Drug development strategies for the treatment of obesity: how to ensure efficacy, safety, and sustainable weight loss

The prevalence of obesity has increased worldwide, and approximately 25%-35% of the adult population is obese in some countries. The excess of body fat is associated with adverse health consequences. Considering the limited efficacy of diet and exercise in the current obese population and the use of bariatric surgery only for morbid obesity, it appears that drug therapy is the only available method to address the problem on a large scale. Currently, pharmacological obesity treatment options are limited. However, new antiobesity drugs acting through central nervous system pathways or the peripheral adiposity signals and gastrointestinal tract are under clinical development. One of the most promising approaches is the use of peptides that influence the peripheral satiety signals and brain-gut axis such as GLP-1 analogs. However, considering that any antiobesity drug may affect one or several of the systems that control food intake and energy expenditure, it is unlikely that a single pharmacological agent will be effective as a striking obesity treatment. Thus, future strategies to treat obesity will need to be directed at sustainable weight loss to ensure maximal safety. This strategy will probably require the coadministration of medications that act through different mechanisms.Instituto de Salud Carlos IIIXunta de GaliciaFundación Mutua Madrileñ

Comparative secretome analysis of rat stomach under different nutritional status

The fact that gastric surgery is at the moment the most effective treatment to fight against obesity highlights the relevance of gastric derived proteins as potential targets to treat this pathology. Taking advantage of a previously established gastric explant model for endocrine studies, the proteomic analysis of gastric secretome was performed. To validate this gastric explant system for proteomic analysis, the identification of ghrelin, a classical gastric derived peptide, was performed by MS. In addition, the differential analysis of gastric secretomes under differential nutritional status (control feeding vs fasting vs re-feeding) was performed. The MS identified proteins are showed in the present manuscript. The data supplied in this article is related to the research article entitled "Comparative secretome analysis of rat stomach under different nutritional status" (L.L. Senin, A. Roca-Rivada, C. Castelao, J. Alonso, C. Folgueira, F.F. Casanueva, M. Pardo, L.M. Seoane Comparative secretome analysis of rat stomach under different nutritional status J. Proteomics (2015))

Effect of excess body adiposity on the expression of genes involved in early steps of mammary carcinogenesis on diet-induced obese female rats

Introduction: Obesity is increasing worldwide and is associated with higher risk for some cancers. However, the mechanisms underlying this association are unclear. Because the obesity microenvironment could promote the onset of carcinogenesis, the aim of this study was to evaluate the association between excess body adiposity and the expression of genes related to the activation of early steps of tumor promotion on the mammary gland. Methods: Three weeks-old female Sprague-Dawley rats were fed a high fat diet (DIO: 60% Kcal/g fat, n = 14) or standard chow (LEAN: 3% Kcal/g fat, n = 15) for 10 weeks. Body weight and food intake were measured weekly. After sacrifice, retroperitoneal fat tissue was weighed and mammary tissue was extracted for qRT-PCR analysis. Genes associated with cell proliferation (Survivin/BIRC5 and MYC), DNA repair (TP53), and antioxidant protection (GSTM2, ALDH3A1) were quantified. Results: The DIO group showed a body weight 14.1% higher than LEAN group (p < 0.001). These differences were reflected on higher retroperitoneal fat content on DIO (3.22 ± 0.89g) vs. LEAN group (2.33 ± 0.52g; p = 0.012). Interestingly, DIO rats showed a higher gene expression for Survivin (∆68.2%), MYC (∆50.1%), TP53 (∆40.5%), ALDH3A1 (∆74.1%), and GSTM2 (∆25.7%) with respect to LEAN group. Conclusion: These data show that obesity is associated with changes potentially involved in early steps of tumor promotion, as shown by an increase in cellular proliferation and DNA damage related genes, even before detecting histological changes on the mammary tissue of obese female individuals. Further studies are needed to elucidate weather reducing body weight might be a therapeutic strategy to prevent this process

Gut Microbiota Composition in Male Rat Models under Different Nutritional Status and Physical Activity and Its Association with Serum Leptin and Ghrelin Levels

Background: Several evidences indicate that gut microbiota is involved in the control of host energy metabolism. Objective: To evaluate the differences in the composition of gut microbiota in rat models under different nutritional status and physical activity and to identify their associations with serum leptin and ghrelin levels. Methods: In a case control study, forty male rats were randomly assigned to one of these four experimental groups: ABA group with food restriction and free access to exercise; control ABA group with food restriction and no access to exercise; exercise group with free access to exercise and feed ad libitum and ad libitum group without access to exercise and feed ad libitum. The fecal bacteria composition was investigated by PCR-denaturing gradient gel electrophoresis and real-time qPCR. Results: In restricted eaters, we have found a significant increase in the number of Proteobacteria, Bacteroides, Clostridium, Enterococcus, Prevotella and M. smithii and a significant decrease in the quantities of Actinobacteria, Firmicutes, Bacteroidetes, B. coccoides-E. rectale group, Lactobacillus and Bifidobacterium with respect to unrestricted eaters. Moreover, a significant increase in the number of Lactobacillus, Bifidobacterium and B. coccoides-E. rectale group was observed in exercise group with respect to the rest of groups. We also found a significant positive correlation between the quantity of Bifidobacterium and Lactobacillus and serum leptin levels, and a significant and negative correlation among the number of Clostridium, Bacteroides and Prevotella and serum leptin levels in all experimental groups. Furthermore, serum ghrelin levels were negatively correlated with the quantity of Bifidobacterium, Lactobacillus and B. coccoides-Eubacterium rectale group and positively correlated with the number of Bacteroides and Prevotella. Conclusions: Nutritional status and physical activity alter gut microbiota composition affecting the diversity and similarity. This study highlights the associations between gut microbiota and appetite-regulating hormones that may be important in terms of satiety and host metabolism

Sistema de información geográfica aplicado a la gestión de minas y cuevas turísticas de la Unión Europea

El objetivo principal de este estudio es el de la realización de un SIG de todas las actividades subterráneas turísticas (minas, cuevas, búnkeres, catacumbas,…) de la Unión Europea (UE) en el año 2012, que tienen una página web y/o correo electrónico operativos, de cara a poder facilitar la gestión de distintos parámetros (seguridad y medio ambiente esencialmente) del conjunto de actividades indicadas. La idea de realizar este trabajo surgió a raíz del proyecto europeo Undersafe financiado por la Unión Europea en el 7th Framework Programme, donde el Departamento de Ingeniería Minera y Recursos Naturales (DEMRN) de la Universidad Politécnica de Catalunya (UPC) está colaborando desde el año 2011. Uno de los primeros aspectos en qué participó el equipo de profesores del DEMRN fue en el estudio de mercado de las actividades subterráneas turísticas existentes en la UE. Para ello tuvo que recopilar toda la información que había disponible por Internet, así como toda la información que pudo extraer de las encuestas en línea enviadas a través de la hoja de cálculo Google Docs a 862 actividades subterráneas turísticas europeas. A partir de aquí surgió la idea de crear un SIG vectorial que relacionara la información temática de las distintas actividades con su información geográfica o espacial, favoreciendo la gestión de estas actividades a nivel europeo. Este SIG podrá ser utilizado como fundamento de futuros estudios ambientales, económicos, seguridad,…Postprint (published version

Obestatin as a regulator of adipocyte metabolism and adipogenesis

The role of obestatin, a 23-amino-acid peptide encoded by the ghrelin gene, on the control of the metabolism of pre-adipocyte and adipocytes as well as on adipogenesis was determined. For in vitro assays, pre-adipocyte and adipocyte 3T3-L1 cells were used to assess the obestatin effect on cell metabolism and adipogenesis based on the regulation of the key enzymatic nodes, Akt and AMPK and their downstream targets. For in vivo assays, white adipose tissue (WAT) was obtained from male rats under continuous subcutaneous infusion of obestatin. Obestatin activated Akt and its downstream targets, GSK3alpha/beta, mTOR and S6K1, in 3T3-L1 adipocyte cells. Simultaneously, obestatin inactivated AMPK in this cell model. In keeping with this, ACC phosphorylation was also decreased. This fact was confirmed in vivo in white adipose tissue (omental, subcutaneous and gonadal) obtained from male rats under continuous sc infusion of obestatin (24 and 72 hrs). The relevance of obestatin as regulator of adipocyte metabolism was supported by AS160 phosphorylation, GLUT4 translocation and augment of glucose uptake in 3T3-L1 adipocyte cells. In contrast, obestatin failed to modify translocation of fatty acid transporters, FATP1, FATP4 and FAT/CD36, to plasma membrane. Obestatin treatment in combination with IBMX and DEX showed to regulate the expression of C/EBPalpha, C/EBPbeta, C/EBPdelta and PPARgamma promoting adipogenesis. Remarkable, preproghrelin expression, and thus obestatin expression, increased during adipogenesis being sustained throughout terminal differentiation. Neutralization of endogenous obestatin secreted by 3T3-L1 cells by anti-obestatin antibody decreased adipocyte differentiation. Furthermore, knockdown experiments by preproghrelin siRNA supported that obestatin contributes to adipogenesis. In summary, obestatin promotes adipogenesis in an autocrine/paracrine manner, being a regulator of adipocyte metabolism. These data point to a putative role in the pathogenesis of metabolic syndrome

Preproghrelin expression is a key target for insulin action on adipogenesis.

This study aimed to investigate the role of preproghrelin-derived peptides in adipogenesis. Immunocytochemical analysis of 3T3-L1 adipocyte cells showed stronger preproghrelin expression compared with that observed in 3T3-L1 preadipocyte cells. Insulin promoted this expression throughout adipogenesis identifying mTORC1 as a critical downstream substrate for this profile. The role of preproghrelin-derived peptides on the differentiation process was supported by preproghrelin knockdown experiments, which revealed its contribution to adipogenesis. Neutralization of endogenous O-acyl ghrelin (acylated ghrelin), unacylated ghrelin, and obestatin by specific antibodies supported their adipogenic potential. Furthermore, a parallel increase in the expression of ghrelin-associated enzymatic machinery, prohormone convertase 1/3 (PC1/3) and membrane-bound O-acyltransferase 4 (MBOAT4), was dependent on the expression of preproghrelin in the course of insulin-induced adipogenesis. The coexpression of preproghrelin system and their receptors, GHSR1a and GPR39, during adipogenesis supports an autocrine/paracrine role for these peptides. Preproghrelin, PC1/3, and MBOAT4 exhibited dissimilar expression depending on the white fat depot, revealing their regulation in a positive energy balance situation in mice. The results underscore a key role for preproghrelin-derived peptides on adipogenesis through an autocrine/paracrine mechanism

The Obestatin/GPR39 System Is Up-regulated by Muscle Injury and Functions as an Autocrine Regenerative System

Background: Satellite cell activation is orchestrated by several signals, which induce their differentiation into skeletal muscle fibers. Results: Obestatin and the GPR39 receptor exert an autocrine role on the control of myogenesis. Conclusion: Our data indicate that obestatin/GPR39 is an injury-regulated signal that functions as a myogenic regenerative system. Significance: Strategies to enhance obestatin-mediated signaling could be useful in treating trauma-induced muscle injuries and skeletal muscle myopathies

Los riesgos de la energía eólia para los ecosistemas marinos

Ante el cambio climático, es urgente reducir las emisiones de gases causantes del efecto invernadero. Ello implica reducir el consumo energético y utilizar energías renovables como la eólica marina, señalada por la Unión Europea (UE) como un sector clave de la llamada “economía azul

Comparison of Plasma Lipoprotein Composition and Function in Cerebral Amyloid Angiopathy and Alzheimer’s Disease

Cerebral amyloid angiopathy (CAA) refers to beta-amyloid (Aβ) deposition in brain vessels and is clinically the main cause of lobar intracerebral hemorrhage (ICH). Aβ can also accumulate in brain parenchyma forming neuritic plaques in Alzheimer's disease (AD). Our study aimed to determine whether the peripheral lipid profile and lipoprotein composition are associated with cerebral beta-amyloidosis pathology and may reflect biological differences in AD and CAA. For this purpose, lipid and apolipoproteins levels were analyzed in plasma from 51 ICH-CAA patients (collected during the chronic phase of the disease), 60 AD patients, and 60 control subjects. Lipoproteins (VLDL, LDL, and HDL) were isolated and their composition and pro/antioxidant ability were determined. We observed that alterations in the lipid profile and lipoprotein composition were remarkable in the ICH-CAA group compared to control subjects, whereas the AD group presented no specific alterations compared with controls. ICH-CAA patients presented an atheroprotective profile, which consisted of lower total and LDL cholesterol levels. Plasma from chronic ICH-CAA patients also showed a redistribution of ApoC-III from HDL to VLDL and a higher ApoE/ApoC-III ratio in HDL. Whether these alterations reflect a protective response or have a causative effect on the pathology requires further investigation