GRUP DE RECERCA NITROGEN-OBESITAT

Departament de Bioquímica i Biomedicina Molecular. Facultat de Biologia.  Universitat de Barcelona (Barcelona)

Director: Xavier Remesar

 xremesar@ub.edu

(+34) 934 02 15 21

Actualització fitxa tècnica del grup: juliol 2017

MEMBRES DEL GRUP INVESTIGADOR

Xavier Remesar Betlloch. Catedràtic d’Universitat. Departament de Bioquímica i Biomedicina Molecular. Facultat de Biologia. Universitat de Barcelona. a/e:  xremesar@ub.edu

José Antonio Fernández López; Professor titular. Departament de Bioquímica i Biomedicina Molecular. Facultat de Biologia. Universitat de Barcelona. a/e: josfernandez@ub.edu

Montserrat Esteve Ràfols. Professora Agregada. Departament de Bioquímica i Biomedicina Molecular. Facultat de Biologia. Universitat de Barcelona. a/e: mesteve@ub.edu

Mª del Mar Grasa Martínez; Professora Agregada. Departament de Bioquímica i Biomedicina Molecular. Facultat de Biologia. Universitat de Barcelona. a/e: mgrasa@ub.edu

Mª del Mar Romero Romero; Investigadora Contractada. Departament de Bioquímica i Biomedicina Molecular. Facultat de Biologia. Universitat de Barcelona. a/e: marromero@ub.edu

Ana Cecilia Ho Palma; Doctoranda. Departament de Bioquímica i Biomedicina Molecular. Facultat de Biologia. Universitat de Barcelona. a/e: ceciliahopalma@ub.edu

Laia Oliva Lorenzo; Doctoranda. Departament de Bioquímica i Biomedicina Molecular. Facultat de Biologia. Universitat de Barcelona. a/e: laia.oliva@ub.edu

ACTIVITATS I CAPACITATS DEL GRUP DE RECERCA

El nostre grup de recerca ha treballat bàsicament en dos aspectes del metabolisme del teixit adipós.

En el primer, relacionat directament amb el funcionament del les cèl·lules adiposes, hem pogut comprovar que el teixit adipós blanc té un actiu metabolisme dels aminoàcids i manifesta la presència completa, i funcional, dels enzims del cicle de la urea en diferents localitzacions del teixit, activitat que no s’afecta pel tractament amb una dieta hiperlipídica. També hem comprovat que la dieta hiperlipídica provoca una acumulació de greix en molts teixits, no solament en el teixit adipós, i de manera proporcional a l’acumulació en el teixit adipós. També hem pogut determinar que les cèl·lules aïllades del teixit utilitzen la glucosa per a convertir-la en lactat i glicerol abans que emprar-la en la lipogènesi.

En la segona línia de treball, estudiem la funció dels glucocorticoids en la obesitat i com la regulació de la seva disponibilitat afecta el desenvolupament de processos inflamatoris en general, des de l’aterosclerosi fins a la pancreatitis i incloent-hi la pròpia obesitat. En aquest sentit, hem publicat recentment que la corticosteroid-binding globulin (proteïna transportadora en sang de glucocorticoides i responsable en part de la seva biodisponibilitat tissular) està implicada en el dimorfisme sexual pel que fa a la disponibilitat de glucocorticoides, i que la seva absència provoca canvis en la distribució del teixit adipós, propiciant el dipòsit visceral davant del subcutani. També hem publicat que l’estimulació de l’activitat 11β-hidroxiesteroid deshidrogenasa de tipus 1, responsable de la síntesi intracel·lular de glucocorticoids, realitza un paper clau en el control de la inflamació en macròfags associada a l’exposició a LDL oxidades, que constitueixen un desencadenant clau del procés ateroscleròtic.

LÍNIES DE RECERCA

Línia de Recerca: Metabolisme de la cèl·lula adiposa. Efecte de la dieta.
Investigadors principals: Xavier Remesar / José Antonio Fernández

Línia de Recerca:Paper de la CBG en el metabolisme del teixit adipós.
Investigadors principals: Mar Grasa / Montserrat Esteve

MILLORS PUBLICACIONS DEL GRUP

S.Arriarán, S.Agnelli, D.Sabater, X.Remesar, J.A.Fernández-López, M.Alemany.
Evidences of basal lactate production in the main white adipose tissue sites of rats. Effects of sex and a cafeteria diet.
PLOS one 2015; 10 (3); e0119572.
PMID:25741703

Abstract: Female and male adult Wistar rats were fed standard chow or a simplified cafeteria diet for one month. Then, the rats were killed and the white adipose tissue (WAT) in four sites: perigonadal, retroperitoneal, mesenteric and subcutaneous (inguinal) were sampled and frozen. The complete WAT weight in each site was measured. Gene expression analysis of key lipid and glucose metabolism enzymes were analyzed, as well as tissue and plasma lactate and the activity of lactate dehydrogenase. Lactate gradients between WAT and plasma were estimated. The influence of sex and diet (and indirectly WAT mass) on lactate levels and their relationships with lactate dehydrogenase activity and gene expressions were also measured. A main conclusion is the high production of lactate by WAT, practically irrespective of site, diet or sex. Lactate production is a direct correlate of lactate dehydrogenase activity in the tissue. Furthermore, lactate dehydrogenase activity is again directly correlated with the expression of the genes Ldha and Ldhb for this enzyme. In sum, the ability to produce lactate by WAT is not directly dependent of WAT metabolic state. We postulate that, in WAT, a main function of the lactate dehydrogenase path may be that of converting excess available glucose to 3C fragments, as a way to limit tissue self-utilization as substrate, to help control glycaemia and/or providing short chain substrates for use as energy source elsewhere. More information must be gathered before a conclusive role of WAT in the control of glycaemia, and the full existence of a renewed glucose-lactate-fatty acid cycle is definitely established.

J Gulfo, A Ledda, E Serra, C Cabot, M Esteve, M Grasa.
Altered lipid partitioning and glucocorticoid availability in CBG-deficient male mice with diet-Induced obesity.
Obesity 2016; 24:1677-1686.
PMID: 27323695

Objective: To evaluate how deficiency in corticosteroid-binding globulin (CBG), the specific carrier of glucocorticoids, affects glucocorticoid availability and adipose tissue in obesity.
Methods: C57BL/6 (WT) and CBG-deficient (KO) male mice were fed during 12 weeks with standard or hyperlipidic diet (HL). Glucocorticoid availability and metabolic parameters were assessed.
Results: Body weight and food intake were increased in KO compared with WT mice fed a standard diet and were similar when fed a HL diet. Expression of CBG was found in white adipose tissue by immunochemistry, real-time PCR, and Western blot. In obesity, the subcutaneous depot developed less in KO mice compared with WT, which was associated with a minor adipocyte area and peroxisome proliferator-activated receptor-γ expression. Conversely, the epididymal depot displayed higher weight and adipocyte area in KO than in WT mice. CBG deficiency caused a fall of hepatic 11β-hydroxysteroid dehydrogenase type 2 expression and an increase in epidymal adipose tissue, particularly in HL mice.
Conclusions: Deficiency in CBG drives lipid partitioning from subcutaneous to visceral adipose depot under a context of lipid excess and differentially modulates 11β-hydroxysteroid dehydrogenase type 2 expression.
A Ledda, M Gonzalez, J Gulfo, I Díaz Ludovico, N Ramella, J Toledo, H Garda, M Grasa, M Esteve.
Decreased OxLDL uptake and cholesterol efflux in THP1 cells elicited by cortisol and by cortisone through 11b-hydroxysteroid dehydrogenase type 1.
Atherosclerosis 2016; 250: 84-94.
PMID: 27187933

Background and aims: Data about glucocorticoids role in the development of atherosclerosis are controversial showing different effects in human than in experimental animal models. Atherosclerosis is the result of a chronic inflammatory response to an injured endothelium where an uncontrolled uptake of OxLDL by macrophages triggers the development of foam cells, the main component of fatty streaks in atherosclerotic plaque. There are few data about the direct effect of glucocorticoids in macrophages of atherosclerotic plaque. The aim of the study was to elucidate the role of glucocorticoids in the development of foam cells in atherosclerosis initiation.
Methods: For this purpose we used THP1 cells differentiated to macrophages with phorbol esters and incubated with OxLDL alone or with cortisol or cortisone. THP1 cells were also incubated with cortisone plus an inhibitor of 11β-hydroxysteroid dehydrogenase 1 (11βHSD1) activity to determine the role of this enzyme on glucocorticoid action in this process.
Results: Ours results showed that cortisol and cortisone decreased significantly the inflammation promoted by OxLDL, and also diminished the expression of genes involved in influx and efflux of cholesterol resulting in a reduced lipid accumulation. Likewise cortisol and cortisone decreased 11βHSD1 expression in THP1 cells. The presence of the inhibitor of 11βHSD1 abolished all the effects elicited by cortisone.
Conclusion: Our results indicate a direct effect of glucocorticoids on macrophages braking atherosclerosis initiation, reducing pro-inflammatory markers and OxLDL uptake and cholesterol re-esterification, but also inhibiting cholesterol output. These effects appear to be mediated, at least in part, by 11βHSD1 activity.
M M Grasa, J Gulfo, N Camps, R Alcalá, L Monserrat, J M Moreno-Navarrete, F J Ortega, M Esteve, X Remesar, J A Fernández-López, J M
Fernández-Real, M Alemany.
Modulation of SHBG binding to testosterone and estradiol by sex and uncomplicated obesity.
European Journal of Endocrinology 2017; 176 (4): 393-404.
PMID: 28077498.

Objective: Sex hormone-binding globulin (SHBG) binds and transports testosterone and estradiol in plasma. The possibility that SHBG is a mixture of transporting proteins has been postulated. We analyzed in parallel the effects of obesity status on the levels and binding capacity of circulating SHBG and their relationship with testosterone and estradiol.
Design: Anthropometric measures and plasma were obtained from apparently healthy young (i.e. 35 ± 7 years) premenopausal women (n = 32) and men (n = 30), with normal weight and obesity (BMI >30 kg/m2).
Methods: SHBG protein (Western blot), as well as the plasma levels of testosterone, estradiol, cortisol and insulin (ELISA) were measured. Specific binding of estradiol and testosterone to plasma SHBG was analyzed using tritium-labeled hormones.
Results: Significant differences in SHBG were observed within the obesity status and gender, with discordant patterns of change in testosterone and estradiol. In men, testosterone occupied most of the binding sites. Estrogen binding was much lower in all subjects. Lower SHBG of morbidly obese (BMI >40 kg/m2) subjects affected testosterone but not estradiol. The ratio of binding sites to SHBG protein levels was constant for testosterone, but not for estradiol. The influence of gender was maximal in morbid obesity, with men showing the highest binding/SHBG ratios.
Conclusions: The results reported here are compatible with SHBG being a mixture of at least two functionally different hormone-binding globulins, being affected by obesity and gender and showing different structure, affinities for testosterone and estradiol and also different immunoreactivity.
S.Arriarán, S.Agnelli, X.Remesar, J.A.Fernández-López, M.Alemany.
The urea cycle of rat white adipose tissue.
SC Advances 2015; 5: 93403-93414.

INSTITUCIONS QUE RECONEIXEN AL GRUP DE RECERCA

  • CIBER de Fisiopatologia de la Obesidad y Nutrición (CIBEROBN) (Instituto de Salud Carlos III).
  • Grup Nutrigenòmica i Obesitat. Departament de Biologia Fonamental i Ciències de la Salut. Universitat de les Illes Balears.
  • Grup de Nutrició Eumetabolisme i Salut: Institut d’Investigació Biomèdica de Girona.
  • Grup d’Ontogènia i Síndrome Metabòlica de l’Institut d’Investigació Biomèdica de Girona.
  • Grupo de Neurofarmacología de la enfermedad de Alzheimer y depresión, Instituto de Investigación Sanitaria de Navarra (IdiSNA) , Pamplona.
  • Grup Lipoproteïna Lipasa: Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, UB.
  • Grup de regulació de la inflamació. Departament de Patologia experimental (IIBB-CSIC) i (IDIBAPS).
  • Grupo de Regulación del Metabolismo lipídico en cultivos celulares y animales de laboratorio por efecto de factores nutricionales, hormonales y ambientales. Instituto de Investigaciones Bioquímicas de La Plata (INIBIOLP-CONICET), Facultad de Ciencias Médicas, Universidad Nacional de La Plata, Argentina.
  • Grup de Trastorns Endocrins del Centro Esther Klopowitz – IDIBAPS. Barcelona.
  • AGAUR. Generalitat de Catalunya. Grup de qualitat (pendent de renovació en 2017).
  • Institut de Biomedicina de la UB (IBUB).