La ghrelina, es el ligando endógeno para el receptor de secretagogos de GH. Se ha aislado a part... more La ghrelina, es el ligando endógeno para el receptor de secretagogos de GH. Se ha aislado a partir de estómago, aunque existen otros tejidos que también expresan ghrelina, como es el caso de la hipófisis, hipotálamo, placenta, ovario, testículo, etc. Se ha visto como la ghrelina está implicada en la secreción de GH, tanto in vivo, como in vitro, existen evidencias que demuestran como la administración de ghrelina induce secreción de GH. Existen datos in vivo, donde se demuestra que la potencia secretora de GH de la ghrelina es incluso superior a la que ejerce el GHRH, que hasta hace poco se consideraba el más potente de los secretagogos de GH endógenos. Existen evidencias de la acción reguladora de la ghrelina sobre la ingesta y la homeostasis energética. Existe un papel claro de la ghrelina en las distintas alteraciones alimentarias como en el caso de la obesidad, anorexia y bulimia.
Figure S2. Bland Altman plots of Resting Metabolic Rate (RMR) for Cosmedâ s Fitmate device compar... more Figure S2. Bland Altman plots of Resting Metabolic Rate (RMR) for Cosmedâ s Fitmate device compared to the Deltatrac. (PDF 11 kb)
Patients with Dunnigan disease (FPLD2) with a pathogenic variant affecting exon 8 of the LMNA gen... more Patients with Dunnigan disease (FPLD2) with a pathogenic variant affecting exon 8 of the LMNA gene are considered to have the classic disease, whereas those with variants in other exons manifest the “atypical” disease. The aim of this study was to investigate the degree of variable expressivity when comparing patients carrying the R482 and N466 variants in exon 8. Thus, 47 subjects with FPLD2 were studied: one group of 15 patients carrying the N466 variant and the other group of 32 patients with the R482 variant. Clinical, metabolic, and body composition data were compared between both groups. The thigh skinfold thickness was significantly decreased in the R482 group in comparison with the N466 group (4.2 ± 1.8 and 5.6 ± 2.0 mm, respectively, p = 0.002), with no other differences in body composition. Patients with the N466 variant showed higher triglyceride levels (177.5 [56–1937] vs. 130.0 [55–505] mg/dL, p = 0.029) and acute pancreatitis was only present in these subjects (20%). O...
Extracellular vesicles (EVs) have recently emerged as a relevant way of cell to cell communicatio... more Extracellular vesicles (EVs) have recently emerged as a relevant way of cell to cell communication, and its analysis has become an indirect approach to assess the cell/tissue of origin status. However, the knowledge about their nature and role on metabolic diseases is still very scarce. We have established an insulin resistant (IR) and two lipid (palmitic/oleic) hypertrophied adipocyte cell models to isolate EVs to perform a protein cargo qualitative and quantitative Sequential Window Acquisition of All Theoretical Mass Spectra (SWATH) analysis by mass spectrometry. Our results show a high proportion of obesity and IR-related proteins in pathological EVs; thus, we propose a panel of potential obese adipose tissue EV-biomarkers. Among those, lipid hypertrophied vesicles are characterized by ceruloplasmin, mimecan, and perilipin 1 adipokines, and those from the IR by the striking presence of the adiposity and IR related transforming growth factor-beta-induced protein ig-h3 (TFGBI). In...
The gastrointestinal-brain axis is a key mediator of the body weight and energy homeostasis regul... more The gastrointestinal-brain axis is a key mediator of the body weight and energy homeostasis regulation. Uroguanylin (UGN) has been recently proposed to be a part of this gut-brain axis regulating food intake, body weight and energy expenditure. Expression of UGN is regulated by the nutritional status and dependent on leptin levels. However, the exact molecular mechanisms underlying this UGN-leptin metabolic regulation at a hypothalamic level still remains unclear. Using leptin resistant diet-induced obese (DIO) mice, we aimed to determine whether UGN could improve hypothalamic leptin sensitivity. The present work demonstrates that the central co-administration of UGN and leptin potentiates leptin’s ability to decrease the food intake and body weight in DIO mice, and that UGN activates the hypothalamic signal transducer and activator of transcription 3 (STAT3) and phosphatidylinositide 3-kinases (PI3K) pathways. At a functional level, the blockade of PI3K, but not STAT3, blunted UGN-...
Angiopoietin-like protein 4 (ANGPTL-4) regulates lipidic metabolism and affects energy homeostasi... more Angiopoietin-like protein 4 (ANGPTL-4) regulates lipidic metabolism and affects energy homeostasis. However, its function in children with obesity remains unknown. We investigated plasma ANGPTL-4 levels in children and its relationship with body mass index (BMI) and different lipidic parameters such as free fatty acids (FFA). Plasma ANGPTL-4 levels were analyzed in two different cohorts. In the first cohort (n = 150, age 3–17 years), which included children with normal weight or obesity, we performed a cross-sectional study. In the second cohort, which included only children with obesity (n = 20, age 5–18 years) followed up for two years after an intervention for weight loss, in which we performed a longitudinal study measuring ANGPTL-4 before and after BMI-loss. In the cross-sectional study, circulating ANGPTL-4 levels were lower in children with obesity than in those with normal weight. Moreover, ANGPTL-4 presented a negative correlation with BMI, waist circumference, weight, insu...
Laminopathies are genetic disorders associated with alterations in nuclear envelope proteins, kno... more Laminopathies are genetic disorders associated with alterations in nuclear envelope proteins, known as lamins. The LMNA gene encodes lamins A and C, and LMNA mutations have been linked to diseases involving fat (type 2 familial partial lipodystrophy [FPLD2]), muscle (type 2 Emery-Dreifuss muscular dystrophy [EDMD2], type 1B limb-girdle muscular dystrophy [LGMD1B], and dilated cardiomyopathy), nerves (type 2B1 Charcot-Marie-Tooth disease), and premature aging syndromes. Moreover, overlapping syndromes have been reported. This study aimed to determine the genetic basis of an overlapping syndrome in a patient with heart disease, myopathy, and features of lipodystrophy, combined with severe metabolic syndrome. We evaluated a 54-year-old woman with rheumatoid arthritis, chronic hypercortisolism (endogenous and exogenous), and a history of cured adrenal Cushing syndrome. The patient presented with a complex disorder, including metabolic syndrome associated with mild partial lipodystrophy ...
Limited evidence supports the use of free testosterone (FT) for diagnosing hypogonadism when sex ... more Limited evidence supports the use of free testosterone (FT) for diagnosing hypogonadism when sex hormone binding globulin (SHBG) is altered. Low total testosterone (TT) is commonly encountered in obesity where SHBG is typically decreased. We aimed to assess the contribution of FT in improving the diagnosis of symptomatic secondary hypogonadism (SH), identified initially by low total testosterone (TT), and then further differentiated by normal FT (LNSH) or low FT (LLSH). Prospective observational study with a median follow-up of 4.3 years. 3369 community-dwelling men aged 40-79 years from eight European centres. Subjects were categorised according to baseline and follow-up biochemical status into persistent eugonadal (referent group; n=1880), incident LNSH (eugonadism to LNSH; n=101) and incident LLSH (eugonadism to LLSH; n=38). Predictors and clinical features associated with the transition from eugonadism to LNSH or LLSH were assessed. The cumulative incidence of LNSH and LLSH over...
The enzyme nicotinamide N-methyltransferase (NNMT) is a major methyltransferase in adipose tissue... more The enzyme nicotinamide N-methyltransferase (NNMT) is a major methyltransferase in adipose tissue. We hypothesized an epigenetic signature in association with NNMT gene expression in adipose tissue. The global human methylome was analyzed in visceral adipose tissue (VAT) from morbidly obese patients using the Infinium HumanMethylation450 BeadChip array (discovery cohort: n = 11). The findings were confirmed in two additional independent cohorts (Cohort 1: n = 60; BMI 20-60 kg/m and cohort 2: n = 40; BMI >40 kg/m ) and validated after weight loss (using microarray data). Among the genes associated with the largest methylation fold change were genes related to metabolic processes, proliferation, inflammation, and extracellular matrix remodeling, such as COL23A1, PLEC1, FBXO21, STEAP3, RGS12, IGDCC3, FOXK2, and ORAI2. In fact, the results showed 577 differentially methylated CpG sites (DMCpGs) associated with the NNMT expression levels, with low methylation levels paralleling ...
Obesity was established as a relevant modifiable risk factor in the onset and progression of colo... more Obesity was established as a relevant modifiable risk factor in the onset and progression of colorectal cancer (CRC). This relationship could be mediated by an epigenetic regulation. The current work aimed to explore the effects of excess body weight on the DNA methylation profile of CRC using a genome-wide DNA methylation approach and to identify an epigenetic signature of obesity-related CRC. Fifty-six CRC-diagnosed patients (50 years) were included in the study and categorized according to their body mass index (BMI) as non-obese (BMI ≤ 25 kg/m) or overweight/obese (BMI > 25 kg/m). Data from Infinium 450k array-based methylomes of 28 CRC tumor samples were coupled with information on BMI categories. Additionally, DNA methylation results were validated in 28 CRC tumor samples. The analysis revealed statistically significant differences at 299 CpG sites, and they were mostly characterized as changes towards CpG hypermethylation occurring in the obese group. The 152 identified ge...
The resting metabolic rate (RMR) decrease, observed after an obesity reduction therapy is a deter... more The resting metabolic rate (RMR) decrease, observed after an obesity reduction therapy is a determinant of a short-time weight regain. Thus, the objective of this study was to evaluate changes in RMR, and the associated hormonal alterations in obese patients with a very low-calorie ketogenic (VLCK)-diet induced severe body weight (BW) loss. From 20 obese patients who lost 20.2 kg of BW after a 4-months VLCK-diet, blood samples and body composition analysis, determined by DXA and MF-Bioimpedance, and RMR by indirect calorimetry, were obtained on four subsequent visits: visit C-1, basal, initial fat mass (FM) and free fat mass (FFM); visit C-2, - 7.2 kg in FM, - 4.3 kg in FFM, maximal ketosis; visit C-3, - 14.4 kg FM, - 4.5 kg FFM, low ketosis; visit C-4, - 16.5 kg FM, - 3.8 kg FFM, no ketosis. Each subject acted as his own control. Despite the large BW reduction, measured RMR varied from basal visit C-1 to visit C-2, - 1.0%; visit C-3, - 2.4% and visit C-4, - 8.0%, without statistica...
La ghrelina, es el ligando endógeno para el receptor de secretagogos de GH. Se ha aislado a part... more La ghrelina, es el ligando endógeno para el receptor de secretagogos de GH. Se ha aislado a partir de estómago, aunque existen otros tejidos que también expresan ghrelina, como es el caso de la hipófisis, hipotálamo, placenta, ovario, testículo, etc. Se ha visto como la ghrelina está implicada en la secreción de GH, tanto in vivo, como in vitro, existen evidencias que demuestran como la administración de ghrelina induce secreción de GH. Existen datos in vivo, donde se demuestra que la potencia secretora de GH de la ghrelina es incluso superior a la que ejerce el GHRH, que hasta hace poco se consideraba el más potente de los secretagogos de GH endógenos. Existen evidencias de la acción reguladora de la ghrelina sobre la ingesta y la homeostasis energética. Existe un papel claro de la ghrelina en las distintas alteraciones alimentarias como en el caso de la obesidad, anorexia y bulimia.
Figure S2. Bland Altman plots of Resting Metabolic Rate (RMR) for Cosmedâ s Fitmate device compar... more Figure S2. Bland Altman plots of Resting Metabolic Rate (RMR) for Cosmedâ s Fitmate device compared to the Deltatrac. (PDF 11 kb)
Patients with Dunnigan disease (FPLD2) with a pathogenic variant affecting exon 8 of the LMNA gen... more Patients with Dunnigan disease (FPLD2) with a pathogenic variant affecting exon 8 of the LMNA gene are considered to have the classic disease, whereas those with variants in other exons manifest the “atypical” disease. The aim of this study was to investigate the degree of variable expressivity when comparing patients carrying the R482 and N466 variants in exon 8. Thus, 47 subjects with FPLD2 were studied: one group of 15 patients carrying the N466 variant and the other group of 32 patients with the R482 variant. Clinical, metabolic, and body composition data were compared between both groups. The thigh skinfold thickness was significantly decreased in the R482 group in comparison with the N466 group (4.2 ± 1.8 and 5.6 ± 2.0 mm, respectively, p = 0.002), with no other differences in body composition. Patients with the N466 variant showed higher triglyceride levels (177.5 [56–1937] vs. 130.0 [55–505] mg/dL, p = 0.029) and acute pancreatitis was only present in these subjects (20%). O...
Extracellular vesicles (EVs) have recently emerged as a relevant way of cell to cell communicatio... more Extracellular vesicles (EVs) have recently emerged as a relevant way of cell to cell communication, and its analysis has become an indirect approach to assess the cell/tissue of origin status. However, the knowledge about their nature and role on metabolic diseases is still very scarce. We have established an insulin resistant (IR) and two lipid (palmitic/oleic) hypertrophied adipocyte cell models to isolate EVs to perform a protein cargo qualitative and quantitative Sequential Window Acquisition of All Theoretical Mass Spectra (SWATH) analysis by mass spectrometry. Our results show a high proportion of obesity and IR-related proteins in pathological EVs; thus, we propose a panel of potential obese adipose tissue EV-biomarkers. Among those, lipid hypertrophied vesicles are characterized by ceruloplasmin, mimecan, and perilipin 1 adipokines, and those from the IR by the striking presence of the adiposity and IR related transforming growth factor-beta-induced protein ig-h3 (TFGBI). In...
The gastrointestinal-brain axis is a key mediator of the body weight and energy homeostasis regul... more The gastrointestinal-brain axis is a key mediator of the body weight and energy homeostasis regulation. Uroguanylin (UGN) has been recently proposed to be a part of this gut-brain axis regulating food intake, body weight and energy expenditure. Expression of UGN is regulated by the nutritional status and dependent on leptin levels. However, the exact molecular mechanisms underlying this UGN-leptin metabolic regulation at a hypothalamic level still remains unclear. Using leptin resistant diet-induced obese (DIO) mice, we aimed to determine whether UGN could improve hypothalamic leptin sensitivity. The present work demonstrates that the central co-administration of UGN and leptin potentiates leptin’s ability to decrease the food intake and body weight in DIO mice, and that UGN activates the hypothalamic signal transducer and activator of transcription 3 (STAT3) and phosphatidylinositide 3-kinases (PI3K) pathways. At a functional level, the blockade of PI3K, but not STAT3, blunted UGN-...
Angiopoietin-like protein 4 (ANGPTL-4) regulates lipidic metabolism and affects energy homeostasi... more Angiopoietin-like protein 4 (ANGPTL-4) regulates lipidic metabolism and affects energy homeostasis. However, its function in children with obesity remains unknown. We investigated plasma ANGPTL-4 levels in children and its relationship with body mass index (BMI) and different lipidic parameters such as free fatty acids (FFA). Plasma ANGPTL-4 levels were analyzed in two different cohorts. In the first cohort (n = 150, age 3–17 years), which included children with normal weight or obesity, we performed a cross-sectional study. In the second cohort, which included only children with obesity (n = 20, age 5–18 years) followed up for two years after an intervention for weight loss, in which we performed a longitudinal study measuring ANGPTL-4 before and after BMI-loss. In the cross-sectional study, circulating ANGPTL-4 levels were lower in children with obesity than in those with normal weight. Moreover, ANGPTL-4 presented a negative correlation with BMI, waist circumference, weight, insu...
Laminopathies are genetic disorders associated with alterations in nuclear envelope proteins, kno... more Laminopathies are genetic disorders associated with alterations in nuclear envelope proteins, known as lamins. The LMNA gene encodes lamins A and C, and LMNA mutations have been linked to diseases involving fat (type 2 familial partial lipodystrophy [FPLD2]), muscle (type 2 Emery-Dreifuss muscular dystrophy [EDMD2], type 1B limb-girdle muscular dystrophy [LGMD1B], and dilated cardiomyopathy), nerves (type 2B1 Charcot-Marie-Tooth disease), and premature aging syndromes. Moreover, overlapping syndromes have been reported. This study aimed to determine the genetic basis of an overlapping syndrome in a patient with heart disease, myopathy, and features of lipodystrophy, combined with severe metabolic syndrome. We evaluated a 54-year-old woman with rheumatoid arthritis, chronic hypercortisolism (endogenous and exogenous), and a history of cured adrenal Cushing syndrome. The patient presented with a complex disorder, including metabolic syndrome associated with mild partial lipodystrophy ...
Limited evidence supports the use of free testosterone (FT) for diagnosing hypogonadism when sex ... more Limited evidence supports the use of free testosterone (FT) for diagnosing hypogonadism when sex hormone binding globulin (SHBG) is altered. Low total testosterone (TT) is commonly encountered in obesity where SHBG is typically decreased. We aimed to assess the contribution of FT in improving the diagnosis of symptomatic secondary hypogonadism (SH), identified initially by low total testosterone (TT), and then further differentiated by normal FT (LNSH) or low FT (LLSH). Prospective observational study with a median follow-up of 4.3 years. 3369 community-dwelling men aged 40-79 years from eight European centres. Subjects were categorised according to baseline and follow-up biochemical status into persistent eugonadal (referent group; n=1880), incident LNSH (eugonadism to LNSH; n=101) and incident LLSH (eugonadism to LLSH; n=38). Predictors and clinical features associated with the transition from eugonadism to LNSH or LLSH were assessed. The cumulative incidence of LNSH and LLSH over...
The enzyme nicotinamide N-methyltransferase (NNMT) is a major methyltransferase in adipose tissue... more The enzyme nicotinamide N-methyltransferase (NNMT) is a major methyltransferase in adipose tissue. We hypothesized an epigenetic signature in association with NNMT gene expression in adipose tissue. The global human methylome was analyzed in visceral adipose tissue (VAT) from morbidly obese patients using the Infinium HumanMethylation450 BeadChip array (discovery cohort: n = 11). The findings were confirmed in two additional independent cohorts (Cohort 1: n = 60; BMI 20-60 kg/m and cohort 2: n = 40; BMI >40 kg/m ) and validated after weight loss (using microarray data). Among the genes associated with the largest methylation fold change were genes related to metabolic processes, proliferation, inflammation, and extracellular matrix remodeling, such as COL23A1, PLEC1, FBXO21, STEAP3, RGS12, IGDCC3, FOXK2, and ORAI2. In fact, the results showed 577 differentially methylated CpG sites (DMCpGs) associated with the NNMT expression levels, with low methylation levels paralleling ...
Obesity was established as a relevant modifiable risk factor in the onset and progression of colo... more Obesity was established as a relevant modifiable risk factor in the onset and progression of colorectal cancer (CRC). This relationship could be mediated by an epigenetic regulation. The current work aimed to explore the effects of excess body weight on the DNA methylation profile of CRC using a genome-wide DNA methylation approach and to identify an epigenetic signature of obesity-related CRC. Fifty-six CRC-diagnosed patients (50 years) were included in the study and categorized according to their body mass index (BMI) as non-obese (BMI ≤ 25 kg/m) or overweight/obese (BMI > 25 kg/m). Data from Infinium 450k array-based methylomes of 28 CRC tumor samples were coupled with information on BMI categories. Additionally, DNA methylation results were validated in 28 CRC tumor samples. The analysis revealed statistically significant differences at 299 CpG sites, and they were mostly characterized as changes towards CpG hypermethylation occurring in the obese group. The 152 identified ge...
The resting metabolic rate (RMR) decrease, observed after an obesity reduction therapy is a deter... more The resting metabolic rate (RMR) decrease, observed after an obesity reduction therapy is a determinant of a short-time weight regain. Thus, the objective of this study was to evaluate changes in RMR, and the associated hormonal alterations in obese patients with a very low-calorie ketogenic (VLCK)-diet induced severe body weight (BW) loss. From 20 obese patients who lost 20.2 kg of BW after a 4-months VLCK-diet, blood samples and body composition analysis, determined by DXA and MF-Bioimpedance, and RMR by indirect calorimetry, were obtained on four subsequent visits: visit C-1, basal, initial fat mass (FM) and free fat mass (FFM); visit C-2, - 7.2 kg in FM, - 4.3 kg in FFM, maximal ketosis; visit C-3, - 14.4 kg FM, - 4.5 kg FFM, low ketosis; visit C-4, - 16.5 kg FM, - 3.8 kg FFM, no ketosis. Each subject acted as his own control. Despite the large BW reduction, measured RMR varied from basal visit C-1 to visit C-2, - 1.0%; visit C-3, - 2.4% and visit C-4, - 8.0%, without statistica...
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