Regulation of NR4A by nutritional status, gender, postnatal development and hormonal deficiency

The NR4A is a subfamily of the orphan nuclear receptors (NR) superfamily constituted by three well characterized members: Nur77 (NR4A1), Nurr1 (NR4A2) and Nor 1 (NR4A3). They are implicated in numerous biological processes as DNA repair, arteriosclerosis, cell apoptosis, carcinogenesis and metabolism. Several studies have demonstrated the role of this subfamily on glucose metabolism, insulin sensitivity and energy balance. These studies have focused mainly in liver and skeletal muscle. However, its potential role in white adipose tissue (WAT), one of the most important tissues involved in the regulation of energy homeostasis, is not well-studied. The aim of this work was to elucidate the regulation of NR4A in WAT under different physiological and pathophysiological settings involved in energy balance such as fasting, postnatal development, gender, hormonal deficiency and pregnancy. We compared NR4A mRNA expression of Nur77, Nurr1 and Nor 1 and found a clear regulation by nutritional status, since the expression of the 3 isoforms is increased after fasting in a leptin-independent manner and sex steroid hormones also modulate NR4A expression in males and females. Our findings indicate that NR4A are regulated by different physiological and pathophysiological settings known to be associated with marked alterations in glucose metabolism and energy status.This work has been supported by grants from Fondo Investigaciones Sanitarias (ST: PI12/02842), Ministerio de Economia y Competitividad (RN: RYC-2008-02219 and BFU2012-35255; MMM: BFU2010-17116), Xunta de Galicia (ML: 10PXIB208164PR and 2012-CP070; RN: EM 2012/039 and 2012-CP069), Centro de Investigación Biomédica en Red (CIBER) de Fisiopatología de la Obesidad y Nutrición. CIBERobn is an initiative of the Instituto de Salud Carlos III (ISCIII) of Spain which is supported by FEDER funds. The research leading to these results has also received funding from the European Community's Seventh Framework Programme under the following grant: ML and RN: FP7/2007-2013: n° 245009: NeuroFASTS

Levels of the Novel Endogenous Antagonist of Ghrelin Receptor, Liver-Enriched Antimicrobial Peptide-2, in Patients with Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a debilitating, chronic, inflammatory, autoimmune disease associated with cachexia. The substitutive therapy of gut hormone ghrelin has been pointed at as a potential countermeasure for the management of metabolic and inflammatory complications in RA. The recent discovery of liver-expressed antimicrobial peptide 2 (LEAP2) as an endogenous inverse agonist/antagonist of the ghrelin receptor makes feasible the development of a more rational pharmacological approach. This work aimed to assess the serum LEAP2 levels, in a cohort of RA patients, in comparison with healthy individuals and determine its correlation with inflammatory parameters. LEAP2 levels were determined by a commercial ELISA kit, plasma C-reactive protein (CRP) levels were evaluated using immunoturbidimetry, and serum levels of inflammatory mediators, namely IL-6, IL-8, IL-1 , MIP1 , MCP1, and LCN2, were measured by XMap multiplex assay. LEAP2 serum levels were significantly increased in RA patients (n = 101) compared with control subjects (n = 26). Furthermore, the LEAP2 levels significantly correlated with CRP and inflammatory cytokines, but not with BMI. These data reveal LEAP2 as a new potential RA biomarker and indicated the pharmacological control of LEAP2 levels as a novel approach for the treatment of diseases with alterations on the ghrelin levels, such as rheumatoid cachexia

Divergent responses to thermogenic stimuli in BAT and subcutaneous adipose tissue from interleukin 18 and interleukin 18 receptor 1-deficient mice

Brown and beige adipocytes recruitment in brown (BAT) or white adipose tissue, mainly in the inguinal fat pad (iWAT), meet the need for temperature adaptation in cold-exposure conditions and protect against obesity in face of hypercaloric diets. Using interleukin18 (Il18) and Il18 receptor 1- knockout (Il18r1-KO) mice, this study aimed to investigate the role of IL18 signaling in BAT and iWAT activation and thermogenesis under both stimuli. Il18-KO, extremely dietary obesity-prone as previously described, failed to develop diet-induced thermogenesis as assessed by BAT and iWAT Ucp1 mRNA levels. Overweight when fed standard chow but not HFD, HFD-fed Il18r1-KO mice exhibited increased iWAT Ucp1 gene expression. Energy expenditure was reduced in pre-obese Il18r1-KO mice and restored upon HFD-challenge. Cold exposure lead to similar results; Il18r1-KO mice were protected against acute body temperature drop, displaying a more brown-like structure, alternative macrophage activation and thermogenic gene expression in iWAT than WT controls. Opposite effects were observed in Il18-KO mice. Thus, Il18 and Il18r1 genetic ablation disparate effects on energy homeostasis are likely mediated by divergent BAT responses to thermogenic stimuli as well as iWAT browning. These results suggest that a more complex receptor-signaling system mediates the IL18 adipose-tissue specific effects in energy expenditure.This work has been supported by European Community (FP7/2007n° 245009: “NeuroFAST”), Ministerio de Economía y Competitividad (PP and MCGG: BFU2007–62683/BFI and PP, MCGG and CD: CIBERobn (CB06/03)) and Xunta de Galicia Grants (MCGG and LL: PGIDIT06PXIB208067PR and GPC2014/030). CIBER de Fisiopatología de la Obesidad y Nutrición is an initiative of ISCIIIS

mTOR signaling in the arcuate nucleus of the hypothalamus mediates the anorectic action of estradiol

The authors dedicate this work to the bright memory of our colleague, master and friend Enrique Aguilar. The research leading to these results has received funding from Xunta de Galicia (R N: 2015-CP080 and 2016- PG057; M L: 2015-CP079), Junta de Andalucía (M T-S: P12-FQM-01943), MINECO co-funded by the FEDER Program of EU (C D: BFU2017-87721; R N: BFU2015-70664R; M T-S: BFU2014-57581-P and PIE14/0005; M L: SAF2015- 71026-R and BFU2015-70454-REDT/Adipoplast). The CiMUS is supported by the Xunta de Galicia (2016–2019, ED431G/05). CIBER Fisiopatología de la Obesidad y Nutrición is an initiative of ISCIII. A E-S is a recipient of a fellowship from MINECO (FPI/BES-2016-077439). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.Peer reviewedPublisher PD

Rational design of polyarginine nanocapsules intended to help peptides overcoming intestinal barriers

The aim of this work was to rationally design and characterize nanocapsules (NCs) composed of an oily core and a polyarginine (PARG) shell, intended for oral peptide delivery. The cationic polyaminoacid, PARG, and the oily core components were selected based on their penetration enhancing properties. Insulin was adopted as a model peptide to assess the performance of the NCs. After screening numerous formulation variables, including different oils and surfactants, we defined a composition consisting of oleic acid, sodium deoxycholate (SDC) and Span 80. This selected NCs composition, produced by the solvent displacement technique, exhibited the following key features: (i) an average size of 180 nm and a low polydispersity (0.1), (ii) a high insulin association efficacy (80–90% AE), (iii) a good colloidal stability upon incubation in simulated intestinal fluids (SIF, FaSSIF-V2, FeSSIF-V2), and (iv) the capacity to control the release of the associated insulin for > 4 h. Furthermore, using the Caco-2 model cell line, PARG nanocapsules were able to interact with the enterocytes, and reversibly modify the TEER of the monolayer. Both cell adhesion and membrane permeabilization could account for the pronounced transport of the NCs-associated insulin (3.54%). This improved interaction was also visualized by confocal fluorescent microscopy following oral administration of PARG nanocapsulesto mice. Finally, in vivo efficacy studies performed in normoglycemic rats showed a significant decrease in their plasma glucose levels after treatment. In conclusion, here we disclose key formulation elements for making possible the oral administration of peptidesThis work was supported by the European TRANS-INT Consortium, which received funding from the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement No. 281035. Z. Niu also would like to thank the Chinese Scholarship Council for his scholarshipS

Proteasome Dysfunction Associated to Oxidative Stress and Proteotoxicity in Adipocytes Compromises Insulin Sensitivity in Human Obesity

AIMS: Obesity is characterized by a low-grade systemic inflammatory state and adipose tissue (AT) dysfunction, which predispose individuals to the development of insulin resistance (IR) and metabolic disease. However, a subset of obese individuals, referred to as metabolically healthy obese (MHO) individuals, are protected from obesity-associated metabolic abnormalities. Here, we aim at identifying molecular factors and pathways in adipocytes that are responsible for the progression from the insulin-sensitive to the insulin-resistant, metabolically unhealthy obese (MUHO) phenotype. RESULTS: Proteomic analysis of paired samples of adipocytes from subcutaneous (SC) and omental (OM) human AT revealed that both types of cells are altered in the MUHO state. Specifically, the glutathione redox cycle and other antioxidant defense systems as well as the protein-folding machinery were dysregulated and endoplasmic reticulum stress was increased in adipocytes from IR subjects. Moreover, proteasome activity was also compromised in adipocytes of MUHO individuals, which was associated with enhanced accumulation of oxidized and ubiquitinated proteins in these cells. Proteasome activity was also impaired in adipocytes of diet-induced obese mice and in 3T3-L1 adipocytes exposed to palmitate. In line with these data, proteasome inhibition significantly impaired insulin signaling in 3T3-L1 adipocytes. INNOVATION: This study provides the first evidence of the occurrence of protein homeostasis deregulation in adipocytes in human obesity, which, together with oxidative damage, interferes with insulin signaling in these cells. CONCLUSION: Our results suggest that proteasomal dysfunction and impaired proteostasis in adipocytes, resulting from protein oxidation and/or misfolding, constitute major pathogenic mechanisms in the development of IR in obesity.IMIBIC/Universidad de Córdoba-SCAI (ProteoRed, PRB2-ISCIII)MINECO/FEDERJunta de Andalucía/FEDERCIBERobn(Instituto de Salud Carlos III

Plasma concentration of leptin is related to food addiction in gambling disorder: Clinical and neuropsychological implications

Background: Data implicate overlaps in neurobiological pathways involved in appetite regulation and addictive disorders. Despite different neuroendocrine measures having been associated with both gambling disorder (GD) and food addiction (FA), how appetite-regulating hormones may relate to the co-occurrence of both entities remain incompletely understood. Aims: To compare plasma concentrations of ghrelin, leptin, adiponectin, and liver-expressed antimicrobial peptide 2 (LEAP-2) between patients with GD, with and without FA, and to explore the association between circulating hormonal concentrations and neuropsychological and clinical features in individuals with GD and FA. Methods: The sample included 297 patients diagnosed with GD (93.6% males). None of the patients with GD had lifetime diagnosis of an eating disorder. FA was evaluated with the Yale Food Addiction Scale 2.0. All patients were assessed through a semi-structured clinical interview and a psychometric battery including neuropsychological tasks. Blood samples to measure hormonal variables and anthropometric variables were also collected. Results: From the total sample, FA was observed in 23 participants (FA+) (7.7% of the sample, 87% males). When compared participants with and without FA, those with FA+ presented both higher body mass index (BMI) (p < 0.001) and leptin concentrations, after adjusting for BMI (p = 0.013). In patients with FA, leptin concentrations positively correlated with impulsivity, poorer cognitive flexibility, and poorer inhibitory control. Other endocrine measures did not differ between groups. Discussion and conclusions: The present study implicates leptin in co-occurring GD and FA. Among these patients, leptin concentration has been associated with clinical and neuropsychological features, such as impulsivity and cognitive performance in certain domains

Una mirada interdisciplinaria

Las enfermedades crónicas no transmisibles son, en la actualidad, uno de los temas de salud de mayor interés alrededor del mundo, dado el rápido crecimiento que han experimentado en las últimas décadas en países desarrollados y en vía de desarrollo y el alto impacto, no solo biológico, sino económico, sanitario y social que generan para el individuo y la sociedad. De acuerdo con la OMS, las enfermedades crónicas (patologías cardiovasculares, diabetes mellitus, todos los tipos de cáncer y las enfermedades respiratorias), son las principales causas de mortalidad en el mundo, ya que se les asigna un peso del 63% de las muertes a nivel global, con más de 36 millones de defunciones (71% en mayores de 60 años). Así las cosas, la diabetes mellitus se ha ido convirtiendo progresivamente en un problema de salud pública a nivel mundial, dada la estrecha relación que tiene con el sobrepeso y con el sedentarismo, fenómenos característicos del estilo de vida de gran parte de la población a nivel mundial. Este libro presenta de manera ordenada y didáctica información actualizada y práctica acerca de esta enfermedad, de tal forma que pueda ser utilizado como material de consulta y referencia por estudiantes y profesionales de la salud en el ejercicio académico y asistencial, desde una perspectiva práctica de naturaleza interdisciplinaria.Acciones mundiales, regionales y locales para reducir el impacto de la diabetes – Diabetes mellitus en la adolescencia – Alteraciones visuales y oculares en pacientes diabéticos – Diabetes mellitus tipo 2, obesidad y síndrome de apnea obstructiva del sueño – Pie diabético: una mirada desde las imágenes diagnosticas – Diabetes mellitus en el paciente quirúrgico – Diabetes mellitus: una mirada desde la medicina tradicional china – prevención de la diabetes mellitus: reflexiones desde la medicina familiar – Diabetes mellitus: prescripción de ejercicio y actividad física – Meta análisis y revisiones sistemáticas aplicadas en el campo de la diabetes melitus