried out in white (WAT) and brown (BAT) adipose tissues. RESULTS: Peptides of the CRF/urocortin system and their cognate receptors were expressed in both pre-adipocyte cell lines. In vitro pharmacological studies showed an inhibition of the expression of the CRF2 pathway by the constitutive activity of the CRF1 pathway. Pharmacological activation of CRF2 and, to a lesser extent, inhibition of CRF1 signaling induced molecular and functional changes indicating transdifferentiation of white pre-adipocytes and differentiation of brown pre-adipocytes. Crhr1(-/-) mice showed increased expression of CRF2 and its agonist Urocortin 2 in adipocytes that was associated to brown conversion of WAT and activation of BAT. Crhr1(-/-) mice were resistant to diet-induced obesity and glucose intolerance. Restoring physiological circulating corticosterone levels abrogated molecular changes in adipocytes and the favorable phenotype of Crhr1(-/-) mice. CONCLUSIONS: Our findings suggest the importance of the CRF2 pathway in the control of adipocyte plasticity. Increased CRF2 activity in adipocytes induces browning of WAT, differentiation of BAT and is associated with a favorable metabolic phenotype in mice lacking CRF1. Circulating corticosterone represses CRF2 activity in adipocytes and may thus regulate adipocyte physiology through the modulation of the local CRF/urocortin system. Targeting CRF receptor signaling specifically in the adipose tissue may represent a novel approach to tackle obesity.

Simultaneous postprandial deregulation of the orexigenic endocannabinoid anandamide and the anorexigenic peptide YY in obesity.

BACKGROUND: The endocannabinoid system is a potential pharmacotherapy target for obesity. However, the role of this system in human food intake regulation is currently unknown. METHODS: To test whether circulating endocannabinoids might functionally respond to food intake and verify whether these orexigenic signals are deregulated in obesity alongside with anorexigenic ones, we measured plasma anandamide (AEA), 2-arachidonoylglycerol (2-AG) and peptide YY (PYY) changes in response to a meal in 12 normal-weight and 12 non-diabetic, insulin-resistant obese individuals. RESULTS: Both normal-weight and obese subjects had a significant preprandial AEA peak. Postprandially, AEA levels significantly decreased in normal-weight, whereas no significant changes were observed in obese subjects. Similarly, PYY levels significantly increased in normal-weight subjects only. No meal-related changes were found for 2-AG. Postprandial AEA and PYY changes inversely correlated with waist circumference, and independently explained 20.7 and 21.3% of waist variance. Multiple regression analysis showed that postprandial AEA and PYY changes explained 34% of waist variance, with 8.2% of the variance commonly explained. CONCLUSION: These findings suggest that AEA might be a physiological meal initiator in humans and furthermore show that postprandially AEA and PYY are concomitantly deregulated in obesity.

Cannabinoid receptor 1 (CB1) antagonism enhances glucose utilisation and activates brown adipose tissue in diet-induced obese mice.

AIMS/HYPOTHESIS: We examined the physiological mechanisms by which cannabinoid receptor 1 (CB1) antagonism improves glucose metabolism and insulin sensitivity independent of its anorectic and weight-reducing effects, as well as the effects of CB1 antagonism on brown adipose tissue (BAT) function. METHODS: Three groups of diet-induced obese mice received for 1 month: vehicle; the selective CB1 antagonist SR141716; or vehicle/pair-feeding. After measurements of body composition and energy expenditure, mice underwent euglycaemic-hyperinsulinaemic clamp studies to assess in vivo insulin action. In separate cohorts, we assessed insulin action in weight-reduced mice with diet-induced obesity (DIO), and the effect of CB1 antagonism on BAT thermogenesis. Surgical denervation of interscapular BAT (iBAT) was carried out in order to study the requirement for the sympathetic nervous system in mediating the effects of CB1 antagonism on BAT function. RESULTS: Weight loss associated with chronic CB1 antagonism was accompanied by increased energy expenditure, enhanced insulin-stimulated glucose utilisation, and marked activation of BAT thermogenesis. Insulin-dependent glucose uptake was significantly increased in white adipose tissue and BAT, whereas glycogen synthesis was increased in liver, fat and muscle. Despite marked weight loss in the mice, SR141716 treatment did not improve insulin-mediated suppression of hepatic glucose production nor increase skeletal muscle glucose uptake. Denervation of iBAT blunted the effect of SR141716 on iBAT differentiation and insulin-mediated glucose uptake. CONCLUSIONS/INTERPRETATION: Chronic CB1 antagonism markedly enhances insulin-mediated glucose utilisation in DIO mice, independent of its anorectic and weight-reducing effects. The potent effect on insulin-stimulated BAT glucose uptake reveals a novel role for CB1 receptors as regulators of glucose metabolism.

mTORC1 signaling in energy balance and metabolic disease.

The mammalian target of rapamycin complex 1 (mTORC1) pathway regulates cellular responses to fuel availability. Recent studies have demonstrated that within the central nervous system, and in particular the hypothalamus, mTORC1 represents an essential intracellular target for the actions of hormones and nutrients on food intake and body weight regulation. By being at the crossroads of a nutrient-hormonal signaling network, mTORC1 also controls important functions in peripheral organs, such as muscle oxidative metabolism, white adipose tissue differentiation and ß-cell-dependent insulin secretion. Notably, dysregulation of the mTORC1 pathway has been implicated in the development of obesity and obesity-related conditions, such as type 2 diabetes. This manuscript will therefore review recent progress made in understanding the role of the mTORC1 pathway in the regulation of energy balance and peripheral metabolism. Furthermore, we will critically discuss the potential relevance of this intracellular pathway as a therapeutic target for the treatment of metabolic disease.

Assessment of benthic changes during 20 years of monitoring the Mexican Salina Cruz Bay.

In this work a non-parametric multivariate analysis was used to assess the impact of metals and organic compounds in the macro infaunal component of the mollusks benthic community using surface sediment data from several monitoring programs collected over 20 years in Salina Cruz Bay, Mexico. The data for benthic mollusks community characteristics (richness, abundance and diversity) were linked to multivariate environmental patterns, using the Alternating Conditional Expectations method to correlate the biological measurements of the mollusk community with the physicochemical properties of water and sediments. Mollusks community variation is related to environmental characteristics as well as lead content. Surface deposit feeders are increasing their relative density, while subsurface deposit feeders are decreasing with respect to time, these last are expected to be more related with sediment and more affected then by its quality. However gastropods with predatory carnivore as well as chemosymbiotic deposit feeder bivalves have maintained their relative densities along time.

[Pseudo-Cushing syndrome. Physiopathologic aspects and differential diagnosis]. / La sindrome da pseudo-Cushing. Aspetti fisiopatologici e diagnosi differenziale.

Pseudo-Cushing Syndromes (PCS) are a heterogeneous group of disorders, including alcoholism and depression, that share many of the clinical and biochemical features of Cushing's Syndrome (CS). It has been suggested that hypercortisolism of PCS may be the result of increased hypothalamic corticotropin-releasing hormone secretion in the context of a hypothalamic-pituitary-adrenal axis that is otherwise normally constituted. The substantial overlap in clinical features and daily urinary free cortisol levels between several patients with CS and those with PCS can make the differential diagnosis difficult. The most accurate tests in the distinction of CS from alcohol-induced PCS are dexamethasone-CRH and a midnight serum cortisol measurement. In depressed patients, the insulin tolerance test may be useful, although some overlap may exist. This brief review summarises the principal pathophysiological events of PCS and provides a useful strategy for differential diagnosis.

[Steroid therapy and adrenal function]. / Terapia steroidea e funzione surrenalica.

Glucocorticoids are frequently used for both diagnostic and therapeutic purposes. Their action mimics endogenous glucocorticoid actions by altering the activity of the hypothalamic-pituitary-adrenal (HPA) axis. Therefore, they can be responsible for iatrogenic diseases, particularly if used at high doses and for a long time. The aim of this brief review is to show the main pharmacological characteristics and the endocrine effects of glucocorticoids. The HPA axis insufficiency, related to acute glucocorticoid withdrawal, is also discussed.

[Spatial-temporal dynamics of red tide precursor organisms at the Pacific coast of North and Central America]. / Dinámica espacio-temporal de organismos precursores de marea roja en la costa Pacífica de América del Norte y Centroamérica.

The Pacific coast of Central and North America has long been and still is impacted by the flourishing of microalgal populations known as Harmful Algal Blooms (HABs). The organisms that have caused recent HABs episodes in the region are among others, Gymnodinium catenatum, Pyrodinium bahamense var. compressum, and recently Cochlodinium cf. catenatum. In spite of the accumulated effects on the human health, the economic activities and the environment, scarce information is available on the subject. The augmented use of coastal zones for human activities is also paralleled by increased awareness of global climate changes. Thus, it is not an easy task to discriminate anthropogenic or natural phenomena, or both, as the major driving forces. The long-term data sets available for limited regions, as well as some sporadic observations during notorious blooms, allowed us to discriminate major changes in the biodiversity and biogeography of HAB organisms. Main changes refer to number of events, covered area, duration and frequency, number of blooming species and appearance of not previously reported harmful taxa. The variables more clearly related to these dynamic phenomena, seems to be sea surface temperature and wind force, but it is not yet possible to weight their contributions. The participation of rain is not fully evaluated to date. The collaborative communication among small-budget monitoring operations in the region allowed to "pass the voice" about peaking concentrations of HAB organisms, diminishing the risk of poisoning.

Cannabinoid type-1 receptors in the paraventricular nucleus of the hypothalamus inhibit stimulated food intake.

Cannabinoid receptor type 1 (CB1)-dependent signaling in the brain is known to modulate food intake. Recent evidence has actually shown that CB1 can both inhibit and stimulate food intake in fasting/refeeding conditions, depending on the specific neuronal circuits involved. However, the exact brain sites where this bimodal control is exerted and the underlying neurobiological mechanisms are not fully understood yet. Using pharmacological and electrophysiological approaches, we show that local CB1 blockade in the paraventricular nucleus of the hypothalamus (PVN) increases fasting-induced hyperphagia in rats. Furthermore, local CB1 blockade in the PVN also increases the orexigenic effect of the gut hormone ghrelin in animals fed ad libitum. At the electrophysiological level, CB1 blockade in slices containing the PVN potentiates the decrease of the activity of PVN neurons induced by long-term application of ghrelin. Hence, the PVN is (one of) the site(s) where signals associated with the body's energy status determine the direction of the effects of endocannabinoid signaling on food intake.

The role of the endocannabinoid system in the regulation of hypothalamic-pituitary-adrenal axis activity.

The endocannabinoid system (ECS) is a recently identified neuromodulatory system, which is involved in several physiological processes and in disease. For example, the ECS not only represents the biological substrate of marijuana's effects, but also is known to modulate several neuroendocrine axes, including the hypothalamic-pituitary-adrenal (HPA) axis. Although previous pharmacological studies using plant-derived or synthetic cannabinoids have implied a stimulating action on the HPA axis, more recent findings have led to the conclusion that an endogenous cannabinoid tone might exist, which is actually inhibiting the release of both adrenocorticotrophic hormone and glucocorticoids. Studies using mice lacking cannabinoid receptor CB(1) have demonstrated that presence and activity of these receptors is essential for the regulation of HPA axis activity. Interestingly, the effects of endocannabinoids on the HPA axis are consistent with their neuromodulatory action on brain neurotransmitter systems. Endocannabinoids have been found to mediate the nongenomic glucocorticoid-induced inhibition of the release of corticotrophin-releasing factor within the paraventricular nucleus of the hypothalamus. Altogether, these observations suggest that alterations of the endocannabinoid tone might be associated with the development of stress-related diseases, including anxiety, depression and obesity.

Environmental assessment of aromatic hydrocarbons-contaminated sediments of the Mexican Salina Cuz Bay.

Concentrations of total aromatic hydrocarbons and extractable organic matter in the water column and sediment were determined in samples collected in the course of the last 20 years from the Salina Cruz Harbor, México, to assess the degree of organic contamination. In sediments, organic compounds accumulate in shallow areas mostly associated with extractable organic matter and fine fractions. Calculated geocumulation index and enrichment factors suggest that contamination could be derived from anthropogenic activities attributed to harbor and ship scrapping activities, as well as transboundary source. Concentration of total aromatic hydrocarbons (as chrysene equivalents) ranged from 0.01 to 534 microg l(-1) in water, and from 0.10 to 2,160 microg g(-1) in sediments. Total aromatic concentration of 5 microg g(-1) is proposed as background concentration.

Distribution, enrichment and accumulation of heavy metals in coastal sediments of Salina Cruz Bay, méxico.

Surface sediment samples collected from the Salina Cruz Bay in the last twenty years, were analyzed for the total available trace elements (Cr, Cu, Fe, Pb, Ni, V, and Zn) to evaluate metal contamination due to possible anthropogenic inputs. Normalization of metals to iron and fine-grained fraction (< 63 microm) indicated relatively high enrichment factors for lead during the last two decades. Sediment Quality Guidelines suggest that lead must be considered as a chemical of potential concern in the marine and estuarine ecosystem. Concentration levels of lead ranged from 5-124 microg/g, while Ni and V below 70 and 30 microg/g, respectively. Geoaccumulation and enrichment factors for the rest of elements show comparable values to those reported for sites with similar activities in the world. Spatial distribution suggests that in addition to harbor activities, a transboundary source for Pb must account for the observed trends.

Relationship between socio-economic and cultural status, psychological factors and body fat distribution in middle-aged women living in Northern Italy.

This study analyses the relationships between body fat distribution and socioeconomic and psychological factors in a cohort of 426 healthy middle-aged women living in Virgilio, Mantua (Northern Italy). The information concerning their occupational, social and psychological conditions and smoking habits were obtained by means of questionnaires. Psychological factors were investigated using the Italian version of the Illness Behaviour Questionnaire and the Symptom Questionnaire. Anthropometric measurements, body mass index (BMI) (kg/m2), waist/hip ratio (WHR) and clinical/hormonal menopausal status were also collected for each subject. The women reported significantly higher or lower psychological factor scores (symptoms of conversion: p=0.005; perception of disease: p=-0.018; denial: p=0.021; hostility: p=0.57; and laxity: p=0.047) as their WHR increased, thus indicating some concern about their health. In a multiple regression model, their WHR and waist circumference (W) significantly correlated with symptoms of conversion (p=0.005 and p=0.029), and W was also significantly related to the perception of disease (p=0.043). There was a significant inverse correlation between the WHR and educational level (p<0.001). The prevalence of partners who were entrepreneurs or self-employed also decreased as WHR increased (p<0.001). Furthermore, the number of women living in the centre of town significantly diminished, whereas those living in the suburbs or in the country significantly increased (p=0.005). However, using age, BMI and menopausal status as covariates, only the partner's work significantly and negatively correlated with the WHR (p=0.029). These results are consistent with the hypothesis that psychological and socio-economic handicaps are associated with a higher prevalence of abdominal fatness in middle-aged women living in Northern Italy

Endogenous cannabinoid system as a modulator of food intake.

The ability of Cannabis sativa (marijuana) to increase hunger has been noticed for centuries, although intensive research on its molecular mode of action started only after the characterization of its main psychoactive component Delta(9)-tetrahydrocannabinol in the late 1960s. Despite the public concern related to the abuse of marijuana and its derivatives, scientific studies have pointed to the therapeutic potentials of cannabinoid compounds and have highlighted their ability to stimulate appetite, especially for sweet and palatable food. Later, the discovery of specific receptors and their endogenous ligands (endocannabinoids) suggested the existence of an endogenous cannabinoid system, providing a physiological basis for biological effects induced by marijuana and other cannabinoids. Epidemiological reports describing the appetite-stimulating properties of cannabinoids and the recent insights into the molecular mechanisms underlying cannabinoid action have proposed a central role of the cannabinoid system in obesity. The aim of this review is to provide an extensive overview on the role of this neuromodulatory system in feeding behavior by summarizing the most relevant data obtained from human and animal studies and by elucidating the interactions of the cannabinoid system with the most important neuronal networks and metabolic pathways involved in the control of food intake. Finally, a critical evaluation of future potential therapeutical applications of cannabinoid antagonists in the therapy of obesity and eating disorders will be discussed.

Dinámica espacio-temporal de organismos precursores de marea roja en la costa Pacífica de América del Norte y Centroamérica / Spatial-temporal dynamics of red tide precursor organisms at the Pacific coast of North and Central America

La región costera del Pacífico de Centro y Norte America ha sido afectada de manera frecuente por fenómenos que se denominan proliferaciones algales nocivas o en inglés, "Harmful Algal Blooms" (HAB). A pesar de la gran cantidad de efectos en la salud pública, las actividades económicas y el medio ambiente, aún existe una abrumadora carencia de información en el tema. Esto no permite establecer si las causas principales de este evidente aumento en el número e intensidad de los eventos son naturales o antropogénicas. La incrementada utilización de las zonas costeras para actividades humanas encuentra paralelo en el denominado cambio climático, lo que dificulta discriminar entre la posible influencia de estos dos fenómenos. Series de datos de larga duración en regiones reducidas, así como las observaciones esporádicas realizadas cuando se presenta algún evento, nos permite comparar regímenes climáticos, condiciones geográficas, disponibilidad de nutrientes (incluyendo la eutroficación) y parámetros oceanográficos que promueven o permiten el desarrollo y mantenimiento de las proliferaciones, haciendo evidentes cambios drásticos en la biodiversidad y la biogeografía de los organismos productores de HAB

The Pacific coast of Central and North America has long been and still is impacted by the flourishing of microalgal populations known as Harmful Algal Blooms (HABs). The organisms that have caused recent HABs episodes in the region are among others, Gymnodinium catenatum, Pyrodinium bahamense var. compressum, and recently Cochlodinium cf. catenatum. In spite of the accumulated effects on the human health, the economic activities and the environment, scarce information is available on the subject. The augmented use of coastal zones for human activities is also paralleled by increased awareness of global climate changes. Thus, it is not an easy task to discriminate anthropogenic or natural phenomena, or both, as the major driving forces. The long-term data sets available for limited regions, as well as some sporadic observations during notorious blooms, allowed us to discriminate major changes in the biodiversity and biogeography of HAB organisms. Main changes refer to number of events, covered area, duration and frequency, number of blooming species and appearance of not previously reported harmful taxa. The variables more clearly related to these dynamic phenomena, seems to be sea surface temperature and wind force, but it is not yet possible to weight their contributions. The participation of rain is not fully evaluated to date. The collaborative communication among small-budget monitoring operations in the region allowed to "pass the voice" about peaking concentrations of HAB organisms, diminishing the risk of poisoning