Publications by authors named "José Manuel Fernández Real"

273 Publications

Gut microbes and health.

Gastroenterol Hepatol 2021 Feb 27. Epub 2021 Feb 27.

Ecología Microbiana, Nutrición y Salud, Instituto de Agroquímica y Tecnología de Alimentos, Consejo Superior de Investigaciones Científicas (IATA-CSIC), Valencia, España.

The human body is populated by myriads of microorganisms throughout its surface and in the cavities connected to the outside. The microbial colonisers of the intestine (microbiota) are a functional and non-expendable part of the human organism: they provide genes (microbiome) and additional functions to the resources of our species and participate in multiple physiological processes (somatic development, nutrition, immunity, etc.). Some chronic non-communicable diseases of developed society (atopias, metabolic syndrome, inflammatory diseases, cancer and some behaviour disorders) are associated with dysbiosis: loss of species richness in the intestinal microbiota and deviation from the ancestral microbial environment. Changes in the vertical transmission of the microbiome, the use of antiseptics and antibiotics, and dietary habits in industrialised society appear to be at the origin of dysbiosis. Generating and maintaining diversity in the microbiota is a new clinical target for health promotion and disease prevention.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.gastrohep.2021.01.009DOI Listing
February 2021

Assessing the quality of the evidence underlying recommendations in type 2 diabetes' commonly used clinical practice guidelines.

JBI Evid Implement 2021 Mar;19(1):31-38

Medicine Department, Universitat de Girona.

Aim: In a world of data overload, clinical practice recommendations are needed to help practitioners and patients to take evidence-based decisions. However, in the field of type 2 diabetes mellitus (T2DM) recommendations on glycemic goals and treatment choice are controversial in spite of being supported by a common body of evidence. We hypothesize that internal and external validity of this body of evidence might not be as sound as expected. The aim of the current study is to appraise the studies supporting recommendations developed by influential medical societies dealing with glycemic goals and the choice of pharmacological treatment in adults with T2DM.

Methods: Clinical practice recommendations and their references were extracted out of eight documents developed by influential scientific societies between 2016 and 2019. Internal and external validity of each study was then appraised with standard tools and in duplicate.

Results: A total of 114 recommendations and their underlying 233 citations were extracted. Out of these 233 citations 81 (35%) corresponded to randomized controlled trials (RCT) and 45 (20%) to systematic reviews. After systematical appraisal only four RCT (5%) and eight systematic reviews (17%) were considered to be unflawed. Indirectness (lack of generalizability) was the most common caveat identified in RCTs. Out of the 114 recommendations analyzed (32 dealing with glycemic goals and 82 with treatment choice), only 21 (18.4%) were supported by at least one high-quality study.

Conclusion: Only one in five recommendations regarding glycemic goals or pharmacological treatment choice in T2DM is based on at least one high-quality study. Clinical practice recommendations dealing with areas of uncertainty should be formulated more transparently to enable real evidence-based decisions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/XEB.0000000000000243DOI Listing
March 2021

Adipose tissue knockdown of lysozyme reduces local inflammation and improves adipogenesis in high-fat diet-fed mice.

Pharmacol Res 2021 Apr 5;166:105486. Epub 2021 Feb 5.

Institut d'Investigació Biomèdica de Girona (IdIBGi), Girona, Spain; CIBER de la Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Madrid, Spain; Department of Diabetes, Endocrinology and Nutrition (UDEN), Hospital of Girona "Dr Josep Trueta", Girona, Spain; Department of Medical Sciences, Faculty of Medicine, University of Girona, Girona, Spain. Electronic address:

Chronic systemic low-level inflammation in metabolic disease is known to affect adipose tissue biology. Lysozyme (LYZ) is a major innate immune protein but its role in adipose tissue has not been investigated. Here, we aimed to investigate LYZ in human and rodents fat depots, and its possible role in obesity-associated adipose tissue dysfunction. LYZ mRNA and protein were identified to be highly expressed in adipose tissue from subjects with obesity and linked to systemic chronic-low grade inflammation, adipose tissue inflammation and metabolic disturbances, including hyperglycemia, dyslipidemia and decreased markers of adipose tissue adipogenesis. These findings were confirmed in experimental models after a high-fat diet in mice and rats and also in ob/ob mice. Importantly, specific inguinal and perigonadal white adipose tissue lysozyme (Lyz2) gene knockdown in high-fat diet-fed mice resulted in improved adipose tissue inflammation in parallel to reduced lysozyme activity. Of note, Lyz2 gene knockdown restored adipogenesis and reduced weight gain in this model. In conclusion, altogether these observations point to lysozyme as a new actor in obesity-associated adipose tissue dysfunction. The therapeutic targeting of lysozyme production might contribute to improve adipose tissue metabolic homeostasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.phrs.2021.105486DOI Listing
April 2021

Activation of Endogenous HS Biosynthesis or Supplementation with Exogenous HS Enhances Adipose Tissue Adipogenesis and Preserves Adipocyte Physiology in Humans.

Antioxid Redox Signal 2021 Mar 11. Epub 2021 Mar 11.

Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), Girona, Spain.

To investigate the impact of exogenous hydrogen sulfide (HS) and its endogenous biosynthesis on human adipocytes and adipose tissue in the context of obesity and insulin resistance. Experiments in human adipose tissue explants and in isolated preadipocytes demonstrated that exogenous HS or the activation of endogenous HS biosynthesis resulted in increased adipogenesis, insulin action, sirtuin deacetylase, and PPARγ transcriptional activity, whereas chemical inhibition and gene knockdown of each enzyme generating HS (, , ) led to altered adipocyte differentiation, cellular senescence, and increased inflammation. In agreement with these experimental data, visceral and subcutaneous adipose tissue expression of HS-synthesising enzymes was significantly reduced in morbidly obese subjects in association with attenuated adipogenesis and increased markers of adipose tissue inflammation and senescence. Interestingly, weight-loss interventions (including bariatric surgery or diet/exercise) improved the expression of HS biosynthesis-related genes. In human preadipocytes, the expression of , , and genes and HS production were dramatically increased during adipocyte differentiation. More importantly, the adipocyte proteome exhibiting persulfidation was characterized, disclosing that different proteins involved in fatty acid and lipid metabolism, the citrate cycle, insulin signaling, several adipokines, and PPAR, experienced the most dramatic persulfidation (85-98%). No previous studies investigated the impact of HS on human adipose tissue. This study suggests that the potentiation of adipose tissue HS biosynthesis is a possible therapeutic approach to improve adipose tissue dysfunction in patients with obesity and insulin resistance. Altogether, these data supported the relevance of HS biosynthesis in the modulation of human adipocyte physiology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/ars.2020.8206DOI Listing
March 2021

Obesity-associated deficits in inhibitory control are phenocopied to mice through gut microbiota changes in one-carbon and aromatic amino acids metabolic pathways.

Gut 2021 Jan 29. Epub 2021 Jan 29.

Department of Diabetes, Endocrinology and Nutrition, Dr. Josep Trueta University Hospital, Girona, Spain

Background: Inhibitory control (IC) is critical to keep long-term goals in everyday life. Bidirectional relationships between IC deficits and obesity are behind unhealthy eating and physical exercise habits.

Methods: We studied gut microbiome composition and functionality, and plasma and faecal metabolomics in association with cognitive tests evaluating inhibitory control (Stroop test) and brain structure in a discovery (n=156), both cross-sectionally and longitudinally, and in an independent replication cohort (n=970). Faecal microbiota transplantation (FMT) in mice evaluated the impact on reversal learning and medial prefrontal cortex (mPFC) transcriptomics.

Results: An interplay among IC, brain structure (in humans) and mPFC transcriptomics (in mice), plasma/faecal metabolomics and the gut metagenome was found. Obesity-dependent alterations in one-carbon metabolism, tryptophan and histidine pathways were associated with IC in the two independent cohorts. Bacterial functions linked to one-carbon metabolism ( exodeoxyribonuclease V), and the anterior cingulate cortex volume were associated with IC, cross-sectionally and longitudinally. FMT from individuals with obesity led to alterations in mice reversal learning. In an independent FMT experiment, human donor's bacterial functions related to IC deficits were associated with mPFC expression of one-carbon metabolism-related genes of recipient's mice.

Conclusion: These results highlight the importance of targeting obesity-related impulsive behaviour through the induction of gut microbiota shifts.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/gutjnl-2020-323371DOI Listing
January 2021

Whole-Brain Dynamics in Aging: Disruptions in Functional Connectivity and the Role of the Rich Club.

Cereb Cortex 2021 Mar;31(5):2466-2481

Computational Neuroscience Group, Center for Brain and Cognition, Department of Information and Communication Technologies, Universitat Pompeu Fabra, Barcelona, Catalonia, Spain.

Normal aging causes disruptions in the brain that can lead to cognitive decline. Resting-state functional magnetic resonance imaging studies have found significant age-related alterations in functional connectivity across various networks. Nevertheless, most of the studies have focused mainly on static functional connectivity. Studying the dynamics of resting-state brain activity across the whole-brain functional network can provide a better characterization of age-related changes. Here, we employed two data-driven whole-brain approaches based on the phase synchronization of blood-oxygen-level-dependent signals to analyze resting-state fMRI data from 620 subjects divided into two groups (middle-age group (n = 310); age range, 50-64 years versus older group (n = 310); age range, 65-91 years). Applying the intrinsic-ignition framework to assess the effect of spontaneous local activation events on local-global integration, we found that the older group showed higher intrinsic ignition across the whole-brain functional network, but lower metastability. Using Leading Eigenvector Dynamics Analysis, we found that the older group showed reduced ability to access a metastable substate that closely overlaps with the so-called rich club. These findings suggest that functional whole-brain dynamics are altered in aging, probably due to a deficiency in a metastable substate that is key for efficient global communication in the brain.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cercor/bhaa367DOI Listing
March 2021

MicroRNA Profile of Cardiovascular Risk in Patients with Obstructive Sleep Apnea.

Respiration 2020;99(12):1122-1128. Epub 2020 Nov 18.

Group of Translational Research in Respiratory Medicine, Hospital Universitari Arnau de Vilanova y Santa Maria, IRB, Lleida, Spain,

Background: Obstructive sleep apnea (OSA) is a common disease caused by repeated episodes of collapse of the upper airway during sleep and is associated with the development of cardiovascular disease (CVD). However, there is high heterogeneity in the impact of OSA on patients. Until now, the profile of OSA patients at risk of developing CVD has not been defined, including the measurable variables that could be used to predict the CVD risk of a patient with OSA.

Objective: The aim of this study was to identify the microRNA (mi-RNA) profile associated with CVD in patients with OSA.

Method: This is an observational, cross-sectional study that included 132 male patients. Three groups were defined as OSA patients, OSA patients with hypertension, and OSA patients who developed a major cardiovascular event. Polysomnography and ambulatory blood pressure measurements were performed. The expression profiling of 188 miRNAs in plasma was performed in 21 subjects (matched by BMI and age) by the TaqMan low density array (TLDA). miRNAs differentially expressed in the different subgroups of patients and miRNAs that correlated with the cardiovascular risk SCORE were selected for validation by RT-qPCR in the 111 remaining patients.

Results: From the TLDA analysis, 7 miRNAs were selected for validation. Differential expression was not confirmed in any of the miRNAs. miR-143 was associated with nocturnal systolic blood pressure. miR-107 correlated with 24-h blood pressure parameters and with nocturnal hypertension. miR-486 was associated with the cardiovascular risk SCORE.

Conclusions: The circulating profile of miRNAs does not seem to be different in any of the subgroups of patients with OSA and different cardiovascular risk factors. Nevertheless, miR-107 and miR-143 are associated with specific blood pressure parameters in patients with OSA and miR-486 is associated with the cardiovascular risk SCORE.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000511093DOI Listing
November 2020

FGF15/19 is required for adipose tissue plasticity in response to thermogenic adaptations.

Mol Metab 2021 01 7;43:101113. Epub 2020 Nov 7.

Department of Biochemistry and Molecular Biomedicine and Institute of Biomedicine, University of Barcelona, Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain; CIBEROBN, Carlos III Health Institute, Spain. Electronic address:

Objective: To determine the role of enterokine FGF15/19 in adipose tissue thermogenic adaptations.

Methods: Circulating FGF19 and gene expression (qRT-PCR) levels were assessed in subcutaneous adipose tissue from obese human patients. Effects of experimentally increased FGF15 and FGF19 levels in vivo were determined in mice using adenoviral and adeno-associated vectors. Adipose tissues were characterized in FGF15-null mice under distinct cold-related thermogenic challenges. The analyses spanned metabolic profiling, tissue characterization, histology, gene expression, and immunoblot assays.

Results: In humans, FGF19 levels are directly associated with UCP1 gene expression in subcutaneous adipose tissue. Experimental increases in FGF15 or FGF19 induced white fat browning in mice as demonstrated by the appearance of multilocular beige cells and markers indicative of a beige phenotype, including increased UCP1 protein levels. Mice lacking FGF15 showed markedly impaired white adipose tissue browning and a mild reduction in parameters indicative of BAT activity in response to cold-induced environmental thermogenic challenges. This was concomitant with signs of altered systemic metabolism, such as reduced glucose tolerance and impaired cold-induced insulin sensitization.

Conclusions: Enterokine FGF15/19 is a key factor required for adipose tissue plasticity in response to thermogenic adaptations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.molmet.2020.101113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7691747PMC
January 2021

Safety and Feasibility of the PEPPER Adaptive Bolus Advisor and Safety System: A Randomized Control Study.

Diabetes Technol Ther 2021 Mar;23(3):175-186

Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom.

The Patient Empowerment through Predictive Personalized Decision Support (PEPPER) system provides personalized bolus advice for people with type 1 diabetes. The system incorporates an adaptive insulin recommender system (based on case-based reasoning, an artificial intelligence methodology), coupled with a safety system, which includes predictive glucose alerts and alarms, predictive low-glucose suspend, personalized carbohydrate recommendations, and dynamic bolus insulin constraint. We evaluated the safety and efficacy of the PEPPER system compared to a standard bolus calculator. This was an open-labeled multicenter randomized controlled crossover study. Following 4-week run-in, participants were randomized to PEPPER/Control or Control/PEPPER in a 1:1 ratio for 12 weeks. Participants then crossed over after a washout period. The primary end-point was percentage time in range (TIR, 3.9-10.0 mmol/L [70-180 mg/dL]). Secondary outcomes included glycemic variability, quality of life, and outcomes on the safety system and insulin recommender. Fifty-four participants on multiple daily injections (MDI) or insulin pump completed the run-in period, making up the intention-to-treat analysis. Median (interquartile range) age was 41.5 (32.3-49.8) years, diabetes duration 21.0 (11.5-26.0) years, and HbA1c 61.0 (58.0-66.1) mmol/mol. No significant difference was observed for percentage TIR between the PEPPER and Control groups (62.5 [52.1-67.8] % vs. 58.4 [49.6-64.3] %, respectively,  = 0.27). For quality of life, participants reported higher perceived hypoglycemia with the PEPPER system despite no objective difference in time spent in hypoglycemia. The PEPPER system was safe, but did not change glycemic outcomes, compared to control. There is wide scope for integrating PEPPER into routine diabetes management for pump and MDI users. Further studies are required to confirm overall effectiveness. ClinicalTrials.gov NCT03849755.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/dia.2020.0301DOI Listing
March 2021

Morbidly obese subjects show increased serum sulfide in proportion to fat mass.

Int J Obes (Lond) 2021 Feb 10;45(2):415-426. Epub 2020 Oct 10.

Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), Girona, Spain.

Background And Objectives: The importance of hydrogen sulfide is increasingly recognized in the pathophysiology of obesity and type 2 diabetes in animal models. Very few studies have evaluated circulating sulfides in humans, with discrepant results. Here, we aimed to investigate serum sulfide levels according to obesity.

Subjects And Methods: Serum sulfide levels were analyzed, using a selective fluorescent probe, in two independent cohorts [cross-sectionally in discovery (n = 139) and validation (n = 71) cohorts, and longitudinally in 82 participants from discovery cohort]. In the validation cohort, blood gene expression of enzymes contributing to HS generation and consumption were also measured.

Results: In the discovery cohort, serum sulfide concentration was significantly increased in subjects with morbid obesity at baseline and follow-up, and positively correlated with BMI and fat mass, but negatively with total cholesterol, haemoglobin, serum ferritin, iron and bilirubin after adjusting by age, gender and fat mass. Fat mass (β = 0.51, t = 3.67, p < 0.0001) contributed independently to age-, gender-, insulin sensitivity- and BMI-adjusted serum sulfide concentration variance. Importantly, receiver operating characteristic analysis demonstrated the relevance of fat mass predicting serum sulfide levels, which was replicated in the validation cohort. In addition, serum sulfide concentration was decreased in morbidly obese subjects with impaired compared to those with normal fasting glucose. Longitudinally, weight gain resulted in increased serum sulfide concentration, whereas weight loss had opposite effects, being the percent change in serum sulfide positively correlated with the percent change in BMI and waist circumference, but negatively with bilirubin. Whole blood CBS, CTH, MPST, SQOR, TST and MPO gene expression was not associated to obesity or serum sulfide concentration.

Conclusions: Altogether these data indicated that serum sulfide concentrations were increased in subjects with morbid obesity in proportion to fat mass and inversely associated with circulating markers of haem degradation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41366-020-00696-zDOI Listing
February 2021

Obesity Impairs Short-Term and Working Memory through Gut Microbial Metabolism of Aromatic Amino Acids.

Cell Metab 2020 Oct;32(4):548-560.e7

Department of Diabetes, Endocrinology and Nutrition, Dr. Josep Trueta University Hospital, Girona, Spain; Nutrition, Eumetabolism and Health Group, Girona Biomedical Research Institute (IdibGi), Girona, Spain; Biomedical Research Networking Center for Physiopathology of Obesity and Nutrition (CIBEROBN), Madrid, Spain; Department of Medical Sciences, Faculty of Medicine, Girona University, Girona, Spain. Electronic address:

The gut microbiome has been linked to fear extinction learning in animal models. Here, we aimed to explore the gut microbiome and memory domains according to obesity status. A specific microbiome profile associated with short-term memory, working memory, and the volume of the hippocampus and frontal regions of the brain differentially in human subjects with and without obesity. Plasma and fecal levels of aromatic amino acids, their catabolites, and vegetable-derived compounds were longitudinally associated with short-term and working memory. Functionally, microbiota transplantation from human subjects with obesity led to decreased memory scores in mice, aligning this trait from humans with that of recipient mice. RNA sequencing of the medial prefrontal cortex of mice revealed that short-term memory associated with aromatic amino acid pathways, inflammatory genes, and clusters of bacterial species. These results highlight the potential therapeutic value of targeting the gut microbiota for memory impairment, specifically in subjects with obesity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cmet.2020.09.002DOI Listing
October 2020

Is the jejunum the fulcrum of glucose metabolism?

Gut 2020 Sep 29. Epub 2020 Sep 29.

Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona Dr Josep Trueta and Hospital Dr Josep Trueta, Girona, Catalunya, Spain.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/gutjnl-2020-322662DOI Listing
September 2020

Nicotine' actions on energy balance: Friend or foe?

Pharmacol Ther 2021 Mar 26;219:107693. Epub 2020 Sep 26.

Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706, Spain. Electronic address:

Obesity has reached pandemic proportions and is associated with severe comorbidities, such as type 2 diabetes mellitus, hepatic and cardiovascular diseases, and certain cancer types. However, the therapeutic options to treat obesity are limited. Extensive epidemiological studies have shown a strong relationship between smoking and body weight, with non-smokers weighing more than smokers at any age. Increased body weight after smoking cessation is a major factor that interferes with their attempts to quit smoking. Numerous controlled studies in both humans and rodents have reported that nicotine, the main bioactive component of tobacco, exerts a marked anorectic action. Furthermore, nicotine is also known to modulate energy expenditure, by regulating the thermogenic activity of brown adipose tissue (BAT) and the browning of white adipose tissue (WAT), as well as glucose homeostasis. Many of these actions occur at central level, by controlling the activity of hypothalamic neuropeptide systems such as proopiomelanocortin (POMC), or energy sensors such as AMP-activated protein kinase (AMPK). However, direct impact of nicotine on metabolic tissues, such as BAT, WAT, liver and pancreas has also been described. Here, we review the actions of nicotine on energy balance. The relevance of this interaction is interesting, because considering the restricted efficiency of obesity treatments, a possible complementary approach may focus on compounds with known pharmacokinetic profile and pharmacological actions, such as nicotine or nicotinic acetylcholine receptors signaling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pharmthera.2020.107693DOI Listing
March 2021

Gut microbiota steroid sexual dimorphism and its impact on gonadal steroids: influences of obesity and menopausal status.

Microbiome 2020 09 20;8(1):136. Epub 2020 Sep 20.

Department of Endocrinology, Diabetes and Nutrition, Departament de Ciències Mèdiques, Hospital of Girona "Dr JosepTrueta", Girona Biomedical Research Institute (IdibGi), University of Girona, Carretera de França s/n, 17007, Girona, Spain.

Background: Gonadal steroid hormones have been suggested as the underlying mechanism responsible for the sexual dimorphism observed in metabolic diseases. Animal studies have also evidenced a causal role of the gut microbiome and metabolic health. However, the role of sexual dimorphism in the gut microbiota and the potential role of the microbiome in influencing sex steroid hormones and shaping sexually dimorphic susceptibility to disease have been largely overlooked. Although there is some evidence of sex-specific differences in the gut microbiota diversity, composition, and functionality, the results are inconsistent. Importantly, most of these studies have not taken into account the gonadal steroid status. Therefore, we investigated the gut microbiome composition and functionality in relation to sex, menopausal status, and circulating sex steroids.

Results: No significant differences were found in alpha diversity indices among pre- and post-menopausal women and men, but beta diversity differed among groups. The gut microbiota from post-menopausal women was more similar to men than to pre-menopausal women. Metagenome functional analyses revealed no significant differences between post-menopausal women and men. Gonadal steroids were specifically associated with these differences. Hence, the gut microbiota of pre-menopausal women was more enriched in genes from the steroid biosynthesis and degradation pathways, with the former having the strongest fold change among all associated pathways. Microbial steroid pathways also had significant associations with the plasma levels of testosterone and progesterone. In addition, a specific microbiome signature was able to predict the circulating testosterone levels at baseline and after 1-year follow-up. In addition, this microbiome signature could be transmitted from humans to antibiotic-induced microbiome-depleted male mice, being able to predict donor's testosterone levels 4 weeks later, implying that the microbiota profile of the recipient mouse was influenced by the donor's gender. Finally, obesity eliminated most of the differences observed among non-obese pre-menopausal women, post-menopausal women, and men in the gut microbiota composition (Bray-Curtis and weighted unifrac beta diversity), functionality, and the gonadal steroid status.

Conclusions: The present findings evidence clear differences in the gut microbial composition and functionality between men and women, which is eliminated by both menopausal and obesity status. We also reveal a tight link between the gut microbiota composition and the circulating levels of gonadal steroids, particularly testosterone. Video Abstract.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40168-020-00913-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7504665PMC
September 2020

Lysozyme is a component of the innate immune system linked to obesity associated-chronic low-grade inflammation and altered glucose tolerance.

Clin Nutr 2021 Mar 4;40(3):1420-1429. Epub 2020 Sep 4.

Department of Diabetes, Endocrinology and Nutrition (UDEN), Hospital of Girona "Dr Josep Trueta", Institut d'Investigació Biomèdica de Girona (IdIBGi), Girona, Spain; CIBER de la Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Madrid, Spain; Department of Medical Sciences, Faculty of Medicine, University of Girona, Girona, Spain. Electronic address:

Background & Aims: Several proteins of the innate immune system are known to be deregulated with insulin resistance. We here aimed to investigate the relationship among circulating lysozyme (both plasma concentration and activity) and obesity-associated metabolic disturbances.

Methods: Plasma lysozyme concentration was determined cross-sectionally in a discovery (Cohort 1, n = 137) and in a replication cohort (Cohort 2, n = 181), in which plasma lysozyme activity was also analyzed. Plasma lysozyme was also evaluated longitudinally in participants from the replication cohort (n = 93). Leukocyte lysozyme expression (LYZ mRNA) were also investigated in an independent cohort (Cohort 3, n = 76), and adipose tissue (AT) LYZ mRNA (n = 25) and plasma peptidoglycan levels (n = 61) in subcohorts from discovery cohort.

Results: Translocation of peptidoglycan (as inferred from its increased circulating levels) was linked to plasma lysozyme, hyperinsulinemia and dyslipidemia in obese subjects. In both discovery and replication cohorts, plasma lysozyme levels and activity were significantly increased in obesity in direct association with obesity-associated metabolic disturbances and inflammatory parameters, being circulating lysozyme negatively correlated with fasting glucose, HbA1c and insulin resistance (HOMA-IR) in obese subjects. Of note, total cholesterol (p < 0.0001) and LDL cholesterol (p = 0.003) contributed independently to age-, gender- and BMI adjusted plasma lysozyme activity. Longitudinally, changes in HbA1c levels and serum LDL cholesterol were negatively associated with circulating lysozyme antimicrobial activity. On the contrary, the change in glucose infusion rate during the clamp (insulin sensitivity) was positively associated with lysozyme concentration.

Conclusions: Increased plasma lysozyme levels and activity are found in obese subjects. The longitudinal findings suggest that plasma lysozyme might be protective on the development of obesity-associated metabolic disturbances.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clnu.2020.08.036DOI Listing
March 2021

Factors associated with prolonged hospital stay after laparoscopic adrenalectomy.

Updates Surg 2021 Apr 17;73(2):693-702. Epub 2020 Sep 17.

Department of Surgery, Department of Medical Sciences, Faculty of Medicine, Dr. Josep Trueta University Hospital, Girona Biomedical Research Institute (IDIBGI), University of Girona, Girona, Spain.

Laparoscopy is the standard technique for resecting adrenal tumors, but short-term outcomes such as length of stay (LOS) vary widely between centers. We aimed to identify factors associated with LOS after lateral transperitoneal laparoscopic adrenalectomy (LTLA). We analyzed consecutive patients undergoing unilateral LTLA between April 2003 and April 2020. Prolonged LOS was defined as a stay longer than the 75th percentile of the overall cohort. To identify potential factors associated with prolonged LOS, we compared collected data from patients with LOS ≤ 2 days versus LOS > 2 days and elaborated multivariate logistic regression models. We included 150 patients (73 men and 77 women, median age 54 years), with benign (n = 128) and malignant tumors (n = 22). The median LOS after LTLA was 2 days; 64 (42.7%) patients had prolonged hospitalization. Variables significantly associated with prolonged LOS in the univariate analysis included ASA III + IV (p = 0.016), pheochromocytoma (p < 0.001), learning curve (p = 0.032), surgery on Thursday or Friday (p < 0.001), 2D laparoscopy (p = 0.003), operative time (p < 0.001), estimated blood loss (p < 0.001), drainage (p < 0.001), specimen size (p = 0.011), conversions (p = 0.002), complications (p = 0.019), and hospital stay (p < 0.001). After adjustment for patient, surgical, and tumor characteristics, risk factors associated with prolonged LOS in the multivariate analysis were specimen size > 9 cm (OR:13.03, p = 0.005), surgery on Thursday or Friday (OR:6.92, p = 0.001), estimated blood loss ≥ 60 ml (OR:6.22, p = 0.021), and drainage (OR:5.29, p = 0.005). Prolonged length of stay after LTLA was associated with specimen size > 9 cm, operating on Thursday or Friday, estimated blood loss ≥ 60 mL, and drainage.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s13304-020-00880-wDOI Listing
April 2021

Permanent cystathionine-β-Synthase gene knockdown promotes inflammation and oxidative stress in immortalized human adipose-derived mesenchymal stem cells, enhancing their adipogenic capacity.

Redox Biol 2020 Aug 2:101668. Epub 2020 Aug 2.

Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), Girona, Spain; Department of Medicine, Universitat de Girona, Girona, Spain. Electronic address:

In the present study, we aimed to investigate the impact of permanent cystathionine-β-Synthase (CBS) gene knockdown in human telomerase reverse transcriptase (hTERT) immortalized human adipose-derived mesenchymal stem cells (ASC52telo) and in their capacity to differentiate into adipocytes. CBS gene KD in ASC52telo cells led to increased cellular inflammation (IL6, CXCL8, TNF) and oxidative stress markers (increased intracellular reactive oxygen species and decreased reduced glutathione levels) in parallel to decreased HS production and rejuvenation (LC3 and SIRT1)-related gene expression. In addition, CBS gene KD in ASC52telo cells resulted in altered mitochondrial respiratory function, characterised by decreased basal respiration (specifically proton leak) and spare respiratory capacity, without significant effects on cell viability and proliferation. In this context, shCBS-ASC52telo cells displayed enhanced adipogenic (FABP4, ADIPOQ, SLC2A4, CEBPA, PPARG)-, lipogenic (FASN, DGAT1)- and adipocyte (LEP, LBP)-related gene expression markers, decreased expression of proinflammatory cytokines, and increased intracellular lipid accumulation during adipocyte differentiation compared to control ASC52telo cells. Otherwise, the increased adipogenic potential of shCBS-ASC52telo cells was detrimental to the ability to differentiate into osteogenic linage. In conclusion, this study demonstrated that permanent CBS gene KD in ASC52telo cells promotes a cellular senescence phenotype with a very increased adipogenic potential, promoting a non-physiological enhanced adipocyte differentiation with excessive lipid storage.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.redox.2020.101668DOI Listing
August 2020

Bariatric Surgery-Induced Changes in Intima-Media Thickness and Cardiovascular Risk Factors in Class 3 Obesity: A 3-Year Follow-Up Study.

Obesity (Silver Spring) 2020 09 9;28(9):1663-1670. Epub 2020 Aug 9.

Department of Radiology (IDI), Girona Biomedical Research Institute (IDIBGI), Hospital Universitari de Girona Dr Josep Trueta, Girona, Spain.

Objective: The impact of weight loss induced by bariatric surgery (BS) and nonsurgical approaches on cardiovascular risk factors (CVRFs) has not been fully elucidated. We assessed the effects of BS and a nonsurgical approach on carotid intima-media thickness (CIMT) and CVRFs in participants with class 3 obesity.

Methods: A total of 87 participants with obesity (59 women; 46 [37-52] years old; BMI, 43 [40-47]) and 75 controls were recruited; 21 (25%) participants with obesity underwent BS. BMI, blood pressure, cholesterol, triglycerides, fasting plasma glucose, C-reactive protein, CIMT, and Framingham Risk Score were measured at baseline and at 3-year follow-up. Independent factors for reduction in CIMT were analyzed. The literature on the effects of BS and CIMT was reviewed.

Results: After BS, BMI decreased from 45.45 to 27.28 (P < 0.001), and mean CIMT decreased from 0.64 mm (0.56-0.75 mm) to 0.54 mm (0.46-0.65) mm (P < 0.012), equivalent to 0.005 mm/kg of weight lost. At 3-year follow-up, participants who had undergone BS had similar CIMT and CVRFs to the control group. No changes in CVRFs were seen related to the nonsurgical approach. BMI reduction after BS had the strongest independent association with decreased CIMT.

Conclusions: Weight loss after BS decreases CIMT and CVRFs in middle-aged participants with class 3 obesity, resulting in CIMT similar to that observed in lean participants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/oby.22905DOI Listing
September 2020

Assessing the quality of the evidence underlying recommendations in type 2 diabetes' commonly used clinical practice guidelines.

Int J Evid Based Healthc 2020 Jul 17. Epub 2020 Jul 17.

Medicine Department, Universitat de Girona.

Aim: In a world of data overload, clinical practice recommendations are needed to help practitioners and patients to take evidence-based decisions. However, in the field of type 2 diabetes mellitus (T2DM) recommendations on glycemic goals and treatment choice are controversial in spite of being supported by a common body of evidence. We hypothesize that internal and external validity of this body of evidence might not be as sound as expected. The aim of the current study is to appraise the studies supporting recommendations developed by influential medical societies dealing with glycemic goals and the choice of pharmacological treatment in adults with T2DM.

Methods: Clinical practice recommendations and their references were extracted out of eight documents developed by influential scientific societies between 2016 and 2019. Internal and external validity of each study was then appraised with standard tools and in duplicate.

Results: A total of 114 recommendations and their underlying 233 citations were extracted. Out of these 233 citations 81 (35%) corresponded to randomized controlled trials (RCT) and 45 (20%) to systematic reviews. After systematical appraisal only four RCT (5%) and eight systematic reviews (17%) were considered to be unflawed. Indirectness (lack of generalizability) was the most common caveat identified in RCTs. Out of the 114 recommendations analyzed (32 dealing with glycemic goals and 82 with treatment choice), only 21 (18.4%) were supported by at least one high-quality study.

Conclusion: Only one in five recommendations regarding glycemic goals or pharmacological treatment choice in T2DM is based on at least one high-quality study. Clinical practice recommendations dealing with areas of uncertainty should be formulated more transparently to enable real evidence-based decisions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/XEB.0000000000000243DOI Listing
July 2020

The Circulating Fatty Acid Transporter Soluble CD36 Is Not Associated with Carotid Atherosclerosis in Subjects with Type 1 and Type 2 Diabetes Mellitus.

J Clin Med 2020 Jun 2;9(6). Epub 2020 Jun 2.

Department of Endocrinology & Nutrition, Hospital de la Santa Creu i Sant Pau, IIB Sant Pau, 08041 Barcelona, Spain.

This study aimed to determine the association of fatty acid transporter plasma soluble cluster of differentiation 36 (sCD36) with subclinical carotid atherosclerosis (SCA). A cross-sectional study was conducted in 1023 subjects, 225 with type 1 diabetes (T1D), 276 with type 2 diabetes (T2D) and 522 who were nondiabetic. Carotid atherosclerotic plaque (CAP) presence was determined using B-mode carotid ultrasound imaging. sCD36 were analysed by ELISA, and CD36 surface receptor and mRNA expression were measured by flow cytometry and real-time PCR. Logistic regression models were used to evaluate sCD36 as a biomarker of SCA. Up to 376 (36.75%) participants had at least one CAP, 76 T1D, 164 T2D and 136 without diabetes, while the remaining 647 (63.25%) did not have any CAP. There were no differences in sCD36 between patients with and without CAP in T1D ( = 0.287) or T2D ( = 0.513). Although nondiabetic subjects with plaques had lower sCD36 levels than those without ( = 0.023), the multivariate models revealed no association of sCD36 with CAP in any of the three study groups. No differences were found in surface CD36 or CD36 mRNA expression between the patients with and without CAP. sCD36 is not associated with SCA in type 1 or type 2 diabetic or in nondiabetic subjects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jcm9061700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7355534PMC
June 2020

The Aging Imageomics Study: rationale, design and baseline characteristics of the study population.

Mech Ageing Dev 2020 07 11;189:111257. Epub 2020 May 11.

Girona Biomedical Research Institute (IDIBGI), Hospital Universitari de Girona Dr Josep Trueta, Girona, Spain; Department of Medical Sciences, School of Medicine, University of Girona, Girona, Spain; Institut d'Assistència Sanitària, Salt, Spain.

Biomarkers of aging are urgently needed to identify individuals at high risk of developing age-associated disease or disability. Growing evidence from population-based studies points to whole-body magnetic resonance imaging's (MRI) enormous potential for quantifying subclinical disease burden and for assessing changes that occur with aging in all organ systems. The Aging Imageomics Study aims to identify biomarkers of human aging by analyzing imaging, biopsychosocial, cardiovascular, metabolomic, lipidomic, and microbiome variables. This study recruited 1030 participants aged ≥50 years (mean 67, range 50-96 years) that underwent structural and functional MRI to evaluate the brain, large blood vessels, heart, abdominal organs, fat, spine, musculoskeletal system and ultrasonography to assess carotid intima-media thickness and plaques. Patients were notified of incidental findings detected by a certified radiologist when necessary. Extensive data were also collected on anthropometrics, demographics, health history, neuropsychology, employment, income, family status, exposure to air pollution and cardiovascular status. In addition, several types of samples were gathered to allow for microbiome, metabolomic and lipidomic profiling. Using big data techniques to analyze all the data points from biological phenotyping together with health records and lifestyle measures, we aim to cultivate a deeper understanding about various biological factors (and combinations thereof) that underlie healthy and unhealthy aging.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.mad.2020.111257DOI Listing
July 2020

Low AMY1 Copy Number Is Cross-Sectionally Associated to an Inflammation-Related Lipidomics Signature in Overweight and Obese Individuals.

Mol Nutr Food Res 2020 06 25;64(11):e1901151. Epub 2020 May 25.

Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, Level 1, 43-51 Kanooka Grove, Clayton, Melbourne, VIC, 3168, Australia.

Scope: Reduced amylase 1 (AMY1) copy numbers are associated with obesity, insulin resistance, and inflammation. Although mechanisms linking AMY1 copy number with metabolic disorders are poorly understood, recent findings suggest that lipids play a key role.

Methods And Results: Plasma lipidomic signatures associated with AMY1 copy number are explored in 57 non-diabetic overweight/obese subjects aged 18-60. Serum amylase and inflammatory cytokines levels are also measured. AMY1 copy number is strongly associated with the serum amylase concentration. Participants are divided into low-(≤4) and high-(>4) AMY1 carriers based on the median. Low-AMY1 carriers have higher BMI and fat mass. They also have higher levels of dihexosylceramides (R = -0.27, p = 0.044), cholesterol esters (CE) (R = -0.32, p = 0.020), alkylphosphatidylcholines [PC(O)] (R = -0.33, p = 0.014), and sphingomyelins (SM) (R = -0.38, p = 0.005). From 459 lipid species, 28 differ between low- and high-AMY1 carriers. These include CE species with long-chain PUFA; PC(O) and PC plasmalogens containing arachidonic acid; and PC, mono-, di-, and tri-hexosylceramides, and SM containing saturated fatty acids (mainly C16:0 and C20:0). This lipidomic signature is strongly associated with inflammatory cytokines, which are also negatively associated with the AMY1 copy number.

Conclusion: A lipidomics signature associated with low AMY1 copy numbers is revealed, which is linked to obesity and chronic low-grade inflammation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mnfr.201901151DOI Listing
June 2020

Gut bacterial ClpB-like gene function is associated with decreased body weight and a characteristic microbiota profile.

Microbiome 2020 04 30;8(1):59. Epub 2020 Apr 30.

Department of Diabetes, Endocrinology and Nutrition, Dr. Josep Trueta University Hospital, Carretera de França s/n, 17007, Girona, Spain.

Background: The chaperone ClpB, a bacterial protein, is a conformational antigen-mimetic of α-melanocyte-stimulating hormone (α-MSH) implicated in body weight regulation in mice. We here investigated the potential associations of gut bacterial ClpB-like gene function with obesity status and gut microbiota in humans.

Results: Gut microbiota ClpB KEGG function was negatively associated with body mass index, waist circumference, and total fat mass (DEXA). The relative abundance (RA) of several phyla and families directly associated with ClpB was decreased in subjects with obesity. Specifically, the RA of Rikenellaceae, Clostridiaceae and not assigned Firmicutes were lower in subjects with obesity and positively associated with gut bacterial ClpB-like gene function (not assigned Firmicutes (r = 0.405, FDR = 2.93 × 10-2), Rikenellaceae (r = 0.217, FDR = 0.031), and Clostridiaceae (r = 0.239, FDR = 0.017)). The gut bacterial ClpB-like gene function was also linked to specific plasma metabolites (hippuric acid and 3-indolepropionic acid) and fecal lupeol. The α-MSH-like epitope similar to that of Escherichia coli ClpB was also identified in some sequences of those bacterial families. After fecal transplantation from humans to mice, the families that more contributed to ClpB-like gene function in humans were also associated with ClpB-like gene function in mice after adjusting for the donor's body mass index (not assigned Firmicutes (r = 0.621, p = 0.003), Prevotellaceae (r = 0.725, p = 4.1 × 10), Rikenellaceae (r = 0.702, p = 3.9 × 10), and Ruminococcaceae (r = 0.526, p = 0.014)). Clostridiaceae (r = - 0.445, p = 0.038) and Prevotellaceae RA (r = - 0.479, p = 0.024) and were also negatively associated with weight gain in mice. The absolute abundance (AA) of Prevotellaceae in mice was also positively associated with the gut bacterial ClpB-like gene function in mice. DESeq2 identified species of Prevotellaceae, both negatively associated with mice' weight gain and positively with gut bacterial ClpB-like gene function.

Conclusions: In summary, gut bacterial ClpB-like gene function is associated with obesity status, a specific gut microbiota composition and a plasma metabolomics profile in humans that could be partially transplanted to mice. Video Abstract.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40168-020-00837-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193372PMC
April 2020

The APOA1bp-SREBF-NOTCH axis is associated with reduced atherosclerosis risk in morbidly obese patients.

Clin Nutr 2020 Nov 8;39(11):3408-3418. Epub 2020 Mar 8.

Department of Endocrinology, Diabetes and Nutrition, Hospital of Girona "Dr Josep Trueta", Departament de Ciències Mèdiques, University of Girona, Girona Biomedical Research Institute (IdibGi), Girona, Spain; CIBERobn Pathophysiology of Obesity and Nutrition, Instituto de Salud Carlos III, Madrid, Spain. Electronic address:

Background & Aims: Atherosclerosis is characterized by an inflammatory disease linked to excessive lipid accumulation in the artery wall. The Notch signalling pathway has been shown to play a key regulatory role in the regulation of inflammation. Recently, in vitro and pre-clinical studies have shown that apolipoprotein A-I binding protein (AIBP) regulates cholesterol metabolism (SREBP) and NOTCH signalling (haematopoiesis) and may be protective against atherosclerosis, but the evidence in humans is scarce.

Methods: We evaluated the APOA1bp-SREBF-NOTCH axis in association with atherosclerosis in two well-characterized cohorts of morbidly obese patients (n = 78) within the FLORINASH study, including liver transcriptomics, H NMR plasma metabolomics, high-resolution ultrasonography evaluating carotid intima-media thickness (cIMT), and haematological parameters.

Results: The liver expression levels of APOA1bp were associated with lower cIMT and leukocyte counts, a better plasma lipid profile and higher circulating levels of metabolites associated with lower risk of atherosclerosis (glycine, histidine and asparagine). Conversely, liver SREBF and NOTCH mRNAs were positively associated with atherosclerosis, liver steatosis, an unfavourable lipid profile, higher leukocytes and increased levels of metabolites linked to inflammation and CVD such as branched-chain amino acids and glycoproteins. APOA1bp and NOTCH signalling also had a strong association, as revealed by the negative correlations among APOA1bp expression levels and those of all NOTCH receptors and jagged ligands.

Conclusions: We here provide the first evidence in human liver of the putative APOA1bp-SREBF-NOTCH axis signalling pathway and its association with atherosclerosis and inflammation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clnu.2020.02.034DOI Listing
November 2020

Plasma Phospholipids with Long-Chain Polyunsaturated Fatty Acids and Dihydroceramides at the Crossroads of Iron Stores and Insulin Resistance.

Mol Nutr Food Res 2020 03 23;64(5):e1901055. Epub 2020 Jan 23.

Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia.

Scope: Iron plays an important role in the pathogenesis of insulin resistance (IR) and type 2 diabetes. Recent studies suggest a role of specific lipids in the induction of IR, but the potential relationships between iron and lipid metabolites in relation to IR have not been explored. Therefore, the aim of the study is to evaluate the association among iron, IR, and the lipidome.

Methods And Results: The plasma lipidome, IR, parameters of iron metabolism, and several cytokines and adipokines in 65 overweight/obese participants are measured. Measurements of IR correlate positively with ferritin, a measure of iron storage (r = 0.35, p = 0.005), and negatively with adiponectin (r = -0.30, p = 0.02). The serum ferritin/adiponectin ratio has a stronger association with IR (r = 0.41, p < 0.001). From multivariate analyses adjusted for age, sex, and BMI, several phospholipids containing long chain polyunsaturated fatty acids (PUFA) with 20-22 carbons (phosphatidylcholines, phosphatidylethanolamines, phosphatidylinositols, and a phosphatidylserine), are positively associated with ferritin and the ferritin/adiponectin ratio. Two dihydroceramides (Cer(18:0/22:0), Cer(18:0/24:0)) and several diglycerides and triglycerides, mainly comprised of C14:0, C16:0, C18:0, C18:1, and C18:2, also have positive correlations with ferritin and the ferritin/adiponectin ratio.

Conclusions: The positive associations between these lipid species and ferritin or the ferritin/adiponectin ratio suggest a potential crosstalk between iron and lipid metabolism in obesity and IR.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mnfr.201901055DOI Listing
March 2020

Deletion of iRhom2 protects against diet-induced obesity by increasing thermogenesis.

Mol Metab 2020 01 31;31:67-84. Epub 2019 Oct 31.

Instituto Gulbenkian de Ciência (IGC), Oeiras, Portugal; Centre for Cancer Research and Cell Biology, Queen's University Belfast, UK. Electronic address:

Objective: Obesity is the result of positive energy balance. It can be caused by excessive energy consumption but also by decreased energy dissipation, which occurs under several conditions including when the development or activation of brown adipose tissue (BAT) is impaired. Here we evaluated whether iRhom2, the essential cofactor for the Tumour Necrosis Factor (TNF) sheddase ADAM17/TACE, plays a role in the pathophysiology of metabolic syndrome.

Methods: We challenged WT versus iRhom2 KO mice to positive energy balance by chronic exposure to a high fat diet and then compared their metabolic phenotypes. We also carried out ex vivo assays with primary and immortalized mouse brown adipocytes to establish the autonomy of the effect of loss of iRhom2 on thermogenesis and respiration.

Results: Deletion of iRhom2 protected mice from weight gain, dyslipidemia, adipose tissue inflammation, and hepatic steatosis and improved insulin sensitivity when challenged by a high fat diet. Crucially, the loss of iRhom2 promotes thermogenesis via BAT activation and beige adipocyte recruitment, enabling iRhom2 KO mice to dissipate excess energy more efficiently than WT animals. This effect on enhanced thermogenesis is cell-autonomous in brown adipocytes as iRhom2 KOs exhibit elevated UCP1 levels and increased mitochondrial proton leak.

Conclusion: Our data suggest that iRhom2 is a negative regulator of thermogenesis and plays a role in the control of adipose tissue homeostasis during metabolic disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.molmet.2019.10.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6909339PMC
January 2020

Microbiota impacts on chronic inflammation and metabolic syndrome - related cognitive dysfunction.

Rev Endocr Metab Disord 2019 12;20(4):473-480

Department of Diabetes, Endocrinology and Nutrition, Dr. Josep Trueta University Hospital, Girona Biomedical Research Institute [IdibGi], Carretera de França s/n, 17007, Girona, Spain.

Cognitive dysfunction, one of the major concerns of increased life expectancy, is prevalent in patients with metabolic disorders. Added to the inflammation in the context of aging (inflammaging), low-grade chronic inflammation (metaflammation) accompanies metabolic diseases. Peripheral and central inflammation underlie metabolic syndrome - related cognitive dysfunction. The gut microbiota is increasingly recognized to be linked to both inflammaging and metaflammation in parallel to the pathophysiology of obesity, type 2 diabetes and the metabolic syndrome. Microbiota composition, diversity and diverse metabolites have been related to different metabolic features and cognitive traits. The study of different mouse models has contributed to identify characteristic microbiota profiles and shifts in the microbial gene richness in association with cognitive function. Diet, exercise and prebiotics, probiotics or symbiotics significantly influence cognition and changes in the microbiota. Few studies have analyzed the gut microbiota composition in association with cognitive function in humans. Impaired attention, mental flexibility and executive function have been observed in association with a microbiota ecosystem in cross-sectional and longitudinal studies. Nevertheless, the evidence in humans is still scarce and not causal relationships may be inferred, so larger and long-term studies are required to gain insight into the possible role of microbiota in human cognition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11154-019-09537-5DOI Listing
December 2019

The gut microbiota modulates both browning of white adipose tissue and the activity of brown adipose tissue.

Rev Endocr Metab Disord 2019 12;20(4):387-397

Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), Girona, Spain.

Given the increasing worldwide prevalence of obesity and associated metabolic disturbances, novel therapeutic strategies are imperatively required. A plausible manner to increase energy expenditure is the enhancement of thermogenic pathways in white (WAT) and brown adipose tissue (BAT). In the last 15 years, the identification of novel endogenous mechanisms to promote BAT activity or browning of WAT has pointed at gut microbiota as an important modulator of host metabolic homeostasis and energy balance. In this review, we focused on the relationship between gut microbiota composition and adipose tissue thermogenic program (including BAT activity and browning of WAT) in both physiological and stress conditions. Specifically, we reviewed the effects of fasting, caloric restriction, cold stress and metabolic endotoxemia on both browning and gut microbiota shifts. Mechanistically speaking, processes related to bile acid metabolism and the endocannabinoid system seem to play an important role. In summary, the gut microbiota seems to impact WAT and BAT physiology at multiple levels.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11154-019-09523-xDOI Listing
December 2019