Publications by authors named "Carolina Gutiérrez-Repiso"

49 Publications

An alcohol-free beer enriched with isomaltulose and a resistant dextrin modulates gut microbiome in subjects with type 2 diabetes mellitus and overweight or obesity: a pilot study.

Food Funct 2021 Apr 31;12(8):3635-3646. Epub 2021 Mar 31.

Hospital Universitario Miguel Servet, Instituto de Investigación Sanitaria Aragón (IIS Aragón), CIBERCV, Zaragoza, Spain.

We aimed to study the effect of consuming an alcohol-free beer with modified carbohydrates composition (almost completely eliminating maltose and adding isomaltulose (16.5 g day) and resistant maltodextrin (5.28 g day)) in gut microbiome, compared to regular alcohol-free beer in subjects with T2DM or prediabetes and overweight/obesity. This is a pilot, randomized, double-blinded, crossover study including a sub-sample of a global study with 14 subjects: (a) consuming 66 cl day of regular alcohol-free beer for the first 10 weeks and 66 cl day of modified alcohol-free beer for the next 10 weeks; (b) the same described intervention in opposite order. BMI homogeneously decreased after both interventions. Glucose and HOMA-IR significantly decreased just after the participants consumed modified alcohol-free beer. These findings were in the same line as those reported in the global study. Dominant bacteria at baseline were Bacteroidetes, Firmicutes, Proteobacteria and Tenericutes. Parabacteroides, from the Porphymonadaceae family, resulted as the feature with the greatest difference between beers (ANCOM analysis, W = 15). Feature-volatility analysis confirmed the importance of Parabacteroides within the model. Alcohol-free beers consumption resulted in an enhancement of pathways related to metabolism according to PICRUSt analysis, including terpenoid-quinone, lipopolysaccharides and N-glycan biosynthesis. Thus, an alcohol-free beer including the substitution of regular carbohydrates for low doses of isomaltulose and the addition of maltodextrin within meals significantly impacts gut microbiota in diabetic subjects with overweight or obesity. This could, at least partially, explain the improvement in insulin resistance previously found after taking modified alcohol-free alcohol.Clinical Trial Registration: Registered under ClinicalTrials.gov identifier no. NCT03337828.
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http://dx.doi.org/10.1039/d0fo03160gDOI Listing
April 2021

Different Weight Loss Intervention Approaches Reveal a Lack of a Common Pattern of Gut Microbiota Changes.

J Pers Med 2021 Feb 8;11(2). Epub 2021 Feb 8.

Unidad de Gestión Clínica de Endocrinología y Nutrición del Hospital Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga (IBIMA), 29010 Málaga, Spain.

Options for treatment of obesity include dietary approaches and bariatric surgery. Previous studies have shown that weight loss interventions have an impact on gut microbiota. However, a pattern of gut microbiota changes associated with weight loss independently of the type of intervention has not been described yet. This study includes 61 individuals who followed different weight loss strategies in three different trials: 21 followed a hypocaloric Mediterranean diet (MedDiet), 18 followed a very-low-calorie ketogenic diet (VLCKD) and 22 patients underwent sleeve gastrectomy bariatric surgery (BS). Gut microbiota profile was assessed by next-generation sequencing. A common taxon that had significantly changed within the three weight loss interventions could not be find. At the family level, significantly increased its abundance with MedDiet and VLCKD, whilst and significantly increased with VLCKD and BS. At genus level, in VLCKD and BS, and significantly increased their abundance whilst decreased. At the species level, BS and VLCKD produced an increase in and a decrease in and , whilst increased its abundance after the BS and MedDiet. Predicted metagenome analysis suggested that most of the changes after VLCKD were focused on pathways related to biosynthesis and degradation/utilization/assimilation, while BS seems to decrease most of the biosynthesis pathways. MedDiet was enriched in several pathways related to fermentation to short-chain fatty acids. Our results show that weight loss is not associated with a specific pattern of gut microbiota changes independently of the strategy used. Indeed, gut microbiota changes according to type of weight loss intervention.
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http://dx.doi.org/10.3390/jpm11020109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915884PMC
February 2021

Oleic Acid Protects Against Insulin Resistance by Regulating the Genes Related to the PI3K Signaling Pathway.

J Clin Med 2020 Aug 12;9(8). Epub 2020 Aug 12.

Unidad de Gestión Clínica de Aparato Digestivo, Hospital Universitario Virgen de la Victoria/Instituto de Investigación Biomédica de Málaga-IBIMA, 29010 Málaga, Spain.

Background: The effects of different types of fatty acids on the gene expression of key players in the IRS1/PI3K signaling pathway have been poorly studied.

Material And Methods: We analyzed IRS1, p85α, and p110β mRNA expression and the fatty acid composition of phospholipids in visceral adipose tissue from patients with morbid obesity and from non-obese patients. Moreover, we analyzed the expression of those genes in visceral adipocytes incubated with oleic, linoleic, palmitic and dosahexaenoic acids.

Results: We found a reduced IRS1 expression in patients with morbid obesity, independent of insulin resistance, and a reduced p110β expression in those with lower insulin resistance. A positive correlation was found between p85α and stearic acid, and between IRS1 and p110β with palmitic and dosahexaenoic acid. In contrast, a negative correlation was found between p85α and oleic acid, and between IRS1 and p110β with linoleic, arachidonic and adrenic acid. Incubation with palmitic acid decreased IRS1 expression. p85α was down-regulated after incubation with oleic and dosahexaenoic acid and up-regulated with palmitic acid. p110β expression was increased and decreased after incubation with oleic and palmitic acid, respectively. The ratio p85α/p110β was decreased by oleic and dosahexaenoic acid and increased by palmitic acid.

Conclusions: Our in vitro results suggest a detrimental role of palmitic acid on the expression of gene related to insulin signaling pathway, with oleic acid being the one with the higher and more beneficial effects. DHA had a slight beneficial effect. Fatty acid-induced regulation of genes related to the IRS1/PI3K pathway may be a novel mechanism by which fatty acids regulate insulin sensitivity in visceral adipocytes.
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http://dx.doi.org/10.3390/jcm9082615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463472PMC
August 2020

Iodine Deficiency and Mortality in Spanish Adults: [email protected] Study.

Thyroid 2021 01 17;31(1):106-114. Epub 2020 Sep 17.

Department of Endocrinology and Nutrition, Hospital Regional Universitario de Málaga, Instituto de Investigación Biomedica de Málaga-IBIMA, Málaga, Spain.

Longitudinal data assessing the impact of iodine deficiency (ID) on mortality are scarce. We aimed to study the association between the state of iodine nutrition and the risk of total and cause-specific mortality in a representative sample of the Spanish adult population. We performed a longitudinal observational study to estimate mortality risk according to urinary iodine (UI) concentrations using a sample of 4370 subjects >18 years representative of the Spanish adult population participating in the nationwide study [email protected] (2008-2010). We used Cox regression to assess the association between UI at the start of the study (<50, 50-99, 100-199, 200-299, and ≥300 μg/L) and mortality during follow-up (National death registry-end of follow-up December 2016) in raw models, and adjusted for possible confounding variables: age, sex, educational level, hypertension, diabetes, obesity, chronic kidney disease, smoking, hypercholesterolemia, thyroid dysfunction, diagnosis of cardiovascular disease or cancer, area of residence, physical activity, adherence to Mediterranean diet, dairy and iodinated salt intake. A total of 254 deaths were recorded during an average follow-up period of 7.3 years. The causes of death were cardiovascular 71 (28%); cancer 85 (33.5%); and other causes 98 (38.5%). Compared with the reference category with adequate iodine nutrition (UI 100-300 μg/L), the hazard ratios (HRs) of all-cause mortality in the category with UI ≥300 μg/L were 1.04 (95% confidence interval [CI 0.54-1.98]); however, in the categories with 50-99 UI and <50 μg/L, the HRs were 1.29 [CI 0.97-1.70] and 1.71 [1.18-2.48], respectively ( for trend 0.004). Multivariate adjustment did not significantly modify the results. Our data indicate an excess mortality in individuals with moderate-severe ID adjusted for other possible confounding factors.
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http://dx.doi.org/10.1089/thy.2020.0131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840306PMC
January 2021

Relationship between environmental temperature and the diagnosis and treatment of gestational diabetes mellitus: An observational retrospective study.

Sci Total Environ 2020 Nov 16;744:140994. Epub 2020 Jul 16.

Department of Endocrinology and Nutrition, Virgen de la Victoria Universitary Hospital, Malaga, Spain.

Introduction: Environmental temperature has been described to affect plasma glucose levels after oral glucose tolerance testing (OGTT).

Aims: We evaluated the relationship between seasons and environmental temperature and gestational diabetes mellitus (GDM) diagnosis and treatment.

Methods: We analyzed data from 2374 women retrospectively. GDM was diagnosed in 473 patients by a 100-g OGTT. OGTT results and needing of insulin therapy were evaluated in relation to seasons and environmental temperature (mean temperature and temperature change) the day of the OGTT and the preceding 14 and 28 days.

Results: We found significant seasonal differences in the percentage of GDM: 24.4% in summer vs. 15.6% in autumn (p < 0.01). The odds ratio (OR) for being diagnosed with GDM was 1.78 in summer relative to autumn, after controlling for age. A higher mean temperature the day of the OGTT and the preceding 14 and 28 days increased the risk of being diagnosed with GDM the months in which temperature was rising (March-August) but not the months in which temperature was decreasing (September-February). We observed a negative correlation between temperature and fasting glucose and a positive correlation with post-load glucose. Neither the season nor the environmental temperature affected the risk of requiring insulin therapy.

Conclusions: There is a higher prevalence of GDM diagnosis at warmer seasons and at rising temperatures the 2-4 weeks prior to the OGTT. The impact of temperature is different between fasting and post-load glucose.
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http://dx.doi.org/10.1016/j.scitotenv.2020.140994DOI Listing
November 2020

miRNA/Target Gene Profile of Endothelial Cells Treated with Human Triglyceride-Rich Lipoproteins Obtained after a High-Fat Meal with Extra-Virgin Olive Oil or Sunflower Oil.

Mol Nutr Food Res 2020 09 23;64(17):e2000221. Epub 2020 Jul 23.

Instituto de Investigación Biomédica de Málaga-IBIMA, 29010, Málaga, Spain.

Scope: The effects of triglyceride-rich lipoproteins (TRLs) on the miRNA expression of endothelial cells, which are very involved in atherosclerosis, according to the type of diet are not known.

Methods And Results: The differences between the effects of TRLs isolated from blood of subjects after a high-fat meal with extra-virgin olive oil (EVOO) and sunflower oil (SO) on the microRNA-Seq profile related to atherosclerosis in human umbilical vein endothelial cells are analyzed. 28 upregulated microRNAs with EVOO-derived TRLs, which can regulate 22 genes related to atherosclerosis, are found. 21 upregulated microRNAs with SO-derived TRLs, which can regulate 20 genes related to atherosclerosis, are found. These microRNAs are mainly involved in angiogenesis, with a predominance of an anti-angiogenic effect with EVOO-derived TRLs. Other microRNAs upregulated with SO-derived TRLs are involved in cardiovascular diseases. Pathways for the target genes obtained from the upregulated microRNA with EVOO-derived TRLs are involved in lipid metabolism and inflammatory and defense response, while those with SO-derived TRLs are involved in lipid metabolic process.

Conclusion: EVOO-derived TRLs seem to produce a more atheroprotective profile than SO-derived TRLs. This study provides alternative mechanisms on the protective role of EVOO against the atherogenic process through microRNA regulation in endothelial cells.
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http://dx.doi.org/10.1002/mnfr.202000221DOI Listing
September 2020

Mucosa-associated microbiota in the jejunum of patients with morbid obesity: alterations in states of insulin resistance and metformin treatment.

Surg Obes Relat Dis 2020 Oct 18;16(10):1575-1585. Epub 2020 Apr 18.

Unidad de Gestión Clínica de Endocrinología y Nutrición del Hospital Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga, Universidad de Málaga, Málaga, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición, CIBERobn, Madrid, Spain. Electronic address:

Background: Stool samples have been widely used to evaluate gut microbiota; however, little is known about the composition of human small intestinal microbiota and the alterations provoked by insulin resistance.

Objective: To describe the composition of jejunal microbiota in morbidly obese patients, as well as its link with insulin resistance and metformin treatment.

Setting: Virgen de la Victoria University Hospital and Regional University Hospital, Málaga, Spain.

Methods: Jejunal biopsies from 46 morbidly obese patients were analyzed by next-generation sequencing method. Patients were classified in the following 3 groups: low homeostasis model assessment of insulin resistance index (HOMA-IR) value, high HOMA-IR value, and metformin-treated type 2 diabetes patients (T2D-metf).

Results: Richness (q = .011) together with Proteobacteria (W = 2), Fusobacteria (W = 2), and Bacteroidetes (W = 1) phyla were significantly higher in high HOMA-IR compared with low HOMA-IR group. At family level, several differences were found between low HOMA-IR and T2D-metf group, being the most important the higher abundance of Halomonadacea in T2D-metf group (W = 22). PICRUSt analysis showed that predicted genes involved in trimethylamine-N-oxide biosynthesis pathway could be increased in jejunal microbiota of T2D-metf group compared with the low HOMA-IR group, while indole biosynthesis pathway could be increased in the low HOMA-IR group compared with the high HOMA-IR group.

Conclusion: An increase in richness and an enrichment in Proteobacteria, Fusobacteria, and Bacteroidetes was observed in jejunal from morbidly obese patients with high insulin resistance. Halomonadaceae family was significantly increased in metformin-treated patients. Functional analysis of predicted metagenome suggests that trimethylamine-N-oxide biosynthesis pathway could be increased in the jejunal microbiota of T2D-meft group, while indole biosynthesis pathway could be increased in low HOMA-IR group. These results contribute to the increase in the scarce knowledge about the mucosal microbiota of the hardly accessible small intestine.
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http://dx.doi.org/10.1016/j.soard.2020.04.008DOI Listing
October 2020

Incidental Prophylactic Appendectomy Is Associated with a Profound Microbial Dysbiosis in the Long-Term.

Microorganisms 2020 Apr 23;8(4). Epub 2020 Apr 23.

Unidad de Gestión Clínica de Endocrinología y Nutrición del Hospital Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, 29010 Málaga, Spain.

Incidental prophylactic surgeries are performed in certain situations. Incidental prophylactic appendectomies were common practice within opened bariatric surgeries. The gut microbiota has emerged as an important actor within the homeostasis of the host. A new hypothesis has been formulated about the appendix function in relation to gut microbiota. Our objective was to study the gut microbiota profiles of patients that had suffered from an incidental prophylactic appendectomy during their bariatric surgeries, while comparing them to patients whose appendixes had remained intact. A case-control observational prospective study of 40 patients who underwent bariatric surgery, with or without an incidental prophylactic appendectomy, during 2004-2008 with an evaluation of their gut microbiota populations at the end of 2016 was conducted by sequencing the 16 S rRNA gene by Next Generation Sequencing of patients' stools and appendix tissues. Patients with their appendix removed showed lower levels of richness and diversity of their gut microbiota populations. , , , and levels were increased in the Intact group, while suffered an expansion in the group without the appendix. Moreover, a linear regression introduced the concept that and may be implicated in insulin regulation. Thus, gut microbiota should be considered in the decisions of practical surgery, regarding the appendix as a mediator of homeostasis in the host. and require further investigation as key bacteria implicated in insulin regulation.
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http://dx.doi.org/10.3390/microorganisms8040609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7232405PMC
April 2020

Jejunal Insulin Signalling Is Increased in Morbidly Obese Subjects with High Insulin Resistance and Is Regulated by Insulin and Leptin.

J Clin Med 2020 Jan 10;9(1). Epub 2020 Jan 10.

Instituto de Investigación Biomédica de Málaga-IBIMA, 29009 Málaga, Spain.

Little is known about the jejunal insulin signalling pathways in insulin resistance/diabetes states and their possible regulation by insulin/leptin. We study in jejunum the relation between insulin signalling and insulin resistance in morbidly obese subjects with low (MO-low-IR) or with high insulin resistance (MO-high-IR), and with type 2 diabetes treated with metformin (MO-metf-T2DM)), and the effect of insulin/leptin on intestinal epithelial cells (IEC). Insulin receptor substrate-1 (IRS1) and the catalytic p110β subunit (p110β) of phosphatidylinositol 3-kinase (PI3K) were higher in MO-high-IR than in MO-low-IR. The regulatory p85α subunit of PI3K (p85α)/p110β ratio was lower in MO-high-IR and MO-metf-T2DM than in MO-low-IR. Akt-phosphorylation in Ser473 was reduced in MO-high-IR compared with MO-low-IR. IRS1 and p110-β were associated with insulin and leptin levels. The improvement of body mass index (BMI) and HOMA-IR (homeostasis model assessment of insulin resistance index) after bariatric surgery was associated with a higher IRS1 and a lower p85α/p110β ratio. IEC (intestinal epithelial cells) incubation with a high glucose + insulin dose produced an increase of p85α and p110β. High dose of leptin produced an increase of IRS1, p85α and p110β. In conclusion, despite the existence of insulin resistance, the jejunal expression of genes involved in insulin signalling was increased in MO-high-IR. Their expressions were regulated mainly by leptin. IRS1 and p85α/p110β ratio was associated with the evolution of insulin resistance after bariatric surgery.
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http://dx.doi.org/10.3390/jcm9010196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7019979PMC
January 2020

GRK2 levels in myeloid cells modulate adipose-liver crosstalk in high fat diet-induced obesity.

Cell Mol Life Sci 2020 Dec 11;77(23):4957-4976. Epub 2020 Jan 11.

Departamento de Biología Molecular and Centro de Biología Molecular "Severo Ochoa", Universidad Autónoma de Madrid (CSIC/UAM), C/Nicolás Cabrera 1, 28049, Madrid, Spain.

Macrophages are key effector cells in obesity-associated inflammation. G protein-coupled receptor kinase 2 (GRK2) is highly expressed in different immune cell types. Using LysM-GRK2 mice, we uncover that a reduction of GRK2 levels in myeloid cells prevents the development of glucose intolerance and hyperglycemia after a high fat diet (HFD) through modulation of the macrophage pro-inflammatory profile. Low levels of myeloid GRK2 confer protection against hepatic insulin resistance, steatosis and inflammation. In adipose tissue, pro-inflammatory cytokines are reduced and insulin signaling is preserved. Macrophages from LysM-GRK2 mice secrete less pro-inflammatory cytokines when stimulated with lipopolysaccharide (LPS) and their conditioned media has a reduced pathological influence in cultured adipocytes or naïve bone marrow-derived macrophages. Our data indicate that reducing GRK2 levels in myeloid cells, by attenuating pro-inflammatory features of macrophages, has a relevant impact in adipose-liver crosstalk, thus preventing high fat diet-induced metabolic alterations.
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http://dx.doi.org/10.1007/s00018-019-03442-5DOI Listing
December 2020

Gut microbiota adaptation after weight loss by Roux-en-Y gastric bypass or sleeve gastrectomy bariatric surgeries.

Surg Obes Relat Dis 2019 Nov 11;15(11):1888-1895. Epub 2019 Sep 11.

Department of Endocrinology and Nutrition, Virgen de la Victoria University Hospital, Institute of Biomedical Research in Malaga (IBIMA) and University of Malaga, Malaga, Spain; Centro de Investigación Biomédica en Red de la Fisiopatología de la Obesidad y Nutrición (CIBEROBN CB06/003), Instituto de Salud Carlos III, Madrid, Spain. Electronic address:

Background: Gut microbiota could be involved in the metabolic improvement after surgery.

Objective: The aim of the present study was to evaluate the short-term evolution of the gut microbiome after different bariatric surgery procedures and their functionality and relate it with obesity resolution.

Setting: University hospital, Spain.

Methods: We studied 28 patients with severe obesity; 14 underwent a Roux-en-Y gastric bypass (RYGB) and 14 underwent laparoscopic sleeve gastrectomy (SG). All patients were examined before and 3 months after the correspondent bariatric surgery. Gut microbiome profile was assessed by the sequencing of amplicons from the 16S rDNA gene by next-generation sequencing.

Results: Gut microbiota profiles significantly differed between surgical procedures. RYGB suffered the largest changes in the microbiota population. SG and RYGB differed in their profiles with higher levels of Akkermansia, Eubacterium, Haemophilus, and Blautia for SG, while Veillonella, Slackia, Granucatiella, and Acidaminococcus occurred with greater levels in RYGB. RYGB microbiota changes were reflected also at the level of functionality, especially in pathways related to environmental adaptation. A biomarker discovery analysis revealed the genus Blautia as characteristic in SG, while Veillonella was of RYGB.

Conclusion: Our study shows a shift of the gut microbiome after a bariatric surgery in a procedure-related manner. Gut microbiome changes are related to the adaptation to the changing gut environment and could be related to the pH fluctuations.
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http://dx.doi.org/10.1016/j.soard.2019.08.551DOI Listing
November 2019

Effect of Synbiotic Supplementation in a Very-Low-Calorie Ketogenic Diet on Weight Loss Achievement and Gut Microbiota: A Randomized Controlled Pilot Study.

Mol Nutr Food Res 2019 10 29;63(19):e1900167. Epub 2019 Aug 29.

Unidad de Gestión Clínica de Endocrinología y Nutrición del Hospital Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, Málaga, 29010, Spain.

Scope: Little is known about the changes that a very-low-calorie ketogenic diet (VLCKD) produces in gut microbiota or the effect of synbiotics during the diet. The aim of this study is to evaluate changes in gut microbiota produced by a VLCKD and synbiotic supplementation.

Methods And Results: A randomized, single-blind, parallel-design trial is conducted in 33 obese patients who follow a weight-loss program (PnK-Method) that include a VLCKD followed by a low-calorie diet (LCD). Subjects are randomly allocated to three groups: one supplemented with synbiotics, a second group supplemented with a placebo during the VLCKD and synbiotics during the LCD phase, and a control group given a placebo. Although symbiotic administration do not produce an effect on microbial diversity, an increase in short-chain fatty aciding producing bacteria and anti-inflammatory mediator signals such as Odoribacter and Lachnospira is shown. The administration of Bifidobacterium animalis subsp. lactis and prebiotics fiber during the LCD is significantly associated with the percentage of weight loss and change in glucose, C-reactive protein and lipopolysaccharide-binding protein.

Conclusions: VLCKD produces important changes in gut microbiota. The administration of synbiotics during VLCKD can improve weight loss through the amelioration of inflammation, which may be mediated by the gut microbiota.
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http://dx.doi.org/10.1002/mnfr.201900167DOI Listing
October 2019

Eradication Treatment Alters Gut Microbiota and GLP-1 Secretion in Humans.

J Clin Med 2019 Apr 4;8(4). Epub 2019 Apr 4.

Department of Endocrinology and Nutrition, Virgen de la Victoria Hospital (IBIMA), Malaga University, 29010 Malaga, Spain.

Changes in the intestinal microbial community and some metabolic disturbances, including obesity and type2 diabetes, are related. Glucagon-like peptide-1 (GLP-1) regulates glucose homeostasis. Microbiota have been linked to incretin secretion. Antibiotic use causes changes in microbial diversity and composition. Our aim was to evaluate the relationship between microbiota changes and GLP-1 secretion. A prospective case-control study with a -positive patient model involving subjects under eradication therapy (omeprazole, clarithromycin, and amoxicillin). Forty patients with infection and 20 matched participants, but negative for antigen. Patients were evaluated before and two months after treatment. We analyzed anthropometric measurements, carbohydrate metabolism, lipid profile, and C-reactive protein. Gut microbiota composition was analyzed through 16S rRNA amplicon sequencing (IlluminaMiSeq). Eradication treatment for decreased bacterial richness (Chao1, 0.041). Changes in gut microbiota profiles were observed at phylum, family, genus and species levels. GLP-1 secretion and variables of carbohydrate metabolism were improved. Correlations were seen between GLP-1 changes and variations within microbial community abundances, specifically , the genus, and family. A conventional treatment to eradicate could improve carbohydrate metabolism possibly in relation with an increase in GLP-1 secretion. GLP-1 secretion may be related to alterations in intestinal microbiota, specifically and .
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http://dx.doi.org/10.3390/jcm8040451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6517938PMC
April 2019

Gut microbiota specific signatures are related to the successful rate of bariatric surgery.

Am J Transl Res 2019 15;11(2):942-952. Epub 2019 Feb 15.

Unidad de Gestión Clínica de Endocrinología y Nutrición del Hospital Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga Málaga, Spain.

Bariatric surgery (BS) success rates vary in the long-time. A better understanding of weight-loss response may help improve the outcomes of BS. Gut microbiome could be implicated in the successful rate of BS. The aim of the study is to analyze the role of gut microbiome in the successful rate of BS. This is a cross-sectional study of a prospective cohort of 24 patients who underwent gastric bypass. Patients were classified based on excess weight loss (EWL) as: Success (EWL50% at nadir weight and throughout follow-up), Primary Failure (EWL<50% at nadir weight and thereafter), and Weight Regain (EWL>50% at nadir weight, but <50% at last follow-up visit). Gut microbiome analysis was assessed by High Throughput Sequencing. Cholesterol metabolism was shown as the most affected parameter among groups. Studied groups registered minor changes between their gut microbiome abundances, with and among them. However, Success group shared a more diverse core microbiome than the other groups. We showed evidence of a possible role of gut microbiome in the cholesterol metabolism, possibly through bile acids, relative to the success or failure of BS outcomes. and from Primary Failure core microbiome, could have implications in its successful rate. abundance was presented as the best genera related to the body mass index (BMI) post-surgery. Gut microbiota could mediate, at least partially, the success rate of BS through their interaction with the bile acids milieu. Further studies are necessary to validate this probe of concept.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413284PMC
February 2019

The changes in the transcriptomic profiling of subcutaneous adipose tissue after bariatric surgery depend on the insulin resistance state.

Surg Obes Relat Dis 2018 Aug 24;14(8):1182-1191. Epub 2018 Apr 24.

Unidad de Gestión Clínica de Aparato Digestivo, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Virgen de la Victoria, Málaga, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Málaga, Spain. Electronic address:

Background: The changes that are produced in the gene expression of subcutaneous adipose tissue after Roux-en-Y gastric bypass are not yet fully known.

Objective: To identify the changes in the subcutaneous adipose tissue gene expression of morbidly obese women with low insulin resistance (MO-low-IR) and high insulin resistance (MO-high-IR) to find a relationship with measured obesity-related co-morbidities.

Setting: A university hospital.

Methods: Subcutaneous adipose tissue samples were assessed by microarray analysis before and 2 years after Roux-en-Y gastric bypass in MO-low-IR and MO-high-IR patients.

Results: There is a group of shared differentially expressed genes (DEG) in both MO-low-IR and MO-high-IR, also there is a group of exclusive DEG in MO-low-IR and another group in MO-high-IR. In MO-high-IR, the downexpressed DEG are related to the regulation of transcription and are involved in the pathways related to cytokine-cytokine receptor interaction, cancer, phosphatidylinositol 3-kinase-protein kinase B signaling, human T-lymphotropic virus I infection, chemokine signaling, and Janus kinase/signal transducers and activators of transcription signaling. In MO-low-IR, the overexpressed DEG are related to carbohydrate metabolic processes, the downexpressed DEG to the glycosaminoglycan metabolic process and regulation of translation, and the pathways are related to phosphatidylinositol 3-kinase-protein kinase B signaling and metabolic pathways. The fold change of DEG mainly correlates with the percentage of change (Δ) of waist, Δhip, Δglucose, and Δtriglycerides. These DEG were mainly related to cancer, inflammation/immune regulation, metabolic pathways, ribonucleic acid/deoxyribonucleic acid regulation, virus infection, and regulation of cellular proliferation.

Conclusions: This study suggests a potential association between high insulin resistance and the expression of genes related to cancer and chronic immune activation/inflammation.
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http://dx.doi.org/10.1016/j.soard.2018.04.010DOI Listing
August 2018

Iron deficiency is associated with Hypothyroxinemia and Hypotriiodothyroninemia in the Spanish general adult population: [email protected] study.

Sci Rep 2018 04 26;8(1):6571. Epub 2018 Apr 26.

Department of Endocrinology and Nutrition, Hospital Regional Universitario de Málaga, IBIMA, Málaga, Spain.

Previous studies have suggested that iron deficiency (ID) may impair thyroid hormone metabolism, however replication in wide samples of the general adult population has not been performed. We studied 3846 individuals free of thyroid disease, participants in a national, cross sectional, population based study representative of the Spanish adult population. Thyroid stimulating hormone (TSH), free thyroxin (FT4) and free triiodothyronine (FT3) were analyzed by electrochemiluminescence (E170, Roche Diagnostics). Serum ferritin was analyzed by immunochemiluminescence (Architect I2000, Abbott Laboratories). As ferritin levels decreased (>100, 30-100, 15-30, <15 µg/L) the adjusted mean concentrations of FT4 (p < 0.001) and FT3 (p < 0.001) descended, whereas TSH levels remained unchanged (p = 0.451). In multivariate logistic regression models adjusted for age, sex, UI, BMI and smoking status, subjects with ferritin levels <30 µg/L were more likely to present hypothyroxinemia (FT4 < 12.0 pmol/L p5): OR 1.5 [1.1-2.2] p = 0.024, and hypotriiodothyroninemia (FT3 < 3.9 pmol/L p5): OR 1.8 [1.3-2.6] p = 0.001 than the reference category with ferritin ≥30 µg/L. There was no significant heterogeneity of the results between men, pre-menopausal and post-menopausal women or according to the iodine nutrition status. Our results confirm an association between ID and hypothyroxinemia and hypotriiodothyroninemia in the general adult population without changes in TSH.
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http://dx.doi.org/10.1038/s41598-018-24352-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5919900PMC
April 2018

Tissue-Specific Phenotype and Activation of iNKT Cells in Morbidly Obese Subjects: Interaction with Adipocytes and Effect of Bariatric Surgery.

Obes Surg 2018 09;28(9):2774-2782

Unidad de Gestión Clínica de Aparato Digestivo, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Virgen de la Victoria, Malaga, Spain.

Background: The immune response of visceral adipose tissue (VAT) in obesity, in particular the role of invariant natural killer T (iNKT) cells, has not yet been fully elucidated.

Objective: To characterize iNKT cells and its activation status in VAT and peripheral blood mononuclear cells (PBMC) in morbidly obese subjects (MO), and to analyze their association with metabolic parameters.

Subjects And Methods: Twenty non-obese and 20 MO subjects underwent Roux-en-Y gastric bypass (RYGB) and were studied before and 6 months after RYGB. VAT and PBMC were obtained.

Results: A decrease in VAT iNKT cells from MO was found, however, not in PBMC. Visceral adipocytes from MO presented increased CD1d expression (p = 0.032). MO presented an increase in early activated CD69+ iNKT cells in PBMC before RYGB (p < 0.001), but not after RYGB nor in VAT, and an increase in later activated CD25+ iNKT in VAT (p = 0.046), without differences in PBMC. The co-expression of early and later markers (CD69+CD25+) in iNKT cells was increased in MO in VAT (p = 0.050) and PBMC (p = 0.006), decreasing after RYGB (p = 0.050). CD69+ iNKT and CD69+CD25+ iNKT cells in PBMC after RYGB correlated negatively with glucose, insulin, and insulin resistance levels.

Conclusions: There is a tissue-specific phenotype and activation of iNKT cells in VAT in morbid obesity, which could be involved in VAT immunometabolism dysregulation. Also, the increase in CD1d expression could be to offset the lack of VAT iNKT cells.
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http://dx.doi.org/10.1007/s11695-018-3215-yDOI Listing
September 2018

Iodine is associated to semen quality in men who undergo consultations for infertility.

Reprod Toxicol 2017 10 26;73:1-7. Epub 2017 Jul 26.

UGC de Endocrinología y Nutrición, Complejo Hospitalario de Jaén, Jaén, Spain.

The role that adequate iodine intake could have on the male reproductive function is not entirely known. The aim of this study is to determine whether there is a relation between male infertility and urinary and semen iodine levels in 96 couples who underwent consultation for infertility. The median of semen iodine was higher in men who consumed iodized salt than in those who consumed non-iodized salt (p=0.019). Men with a higher semen iodine level had more morphological alterations in spermatozoa (p=0.032). Men with a higher urinary iodine level had a lower motile sperm count according to the "direct swim-up" technique (p=0.044). Men >3years without successfully achieving pregnancy had a higher urinary iodine level than those with ≤ 3years (p=0.035). In conclusion, iodine may play a role in the quality of semen: an increase in semen iodine levels is associated with different variables related to male infertility.
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http://dx.doi.org/10.1016/j.reprotox.2017.07.020DOI Listing
October 2017

Changes in SCD gene DNA methylation after bariatric surgery in morbidly obese patients are associated with free fatty acids.

Sci Rep 2017 04 10;7:46292. Epub 2017 Apr 10.

CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Málaga, Spain.

Stearoyl CoA Desaturase-1 (SCD) is considered as playing an important role in the explanation of obesity. The aim of this study was to evaluate whether the DNA methylation SCD gene promoter is associated with the metabolic improvement in morbidly obese patients after bariatric surgery. The study included 120 subjects with morbid obesity who underwent a laparoscopic Roux-en Y gastric by-pass (RYGB) and a control group of 30 obese subjects with a similar body mass index (BMI) to that found in morbidly obese subjects six months after RYGB. Fasting blood samples were obtained before and at six months after RYGB. DNA methylation was measured by pyrosequencing technology. DNA methylation levels of the SCD gene promoter were lower in morbidly obese subjects before bariatric surgery but increased after RYGB to levels similar to those found in the control group. Changes of DNA methylation SCD gene were associated with the changes of free fatty acids levels (r = -0.442, p = 0.006) and HOMA-IR (r = -0.249, p = 0.035) after surgery. RYGB produces an increase in the low SCD methylation promoter levels found in morbidly obese subjects. This change of SCD methylation levels is associated with changes in FFA and HOMA-IR.
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http://dx.doi.org/10.1038/srep46292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5385880PMC
April 2017

Reference values for TSH may be inadequate to define hypothyroidism in persons with morbid obesity: [email protected] study.

Obesity (Silver Spring) 2017 04 9;25(4):788-793. Epub 2017 Mar 9.

Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.

Objective: To analyze the reference range of thyroid-stimulating hormone (TSH) in different BMI categories and its impact on the classification of hypothyroidism.

Methods: The study included 3,928 individuals free of thyroid disease (without previous thyroid disease, no interfering medications, TSH <10 µUI/mL and thyroid peroxidase antibodies [TPO Abs] <50 IU/mL) who participated in a national, cross-sectional, population-based study and were representative of the adult population of Spain. Data gathered included clinical and demographic characteristics, physical examination, and blood and urine sampling. TSH, free thyroxine, free triiodothyronine, and TPO Ab were analyzed by electrochemiluminescence (E170, Roche Diagnostics, Basel, Switzerland).

Results: The reference range (p2.5-97.5) for TSH was estimated as 0.6 to 4.8 µUI/mL in the underweight category (BMI<20 kg/m ), 0.6 to 5.5 µUI/mL in the normal-weight category (BMI 20-24.9 kg/m ), 0.6 to 5.5 µUI/mL in the overweight category (BMI 25-29.9 kg/m ), 0.5 to 5.9 µUI/mL in the obesity category (BMI 30-39.9 kg/m ), and 0.7 to 7.5 µUI/mL in the morbid obesity category (BMI ≥40). By using the reference criteria for the normal-weight population, the prevalence of high TSH levels increased threefold in the morbid obesity category (P < 0.01).

Conclusions: Persons with morbid obesity might be inappropriately classified if the standard ranges of normality of TSH for the normal-weight population are applied to them.
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http://dx.doi.org/10.1002/oby.21796DOI Listing
April 2017

Jejunal gluconeogenesis associated with insulin resistance level and its evolution after Roux-en-Y gastric bypass.

Surg Obes Relat Dis 2017 Apr 2;13(4):623-630. Epub 2016 Dec 2.

Unidad de Gestión Clínica de Aparato Digestivo, Instituto de Investigación Biomédica de Málaga/Hospital Clínico Virgen de la Victoria, Málaga, Spain; CIBEROBN, Instituto de Salud Carlos III, Málaga, Spain. Electronic address:

Background: Intestinal gluconeogenesis (GNG) may play an important role in glucose homeostasis, but there is little information about the condition in humans.

Objectives: To study the relationship between intestinal GNG and insulin resistance, its association with the evolution of morbidly obese patients after bariatric surgery, and the effect of insulin and or leptin.

Setting: Regional university hospital, Malaga (Spain).

Methods: Jejunal mRNA expression of genes involved in GNG was analyzed in 3 groups of morbidly obese patients who underwent Roux-en-Y gastric bypass: with low insulin resistance (MO-low-IR), with high insulin resistance (MO-high-IR), and with type 2 diabetes treated with metformin (MO-metf-T2D). Also, intestinal epithelial cells (IEC) from MO-low-IR were incubated with different doses of insulin and or leptin.

Results: In MO-high-IR, glutaminase, phosphoenolpyruvate carboxykinase (PEPCK), glucose 6-phosphatase (G6 Pase), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1 α), and sterol regulatory element-binding proteins 1 c (SREBP-1 c) expressions were significantly higher than in MO-low-IR. In MO-metf-T2 D, only PEPCK was significantly lower than in MO-high-IR. In IEC, an incubation with a high glucose and insulin dose produced an increase of PEPCK and SREBP-1 c, and a decrease of glutaminase, fructose 1,6-bisphosphatase (FBPase), and PGC-1 α expression. At high doses of leptin, G6 Pase and FBPase were significantly increased. The improvement of insulin resistance 3 months after bariatric surgery was positively associated with high G6 Pase and FBPase expression.

Conclusion: mRNA expression of genes involved in GNG is increased in the jejunum of MO-high-IR, and regulated by insulin and or leptin. High mRNA expression of genes involved in GNG is associated with a better evolution of insulin resistance after bariatric surgery.
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http://dx.doi.org/10.1016/j.soard.2016.11.021DOI Listing
April 2017

Population-Based National Prevalence of Thyroid Dysfunction in Spain and Associated Factors: [email protected] Study.

Thyroid 2017 02 4;27(2):156-166. Epub 2017 Jan 4.

1 Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III , Madrid, Spain .

Background: The aim of this study was to investigate the national prevalence of thyroid dysfunction in Spain and its association with various clinical, environmental, and demographic variables.

Methods: The study included 4554 subjects (42.4% men) with a mean age of 50 years (range 18-93 years), who were participants in a national, cross-sectional, population-based survey conducted in 2009-2010. Data gathered included clinical and demographic characteristics, physical examination, and blood sampling. Thyrotropin, free thyroxine, free triiodothyronine, and thyroid peroxidase antibody (TPOAb) concentrations were analyzed by electrochemiluminescence. Urinary iodine (UI) levels were measured in an isolated urine sample.

Results: The prevalence of treated hypothyroidism, untreated subclinical hypothyroidism, and untreated clinical hypothyroidism was 4.2% [confidence interval (CI) 3.6-4.9%], 4.6% [CI 4.0-5.2%], and 0.3% [CI 0.1-0.5%], respectively. The prevalence of total hypothyroidism (including all fractions) was 9.1% [CI 8.2-10.0%]. The prevalence of total hyperthyroidism was 0.8% [CI 0.6-1.1]. A total of 7.5% [CI 6.7-8.3%] of the population tested positive for TPOAbs (≥50 IU/mL). In multivariate logistic regression models, TPOAbs were strongly associated with both hypothyroidism (p < 0.001) and hyperthyroidism (p = 0.005), whereas high UI levels (>200 μg/g creatinine) were associated with hypothyroidism (p < 0.001). The positive association between UI and hypothyroidism remained for both treated (p < 0.001) and untreated (p < 0.05) hypothyroidism, whereas it was especially significant for non-autoimmune (TPOAbs negative) forms (p < 0.001). At UI levels ≥200 μg/g, there was a positive correlation between UI and thyrotropin levels (β = 0.152, p < 0.001) and a negative correlation between UI and free triiodothyronine levels (β = -0.134, p = 0.001).

Conclusion: According to the data, a large proportion (10%) of the Spanish population has some evidence of thyroid dysfunction. High TPOAb concentrations were associated with both hypo- and hyperthyroidism, whereas high UI concentrations were associated with hypothyroidism.
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http://dx.doi.org/10.1089/thy.2016.0353DOI Listing
February 2017

The pro-/anti-inflammatory effects of different fatty acids on visceral adipocytes are partially mediated by GPR120.

Eur J Nutr 2017 Jun 14;56(4):1743-1752. Epub 2016 Jun 14.

Unidad de Gestión Clínica de Endocrinología y Nutrición, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario, Málaga, Spain.

Purpose: This study examines whether G-protein coupled receptor 120 (GPR120) is involved in the pro-/anti-inflammatory effects of different types of fatty acids (FAs) in human visceral adipocytes, and whether these effects may be altered in obesity, a state with a chronic inflammation.

Methods: Pro-/anti-inflammatory effects of palmitic, oleic, linoleic and docosahexaenoic acids on human visceral adipocytes were tested in mature adipocytes from non-obese and morbidly obese (MO) subjects. Also, the effects of these FAs were tested when the GPR120 gene was silenced.

Results: In adipocytes from non-obese subjects, palmitic and linoleic acids increased TNF-α and IL-6 mRNA expression (p < 0.05), and decreased IL-10 and adiponectin expression (p < 0.05). However, oleic and docosahexaenoic acids (DHA) produced the opposite effect (p < 0.05). In adipocytes from MO subjects, all FAs used increased TNF-α and IL-6 expression (p < 0.05). Palmitic and linoleic acids decreased IL-10 and adiponectin expression (p < 0.05), but oleic acid and DHA did not have significant effects. Only oleic acid increased adiponectin expression (p < 0.05). The effects of FAs on TNF-α, IL-6, IL-10 and adiponectin expression in non-obese and MO subjects were significantly annulled when the GPR120 gene was silenced in visceral adipocytes differentiated from human mesenchymal stem cells.

Conclusions: FAs are capable of directly acting on visceral adipocytes to modulate differently TNF-α, IL-6, IL-10 and adiponectin expression, with a different and greater effect in MO subjects. These effects are largely annulled when GPR120 expression was silenced, which suggests that they could be mediated by GPR120.
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http://dx.doi.org/10.1007/s00394-016-1222-0DOI Listing
June 2017

Bioactive Components in Human Milk Along the First Month of Life: Effects of Iodine Supplementation during Pregnancy.

Ann Nutr Metab 2016 30;68(2):130-6. Epub 2016 Jan 30.

Pediatrics, Obstetrics and Gynecology Unit, Riotinto Hospital, Andalusian Health Service, Huelva, Spain.

Background/aims: Human milk is considered the most suitable food for infants. The potential benefits of breastfeeding can be explained by the presence of different growth and neurotrophic factors in human milk. This study was designed to detect some biomarkers in human milk, which could be involved in the infant neurodevelopment and in the regulation of the maturation of neonatal intestine (brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), glial fibrillary acidic protein (GFAP), fibroblast growth factor 21 (FGF21), lysophosphatidic acid (LPA) and autotaxin (ATX)), and compare them on the basis of the consumption of iodine supplements or multivitamins.

Methods: A prospective study included 37 healthy breastfeeding mothers, divided into 3 different groups: (1) 10 mothers who did not take supplements, (2) 17 mothers who took potassium iodine (KI) 200 µg/day and (3) 10 mothers who took a multivitamin supplement.

Results: The concentrations of BDNF, GDNF, GFAP, FGF21, LPA and ATX in human milk were not significantly different in women who took a multivitamin or KI supplement compared with those who did not take any supplement.

Conclusions: The presence of neurotrophic factors in human milk is neither modified by the consumption of supplements nor by their type.
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http://dx.doi.org/10.1159/000443800DOI Listing
October 2016

Thyroid Function and Thyroid Autoimmunity in Relation to Weight Status and Cardiovascular Risk Factors in Children and Adolescents: A Population-Based Study.

J Clin Res Pediatr Endocrinol 2016 Jun 18;8(2):157-62. Epub 2015 Jan 18.

Hospital Torrecárdenas, Clinic of Pediatrics, Almeria, Spain Phone: +34 605076059 E-mail:

Objective: In obese subjects, slight increases have been observed in thyrotropin [thyroid-stimulating hormone (TSH)] levels, but data in children are scarce. The aim of this study was to evaluate whether thyroid function and autoimmunity vary with weight status in a healthy population of children and adolescents and to determine whether hyperthyrotropinemia is associated with any cardiovascular risk factor.

Methods: This cross-sectional epidemiological study was conducted in Almería (Spain) on a representative sample of 1317 healthy subjects aged 2-16 years. Thyroid function, thyroid autoimmunity and cardiovascular risk factors were measured. Chi-square test, analysis of variance and multiple linear regression were used in the statistical analyses.

Results: The obese children and adolescents had thyrotropin levels (mean ± standard deviation) of 3.12±2.44 mU/L. These levels were higher than those of overweight subjects (2.79±1.51 mU/L) and of normal weight subjects (2.73±1.30 mU/L) (p=0.02). Levels of free thyroxine and urinary iodine did not differ significantly between the groups. The prevalence (95% confidence interval) of thyroid autoimmunity was lower in the individuals with normal weight (2.9%; 2.0-4.2) than in the overweight (6.3%; 3.9-9.9) and obese subjects (5.6%, 2.5-11.3) (p=0.02). TSH levels were associated with obesity (β=0.36; p<0.001) and thyroid autoimmunity (β=1.10; p<0.001). They were not associated with any cardiovascular risk factor.

Conclusion: Obese children and adolescents had higher levels of thyrotropin than those who were overweight and of normal weight. The differences among the groups were of very little clinical significance and could possibly be linked to the higher prevalence of thyroid autoimmunity in obese subjects. The hyperthyrotropinemia in these subjects was not associated with any cardiovascular risk factor.
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http://dx.doi.org/10.4274/jcrpe.2687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5096470PMC
June 2016

Hypoxia is associated with a lower expression of genes involved in lipogenesis in visceral adipose tissue.

J Transl Med 2015 Nov 30;13:373. Epub 2015 Nov 30.

CIBEROBN, Institute of Health Carlos III, Malaga, Spain.

Background: A key role for HIF-1α in the promotion and maintenance of dietary obesity has been proposed. We analyzed the association between hypoxia and de novo lipogenesis in human adipose tissue.

Methods: We studied HIF-1α mRNA and protein expression in fasting status in visceral adipose tissue (VAT) from non-obese and morbidly obese subjects, and in VAT from wild-type and ob/ob C57BL6J mice in both fasting and feeding status. We also analyzed the effect of hypoxia on the VAT mRNA expression of genes involved in lipogenesis.

Results: HIF-1α was increased in VAT from morbidly obese subjects. In fasting status, C57BL6J ob/ob mice had a higher VAT HIF-1α mRNA expression than C57BL6J wild-type mice. In feeding status, VAT HIF-1α mRNA expression significantly increased in C57BL6J wild-type, but not in C57BL6J ob/ob mice. In humans, HIF-1α mRNA expression correlated positively with body mass index and insulin resistance. VAT HIF-1α mRNA expression correlated negatively with ACC1, PDHB and SIRT3 mRNA expression, and positively with PPAR-γ. VAT explants incubated in hypoxia showed reduced SIRT3 and increased PPAR-γ, SREBP-1c, ACLY, ACC1 and FASN mRNA expression.

Conclusions: Morbidly obese subjects have a higher level of VAT HIF-1α. Postprandial status is associated with an increase in HIF-1α mRNA expression in C57BL6J wild-type mice. Hypoxia alters the mRNA expression of genes involved in de novo lipogenesis in human VAT.
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http://dx.doi.org/10.1186/s12967-015-0732-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4663723PMC
November 2015

Effect of Roux-en-Y gastric bypass-induced weight loss on the transcriptomic profiling of subcutaneous adipose tissue.

Surg Obes Relat Dis 2016 Feb 13;12(2):257-63. Epub 2015 Jul 13.

Unidad de Gestión Clínica de Endocrinología y Nutrición, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario, Málaga, Spain; CIBER Fisiopatología de la Obesidad y Nutrición Asociadas (CIBEROBN), Málaga, Spain. Electronic address:

Background: The changes in the transcriptomic profiling of subcutaneous adipose tissue (SAT) when weight loss stabilizes after a Roux-en-Y gastric bypass (RYGB) are still largely unknown.

Objectives: To investigate the changes produced in SAT gene expression of morbidly obese women when their weight loss stabilizes 2 years after RYGB.

Setting: University hospital.

Methods: SAT biopsies of the periumbilical area were taken before and 2 years after RYGB. Gene expression levels were assessed by microarray analysis and significant differences in gene expression were validated by real-time quantitative polymerase chain reaction. The findings were also confirmed in an independent population of morbidly obese women.

Results: Microarray analysis revealed that the overexpressed differentially expressed genes have a prominent role in the pathways involved in biosynthetic processes, especially lipid or carboxylic ones (stearoyl-Coenzyme A desaturase-1, fatty acid desaturase-1, fatty acid elongase-6, ATP citrate lyase, fatty acid synthase, lipin-1, monoacylglycerol O-acyltransferase, patatin-like phospholipase domain containing-3, phosphate cytidylyltransferase-2, cholesteryl ester transfer protein, transmembrane 7 superfamily member 2, pyruvate carboxylase, and glycogen synthase 2). Most of the underexpressed differentially expressed genes are related with immune system and inflammation processes (immune responses, response to stress, cell death, regulation of biological quality, immune effector process, the response to endogenous stimulus, and the response to other types of stimulus).

Conclusion: An improvement of the SAT inflammatory and immune profile and an induction of genes involved in the regulation of lipid metabolism are shown when weight loss stabilizes 2 years after RYGB. Most of the genes shown are clearly linked to obesity and other metabolic disorders.
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http://dx.doi.org/10.1016/j.soard.2015.07.007DOI Listing
February 2016

The expression of genes involved in jejunal lipogenesis and lipoprotein synthesis is altered in morbidly obese subjects with insulin resistance.

Lab Invest 2015 Dec 14;95(12):1409-17. Epub 2015 Sep 14.

CIBEROBN, Instituto de Salud Carlos III, Málaga, Spain.

The dyslipidemia associated with type 2 diabetes mellitus (T2DM) is an important risk factor for atherosclerotic cardiovascular disease. However, until now little attention has been paid to the role that the intestine might have. The aim of this research was to determine the relation between insulin resistance and intestinal de novo lipogenesis/lipoprotein synthesis in morbidly obese subjects and to study the effect of insulin on these processes. Jejunal mRNA expression of the different genes involved in the intestinal de novo lipogenesis/lipoprotein synthesis was analyzed in three groups of morbidly obese subjects: Group 1 with low insulin resistance (MO-low-IR), group 2 with high insulin resistance (MO-high-IR), and group 3 with T2DM and treatment with metformin (MO-metf-T2DM). In addition, intestinal epithelial cells (IECs) from MO-low-IR were incubated with different doses of insulin/glucose. In Group 2 (MO-high-IR), the jejunal mRNA expression levels of apo A-IV, ATP-citrate lyase (ACLY), pyruvate dehydrogenase (lipoamide) beta (PDHB), and sterol regulatory element-binding protein-1c (SREBP-1c) were significantly higher and acetyl-CoA carboxylase alpha (ACC1) and fatty-acid synthase lower than in Group 1 (MO-low-IR). In Group 3 (MO-metf-T2DM), only the ACLY and PDHB mRNA expressions were significantly higher than in Group 1 (MO-low-IR). The mRNA expression of most of the genes studied was significantly linked to insulin and glucose levels. The incubation of IEC with different doses of insulin and glucose produced a higher expression of diacylglycerol acyltransferase 2, microsomal triglyceride transfer protein, apo A-IV, SREBP-1c, and ACC1 when both, glucose and insulin, were at a high concentration. However, with only high insulin levels, there were higher apo A-IV, PDHB and SREBP-1c expressions, and a lower ACLY expression. In conclusion, the jejunum of MO-high-IR has a decreased mRNA expression of genes involved in de novo fatty-acid synthesis and an increase of genes involved in acetyl-CoA and lipoprotein synthesis. This effect is attenuated by metformin. In addition, the expression of most of the genes studied was found to be regulated by insulin.
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http://dx.doi.org/10.1038/labinvest.2015.115DOI Listing
December 2015

C-peptide modifies leptin and visfatin secretion in human adipose tissue.

Obesity (Silver Spring) 2015 Aug 6;23(8):1607-15. Epub 2015 Jul 6.

Unidad De Gestión Clínica De Endocrinología Y Nutrición, Instituto De Investigacion Biomédica De Málaga (IBIMA), Hospital Regional Universitario, Málaga, Spain.

Objective: The effects of C-peptide on adipose tissue, an organ involved in the development of obesity and insulin resistance, are not yet well known. The aim of this study was to determine whether C-peptide could be involved in the regulation of the adipocytokine synthesis in human visceral adipose tissue.

Methods: The association between C-peptide and different serum adipocytokines, with an intravenous glucose tolerance test (IVGTT), and in an in vitro study in subjects without obesity and in subjects with morbid obesity were analyzed.

Results: In different multiple regression analysis models, C-peptide and C-peptide increase above basal levels during total IVGTT and between 0 and 10 min were associated positively with leptin and negatively with visfatin. Rhodamine-labeled C-peptide binds to human adipocytes, and this binding was blocked with excess of unlabeled C-peptide. Exposure of human visceral explants and adipocytes from subjects with morbid obesity to C-peptide at 1 and 10 nM induced a significant increase in leptin and a decrease in visfatin secretion. In subjects without obesity, these C-peptide effects were found mainly at 10 nM. These effects can be inhibited by phosphatidylinositol 3-kinase (PI3K) or protein kinase B (PKB) inhibitors.

Conclusions: C-peptide may be involved in the regulation of leptin and visfatin secretion, molecules intimately involved in energy homeostasis processes, through PI3K or PKB pathways.
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http://dx.doi.org/10.1002/oby.21137DOI Listing
August 2015

Night-time sleep duration and the incidence of obesity and type 2 diabetes. Findings from the prospective Pizarra study.

Sleep Med 2014 Nov 11;15(11):1398-404. Epub 2014 Aug 11.

Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Spain; UGCI de Endocrinología y Nutrición, Hospital Regional Universitario, Málaga, Spain; Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain.

Background: Several recent studies have related short sleep duration with different health problems, though the results related with the risk of obesity and type 2 diabetes (T2D) are far from conclusive. The aim of this study was to investigate the association between night-time sleep duration and the incidence of obesity and T2D in a prospective study with a follow-up of 11 years.

Material And Methods: The study comprised 1145 people evaluated in 1997-1998 and re-evaluated after 6 years and 11 years. At the three study points, subjects without known diabetes mellitus (KDM) were given an oral glucose tolerance test (OGTT). Anthropometric and biochemical variables were measured. The subjects were asked about their number of hours of night-time sleep.

Results: After adjustment, the OR of becoming obese was significantly higher in subjects who slept ≤ 7 hours per night, at both the 6-year follow-up (OR = 1.99; 95% CI = 1.12-3.55) and the 11-year follow-up (OR = 2.73; 95% CI = 1.47-5.04). The incidence of T2D at the 6-year follow-up in subjects without T2D at baseline was higher in those who slept ≤ 7 hours per night (OR = 1.96; 95% CI = 1.10-3.50). However, this association was not independent of obesity, weight gain or abnormal glucose regulation at baseline. At the 11-year follow-up however there was no association between night-time sleep duration and the incidence of T2D.

Conclusions: The incidence of obesity over the 11-year follow-up increased in subjects with fewer hours of night-time sleep. The incidence of T2D according to the hours of night-time sleep depended on obesity and the carbohydrate metabolism phenotype.
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http://dx.doi.org/10.1016/j.sleep.2014.06.014DOI Listing
November 2014