The low-grade inflammation observed in obesity has been associated with a high-fat diet, though this relation is not fully understood. Bacterial endotoxin, produced by gut microbiota, may be the ...linking factor. However, this has not been confirmed in obese patients. To study the relationship between a high-fat diet and bacterial endotoxin, we analyzed postprandial endotoxemia in morbidly obese patients after a fat overload. The endotoxin levels were determined in serum and the chylomicron fraction at baseline and 3 h after a fat overload in 40 morbidly obese patients and their levels related with the degree of insulin resistance and postprandial hypertriglyceridemia. The morbidly obese patients with the highest postprandial hypertriglyceridemia showed a significant increase in lipopolysaccharide (LPS) levels in serum and the chylomicron fraction after the fat overload. Postprandial chylomicron LPS levels correlated positively with the difference between postprandial triglycerides and baseline triglycerides. There were no significant correlations between C-reactive protein (CRP) and LPS levels. The main variables contributing to serum LPS levels after fat overload were baseline and postprandial triglyceride levels but not glucose or insulin resistance. Additionally, superoxide dismutase activity decreased significantly after the fat overload. Postprandial LPS increase after a fat overload is related to postprandial hypertriglyceridemia but not to degree of insulin resistance in morbidly obese patients.
The nuclear protein high-mobility group box 1 (HMGB1) can be passively released by necrotic cells or secreted actively by several cell types to regulate immune and inflammatory responses, as well as ...tissue remodeling. We herein aimed to characterize the effect of insulin resistance on HMGB1 in adipose tissue and to examine its potential role as a metabolic regulator in β-pancreatic cells.
Plasma HMGB1 concentration and adipose HMGB1 expression were assessed in relation to obesity and insulin resistance. Cultured adipocytes from lean and obese patients were used to investigate the intracellular distribution and factors regulating HMGB1 release, as well as to test its effects on adipogenesis and lipid metabolism. A regulatory role for HMGB1 in insulin secretion was also investigated.
Circulating HMGB1 was positively associated with body mass index, while adipose HMGB1 mRNA levels correlated with the expression of inflammatory markers. Insulin resistance modified the intracellular distribution of HMGB1 in human adipocytes, with HMGB1 being predominantly nuclear in lean and obese normoglycemic individuals while localized to the cytosol in obese patients with type 2 diabetes. Adipocytes from lean individuals exposed to conditioned media from lipopolysaccharide-stimulated macrophages induced HMGB1 redistribution to the cytoplasm and release. HMGB1 treatment had no effect on differentiation and lipid metabolism in adipocytes. However, HMGB1, whose circulating levels correlated with postload insulin concentration, increased both insulin release and intracellular Ca(2+) concentration in INS-1 cells.
These findings show, for the first time, that HMGB1 expression and release by human adipocytes is altered by inflammatory conditions as those imposed by obesity and insulin resistance. Our data reveal a novel role for HMGB1 as a stimulatory factor of insulin secretion of β-pancreatic cells.
The purpose of this study was to investigate the expression of human adipose tissue protein 53 (p53) in subjects who varied widely in terms of obesity and insulin resistance. We also analyzed ...different in vivo and in vitro models to try to comprehend the associations found in humans.
p53 was analyzed in human adipose and isolated adipocytes, in high fat-fed and GLP-1R KO mice, during in vitro adipogenesis, and in adipocytes after high glucose, rosiglitazone and inflammatory conditions. The effects of surgery-induced weight loss and ex vivo metformin were also evaluated.
Omental (OM) p53 gene expression (+27%, P=0.001) and protein (+11%, P=0.04) were increased in obese subjects and high fat diet-induced obese mice (+86%, P=0.018). Although the obesity-associated inflammatory milieu was associated with increased OM p53, this was negatively related to insulin resistance and glycated hemoglobin, and positively with biomarkers for insulin sensitivity. Multiple linear regression analyses revealed that glycated hemoglobin (P<0.0001) and body mass index (P=0.048) contributed independently to explain 13.7% (P<0.0001) of the OM p53 variance. Accordingly, the improvement of insulin sensitivity with surgery-induced weight loss (+51%, P=0.01) and metformin (+42%, P=0.02) led to increased adipose p53. While the glucose-intolerant GLP-1R KO mice showed decreased mesenteric p53 (-45.4%, P=0.017), high glucose led to decreased p53 in pre-adipocytes (-27%, P<0.0001). Inflammatory treatments led to increased p53 (+35%, P<0.0001), while Rs downregulated this expression (-40%, P=0.005) in mature adipocytes.
Inflammation and insulin resistance exert dual effects on adipose p53, which seems to be the final result of these opposing forces.
Fibroblast growth factor 21 (FGF21) has been suggested to be an endocrine signal of nutritional status and an active regulator of metabolism. However, there is no agreement on the effect of ...weight-loss therapies on circulating levels of FGF21 in humans.
To assess FGF21 circulating levels in adiposity excess and after different weight-loss strategies prescribed in five different groups from four independent centers.
Body composition, ketosis, insulin sensitivity and FGF21 were evaluated in 181 excess body weight and 14 normal-weight subjects. From the excess body weight patients, two independent groups (discovery cohort; n=20 and validation cohort; n=28) undertook a very low-calorie ketogenic (VLCK) diet, a third group followed a low-calorie (LC) diet (n=84) and other two groups underwent bariatric surgery (discovery cohort; n=24 and validation cohort; n=25). The follow-up was 4 to 6 or 12 months, respectively.
FGF21 levels were higher in excess body weight patients than in normal-weight subjects. The energy-restriction therapy to lose weight induced a significant decrease, with respect to baseline, in circulating levels of FGF21 (VLCK: -62.5 pg ml
or -14.8 pg ml
and LC diet: -67.9 pg ml
). There were no differences in FGF21 levels between both energy-restriction treatments. On the contrary, after bariatric surgery morbidly obese patients showed a significant increase in FGF21, especially 1 month after surgery (148.8 pg ml
higher than baseline). The FGF21 differential changes occur concomitantly with a non-induced ketosis situation (0.66±0.56 mm) in bariatric surgery, and an improvement in adiposity and insulin sensitivity induced by the three therapies.
FGF21 levels were reduced after energy-restricted treatments and severely increased after bariatric surgery, independently of the weight reduction magnitude, insulin sensitivity or ketosis. Therefore, FGF21 appears to be a marker of severe nutritional stress.
Aim: The Wnt/β-catenin signaling network offers potential targets to diagnose and uncouple obesity from its metabolic complications. In this study, we investigate the role of the Wnt antagonist, ...secreted frizzled-related protein 1 (SFRP1), in promoting adipogenesis in vitro and adipose tissue expansion in vivo. Methods: We use a combination of human and murine, in vivo and in vitro models of adipogenesis, adipose tissue expansion and obesity-related metabolic syndrome to profile the involvement of SFRP1. Results: SFRP1 is expressed in both murine and human mature adipocytes. The expression of SFRP1 is induced during in vitro adipogenesis, and SFRP1 is preferentially expressed in mature adipocytes in human adipose tissue. Constitutive ectopic expression of SFRP1 is proadipogenic and inhibits the Wnt/β-catenin signaling pathway. In vivo endogenous levels of adipose SFRP1 are regulated in line with proadipogenic states. However, in longitudinal studies of high-fat-diet-fed mice, we observed a dynamic temporal but biphasic regulation of endogenous SFRP1. In agreement with this profile, we observed that SFRP1 expression in human tissues peaks in patients with mild obesity and gradually falls in morbidly obese subjects. Conclusions: Our results suggest that SFRP1 is an endogenous modulator of Wnt/β-catenin signaling and participates in the paracrine regulation of human adipogenesis. The reduced adipose expression of SFRP1 in morbid obesity and its knock-on effect to prevent further adipose tissue expansion may contribute to the development of metabolic complications in these individuals.
Objectives
We tested the effects of a weight-loss intervention encouraging energy-reduced MedDiet and physical activity (PA) in comparison to
ad libitum
MedDiet on COVID-19 incidence in older adults.
...Design
Secondary analysis of PREDIMED-Plus, a prospective, ongoing, multicentre randomized controlled trial.
Setting
Community-dwelling, free-living participants in PREDIMED-Plus trial.
Participants
6,874 Spanish older adults (55–75 years, 49% women) with overweight/obesity and metabolic syndrome.
Intervention
Participants were randomised to Intervention (IG) or Control (CG) Group. IG received intensive behavioural intervention for weight loss with an energy-reduced MedDiet intervention and PA promotion. CG was encouraged to consume
ad libitum
MedDiet without PA recommendations.
Measurements
COVID-19 was ascertained by an independent Event Committee until December 31, 2021. COX regression models compared the effect of PREDIMED-Plus interventions on COVID-19 risk.
Results
Overall, 653 COVID-19 incident cases were documented (IG:317; CG:336) over a median (IQR) follow-up of 5.8 (1.3) years (inclusive of 4.0 (1.2) years before community transmission of COVID-19) in both groups. A significantly lowered risk of COVID-19 incidence was not evident in IG, compared to CG (fully-adjusted HR (95% CI): 0.96 (0.81,1.12)).
Conclusions
There was no evidence to show that an intensive weight-loss intervention encouraging energy-reduced MedDiet and PA significantly lowered COVID-19 risk in older adults with overweight/ obesity and metabolic syndrome in comparison to
ad libitum
MedDiet. Recommendations to improve adherence to MedDiet provided with or without lifestyle modification suggestions for weight loss may have similar effects in protecting against COVID-19 risk in older adults with high cardiovascular risks.
Aim: To study the prevalence of hypertriglyceridemic waist (HTGW) in an urban adult Spanish population and its association with type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). ...Methods: We undertook a cross-sectional analysis in a random sample of 2270 individuals (18–80 years of age). All participants provided a clinical history and underwent a physical examination. Blood and urine analyses were conducted. HTGW was diagnosed using anthropometric criteria for the European population (waist circumference: for men, 94 cm; for women, 80 cm) and fasting plasma triglycerides (TGs) 1.71 mmol l−1 (150 mg per 100 ml). Results: The prevalence of HTGW was 14.5% (men: 18.2%, women: 10.8%) and was significantly greater in men <59 years (P<0.001). HTGW was associated with older individuals, a low educational level and, in men, with a sedentary lifestyle (P<0.001). Subjects with HTGW had higher levels of total cholesterol, low-density lipoprotein-cholesterol (LDL-c) and uric acid, lower levels of high-density lipoprotein-cholesterol, a higher blood pressure, a greater degree of obesity and a higher prevalence of T2DM (20.00 vs 6.4%, P<0.001) (odds ratio (OR) 3.61; 95% confidence interval (95% CI), 2.60–5.01) and CVD (8.5 vs 3.4%, P<0.001) (OR 2.63; 95% CI, 1.66–4.16). The association of HTGW with T2DM and CVD disappeared after adjusting for age. The degree of concordance between HTGW and the metabolic syndrome (MS) was moderate, with both the Adult Treatment Panel III Report (ATP-III) and the International Diabetes Federation criteria (κ=0.51 and κ=0.58, respectively). Subjects with isolated HTGW as compared with those with isolated MS (ATP-III) were younger, had greater levels of total cholesterol, LDL-c and TGs and a lower prevalence of obesity, high blood pressure and dysglycemia. Conclusion: HTGW is a phenotype of cardiometabolic risk prevalent in the adult population in our environment. HTGW may be an alternative to MS to detect the population at risk for T2DM and CVD, especially in young individuals who do not fulfill the criteria for MS.
Surfactant protein-D (SFTPD) is a component of the lung innate immunity that enhances clearance of pathogens and modulates inflammatory responses. An inverse association of putative, lung-derived ...circulating SFTPD with obesity has been reported but no information is available concerning possible SFTPD gene expression in human adipose tissue.
SFTPD gene expression was analyzed in human omental (OM; n=156) and subcutaneous (SC; n=106) adipose tissue, and in isolated fat cells (n=12) in association with measures of obesity and glucose tolerance.
SFTPD gene was expressed in human adipose tissue and adipocytes. This expression was decreased in OM and SC adipose tissue from obese subjects with (-47%, P<0.0001; and -37%, P=0.048) and without (-34%, P=0.001; and -22%, P=0.08; respectively) type 2 diabetes when compared with the control group. Indeed, OM SFTPD was inversely associated with body mass index (r=-0.33, P<0.0001), percent fat mass (r=-0.36, P<0.0001), waist perimeter (r=-0.26, P=0.002), diastolic blood pressure (r=-0.21, P=0.018) and fasting glucose (r=-0.21, P=0.012); and positively linked to the expression of insulin receptor substrate 1 (IRS1; r=0.25, P=0.004), perilipin A (PLIN; r=0.38, P=0.007) and fatty acid synthase (FASN; r=0.36, P<0.0001). Accordingly, increased SFTPD (4.5-fold, P=0.02) was detected in isolated adipocytes when compared with the stromal-vascular cell fraction, in parallel to IRS1, FASN and PLIN.
Both OM and SC adipose tissue (mainly mature adipocytes) express SFTPD. This expression decreases with obesity and impaired glucose tolerance.
Background
Obesity is produced by the enlargement of the adipose tissue. Functioning as an endocrine organ, it releases and receives information through a complex network of cytokines, hormones, and ...substrates contributing to a low-chronic inflammation environment. Diet and healthy habits play key roles in the prevention of obesity and its related pathologies. In this regard, there is a need to switch to healthier and more appetizing diets, such as the Mediterranean one.
Objective
To compare the mid-and long-term effects of two Mediterranean diet (MedDiet) interventions, one energy-reduced plus physical activity promotion versus a non-restrictive diet, on peripheral satiety-related hormones, weight loss, glucose/lipid metabolism, and pro-inflammatory markers in subjects with obesity/overweight and metabolic syndrome.
Materials and methods
A randomized, lifestyle intervention was conducted in 23 Spanish centers, with a large cohort of patients presenting metabolic syndrome. Our study is a subproject set in IMIM (Hospital del Mar Research Institute). Participants were men and women, aged 55–75 and 60–75, respectively, who at baseline met at least three metabolic syndrome components. Subjects were assigned to two intervention groups: (1) an intensive lifestyle intervention with an energy-reduced MedDiet and physical activity promotion (intervention group) with the aim of weight loss; and (2) a normocaloric MedDiet (control). We quantified in a subsample of 300 volunteers from Hospital del Mar Research Institute (Barcelona), following analytes at baseline, 6 months, and 1 year: glucose, HbA1c, triglycerides, total cholesterol, high-density lipoprotein cholesterol, LDL cholesterol, C-peptide, ghrelin, GLP-1, glucagon, insulin, leptin, PAI-1, resistin, and visfatin. Anthropometric and classical cardiovascular risk factors were also determined. A multivariate statistical model was employed to compare the two groups. Linear mixed-effect models were performed to compare changes in risk factors and biomarkers between intervention groups and over time.
Results
Compared to participants in the control group, those in intervention one showed greater improvements in weight, waist circumference, insulin (
P
< 0.001), glucose metabolism-related compounds (
P
< 0.05), triglyceride-related lipid profile (
P
< 0.05), leptin, blood pressure, and pro-inflammatory markers such as PAI-1 (
P
< 0.001) at mid-and/or long-term. High-sensitivity C-reactive protein, resistin, and vifastin also decreased in both groups.
Conclusion
A weight loss intervention employing a hypocaloric MedDiet and physical activity promotion has beneficial effects on adiposity, glucose metabolism, lipid profile, leptin, and pro-inflammatory markers, such as PAI-1 in both mid-and long-term.
Abstract Background The impact of a lifestyle intervention (LSI) program for the long-term management of subjects with metabolic syndrome in a primary care setting is not known. Methods This 3-year ...prospective controlled trial randomized adult subjects with metabolic syndrome to receive intensive LSI or to usual care in a community health centre in Malaga, Spain. LSI subjects received instruction on Mediterranean diet and a regular aerobic exercise program by their primary care professionals. Primary outcome included changes from baseline on different components of metabolic syndrome (abdominal circumference, blood pressure, HDL-cholesterol, fasting plasma glucose and triglycerides). Results Among the 2,492 subjects screened, 601 subjects with metabolic syndrome (24.1%) were randomized to LSI ( n = 298) or to usual care ( n = 303); of them, a 77% and a 58%, respectively, completed the study. At the end of the study period, LSI resulted in significant differences vs. usual care in abdominal circumference (− 0.4 ± 6 cm vs. + 2.1 ± 6.7 cm, p < 0.001), systolic blood pressure (− 5.5 ± 15 mmHg vs. -0.6 ± 19 mmHg, p = 0.004), diastolic blood pressure (− 4.6 ± 10 mmHg vs. -0.2 ± 13 mmHg, p < 0.001) and HDL-cholesterol (+ 4 ± 12 mg/dL vs. + 2 ± 12 mg/dL, p = 0.05); however, there were no differences in fasting plasma glucose and triglyceride concentration (− 4 ± 35 mg/dl vs. -1 ± 32 mg/dl, p = 0.43 and − 0.4 ± 83 mg/dl vs. + 6 ± 113 mg/dl, p = 0.28). Conclusion Intensive LSI counseling provided by primary care professionals resulted in significant improvements in abdominal circumference, blood pressure and HDL-cholesterol but had limited effects on glucose and triglyceride levels in patients with metabolic syndrome.
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