Can obesity-induced inflammation in skeletal muscle and intramuscular adipose tissue accurately detect liver fibrosis?

OBJECTIVES: Obesity is characterized by a chronic, low grade, systemic inflammation. However, little is known about the role of skeletal muscle, which represents an active metabolic organ whose activities need to be determined. The purpose of our study was to detect relationships between skeletal muscle and adipose tissue inflammation with nonalcoholic fatty liver disease (NAFLD) and diabetes, as well as to explore associations with clinicopathological parameters. METHODS: Our study population consisted of 50 morbidly obese patients undergoing planned bariatric surgery. Biopsies were taken from visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), skeletal muscle (SM), extramyocellular adipose tissue (EMAT) and liver. The expression of CD68 and CD3 was assessed by immunohistochemistry. RESULTS: Our findings suggest a complex inter- and intra-tissue co-expression network that links obesity-induced inflammation in adipose depots and skeletal muscle with NAFLD. A novel finding is the intricate cross-talk between SM, EMAT and the liver and the probable correlation between SM, EMAT inflammation and the presence of liver fibrosis. CONCLUSIONS: Although the mechanisms of obesity-induced inflammation and its association with NAFLD and liver fibrosis are incompletely understood, our findings indicate an extensive and complex tissue network that needs to be further investigated.

SRC-3/AIB-1 may Enhance Hepatic NFATC1 Transcription and Mediate Inflammation in a Tissue-Specific Manner in Morbid Obesity.

BACKGROUND: Obesity is a global epidemic which is associated with several cardiometabolic comorbidities and is characterized by chronic, low grade systemic inflammation. Numerous biomarkers have been implicated in the pathophysiology of the disease, including transcription factors and coregulators. Steroid Receptor Coactivator (SRC)-family represent the master regulators of metabolic pathways and their dysregulation is strongly associated with numerous metabolic disorders. METHODS: 50 morbidly obese patients participated in the present study. Biopsies were collected from visceral adipose tissue, subcutaneous adipose tissue, skeletal muscle, extra-myocellular adipose tissue and liver. We evaluated the differential protein expression of NFATc1, SRC-2/TIF-2, SRC-3/AIB-1 and inflammatory biomarkers CD68 and CD3 by immunohistochemistry. The current study was designed to determine any correlations between the transcription factor NFATc1 and the SRC coregulators, as well as any associations with the inflammatory biomarkers. RESULTS: We identified SRC-3 as a hepatic NFATc1 coactivator and we demonstrated its possible role in energy homeostasis and lipid metabolism. Moreover, we revealed a complex and extensive intraand inter-tissue network among the three main investigated proteins and the inflammatory biomarkers, suggesting their potential participation in the obesity-induced inflammatory cascade. CONCLUSION: Steroid receptor coactivators are critical regulators of human metabolism with pleiotropic and tissue-specific actions. We believe that our study will contribute to the better understanding of the complex multi-tissue interactions that are disrupted in obesity and can therefore lead to numerous cardiometabolic diseases. Further on, our present findings suggest that SRC-3/AIB-1 could constitute possible future drug targets.

Early histological changes in the kidney of people with morbid obesity.

BACKGROUND: Morbid obesity represents a major health problem with increasing incidence worldwide. The clinical manifestation of renal involvement in obesity is proteinuria, and the histological feature is glomerulomegaly with or without focal and segmental glomerulosclerosis (FSGS). In this study, we have investigated the very early histological changes in kidneys of people with morbid obesity and no proteinuria. Patients and methods. Eighteen patients with body mass index (BMI) >50 kg/m(2) who underwent a variant of biliopancreatic diversion with Roux-en-Y reconstruction (BPD-RYGBP) and consented to undergo a renal biopsy during the surgical procedure were included in the study. The estimation of early histological changes was performed on light (n = 18) and electron microscopy (n = 13). RESULTS: The mean glomerular cross-sectional area was 30 943 +/- 10,984 microm(2) that is higher than that observed in non-obese individuals. In 21% of the examined glomeruli, the glomerular planar surface area (GPSA) was >40,000 microm(2). Thickening of the glomerular basement membrane (GBM) and scattered paramesangial deposits were identified in 9 of 13 patients (70%) whose renal tissue was examined by electron microscopy. A reduction in the slit pore frequency was observed in obese patients due to extensive foot process effacement. Significant positive correlations between mean GPSA and body weight (r = 0.462, P = 0.05), and between GBM thickness and HbA1c, serum total cholesterol and triglyceride levels (r = 0.60, P = 0.05; r = 0.789, P = 0.004; r = 0.70, P = 0.016, respectively), were observed. CONCLUSIONS: Glomerulomegaly as well as histological lesions resembling those of early diabetic nephropathy are observed in kidney biopsies of patients with morbid obesity even before the appearance of microalbuminuria. The potential regression of these changes after weight loss needs to be clarified.

Inter-tissue expression patterns of the key metabolic biomarker PGC-1α in severely obese individuals: Implication in obesity-induced disease.

OBJECTIVE: PGC-1α is already known as a significant regulator of mitochondrial biogenesis, oxidative phosphorylation and fatty acid metabolism. Our study focuses on the role of PGC1α in morbid obesity, in five different tissues, collected from 50 severely obese patients during planned bariatric surgery. METHODS: The investigated tissues included subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), skeletal muscle (SM), extramyocellular adipose tissue (EMAT) and liver. PGC1α expression was investigated with immunohistochemistry and evaluated with microscopy. RESULTS: Our findings highlighted significant positive inter-tissue correlations regarding PGC-1α expression between several tissue pairs (VAT-SAT, VAT-SM, VAT-EMAT, SAT-SM, SAT-EMAT, SM-EMAT). Moreover, we found significant negative correlations between PGC1α expression in VAT with CD68 expression in skeletal muscle and EMAT, implying a possible protective role of PGC1α against obesity-induced inflammation. CONCLUSION: Unmasking the inter-tissue communication networks regarding PGC-1α expression in morbid obesity, will give more insight into its significant role in obesity-induced diseases. PGC1α could potentially represent a future preventive and therapeutic target against obesity-induced disease, probably through enhancing mitochondrial biogenesis and metabolism.

Restoration of euglycemia and normal acute insulin response to glucose in obese subjects with type 2 diabetes following bariatric surgery.

Insulin resistance and loss of glucose-stimulated acute insulin response (AIR) are the two major and earliest defects in the course of type 2 diabetes. We investigated whether weight loss after bariatric surgery in patients with morbid obesity and type 2 diabetes could restore euglycemia and normal AIR to an intravenous glucose tolerance test (IVGTT). We studied 25 morbidly obese patients-12 with type 2 diabetes, 5 with impaired glucose tolerance, and 8 with normal glucose tolerance (NGT)-before and after a biliopancreatic diversion (BPD) with Roux-en-Y gastric bypass (RYGBP). Twelve individuals with normal BMI served as control subjects. Twelve months after surgery, in the diabetes group, BMI decreased from 53.2 +/- 2.0 to 29.2 +/- 1.7 kg/m(2), fasting glucose decreased from 9.5 +/- 0.83 to 4.5 +/- 0.13 mmol/l, and fasting insulin decreased from 168.4 +/- 25.9 to 37.7 +/- 4.4 pmol/l (mean +/- SE; P < 0.001). AIR, the mean of insulin concentration at 2, 3, and 5 min over basal in the IVGTT, increased by 770 and 935% at 3 and 12 months after surgery, respectively (from 24.0 +/- 22.7 to 209 +/- 43.4 and 248 +/- 33.1 pmol/l, respectively; P < 0,001). Conversely, in the NGT group, the AIR decreased by 40.5% (from 660 +/- 60 to 393 +/- 93 pmol/l; P = 0.027) 12 months after surgery. BPD with RYGBP performed in morbidly obese patients with type 2 diabetes leads to significant weight loss, euglycemia, and normal insulin sensitivity; but most importantly, it restores a normal beta-cell AIR to glucose and a normal relationship of AIR to insulin sensitivity. This is the first study to demonstrate that the lost glucose-induced AIR in patients with type 2 diabetes of mild or moderate severity is a reversible abnormality.

Cortisol in tissue and systemic level as a contributing factor to the development of metabolic syndrome in severely obese patients.

CONTEXT: Adrenal and extra-adrenal cortisol production may be involved in the development of metabolic syndrome (MetS). OBJECTIVE: To investigate the activity of the hypothalamic-pituitary-adrenal (HPA) axis and the expression of HSD11B1, nuclear receptor subfamily 3, group C, member 1 (glucocorticoid receptors) α (NR3C1α) and ß (NR3C1ß) in the liver, subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) of severely obese patients with and without MetS. METHODS: The study included 37 severely obese patients (BMI ≥ 40 kg/m(2)), 19 with MetS (MetS+ group) and 18 without (MetS- group), studied before and during bariatric surgery. Before the day of surgery, urinary free cortisol (UFC) and diurnal variation of serum and salivary cortisol were estimated. During surgery, biopsies of the liver, VAT and SAT were obtained. The expression of HSD11B1, NR3C1α and NR3C1ß was evaluated by RT-PCR. RESULTS: UFC and area under the curve for 24-h profiles of serum and salivary cortisol were lower in the MetS- group. In the MetS- group, mRNA levels of HSD11B1 in liver exhibited a negative correlation with liver NR3C1α (LNR3C1α) and VAT expression of HSD11B1 was lower than the MetS+ group. CONCLUSIONS: We observed a downregulation of the NR3C1α expression and lower VAT mRNA levels of HSD11B1 in the MetS- group, indicating a lower selective tissue cortisol production and action that could protect these patients from the metabolic consequences of obesity. In the MetS- group, a lower activity of the HPA axis was also detected. Taken together, cortisol in tissue and systematic level might play a role in the development of MetS in severely obese patients.

The effect of bariatric surgery on patient HRQOL and sexual health during a 1-year postoperative period.

BACKGROUND: Negative consequences of the obesity epidemic include decreased physical, psychological, and sexual health. Bariatric surgery is a well-tolerated and effective treatment for morbid obesity. This study aimed to determine the effect of bariatric surgery on health-related quality of life (HRQOL) and sexual functioning and to identify potential predictors of this effect. METHODS: Eighty morbidly obese patients (50 women) completed the study. HRQOL was measured using the Short Form 36 questionnaire (SF-36). Sexual functioning was assessed using the Female Sexual Functioning Index (FSFI) and the International Index of Erectile Function (IIEF). All participants were evaluated four times as follows: presurgery (T1), 1 month (T2), 6 months (T3), and 1 year (T4) after surgery. RESULTS: Body mass index (BMI) significantly decreased over time (p < 0.001). Apart from male orgasm, all sexual functioning components as well as all SF-36 sub-scales improved between T1 and T4. The maximum improvement was observed between T2 and T3. Baseline HRQOL scores correlated with postoperative improvement in all HRQOL components. BMI improvement was correlated with improvement in role physical, bodily pain, and mental health scores. Baseline total sexual satisfaction score independently predicted total satisfaction improvement in both genders. CONCLUSIONS: The present findings indicate that bariatric surgery represents an effective obesity treatment, leading to significant BMI reduction and improvement in HRQOL and sexual functioning, especially in the first 6 months postoperatively.

Effects of bariatric surgery on HDL structure and functionality: results from a prospective trial.

BACKGROUND: In addition to high-density lipoprotein cholesterol (HDL-C) levels, HDL quality appears also very important for atheroprotection. Obese patients with metabolic syndrome have significantly reduced HDL-C levels and are usually at increased risk for coronary heart disease. Despite that weight loss benefits these patients, its effects on HDL quality and functionality is currently poorly studied. OBJECTIVES: We investigated how rapid weight loss affects HDL structure and its antioxidant potential in patients undergoing a malabsorptive bariatric procedure. METHODS: Fasting plasma samples were collected the day before and 6 months after the bariatric procedure from 20 morbidly obese patients with body mass index >50, then HDL was isolated and analyzed by biochemical techniques. RESULTS: We report a dramatic alteration in the apolipoprotein ratio of HDL that was accompanied by the presence of more mature HDL subspecies and a concomitant increase in the antioxidant potential of HDL. Interestingly, our obese cohort could be distinguished into 2 subgroups. In 35% of patients (n = 7), HDL before surgery had barely detectable apolipoprotein (apo) A-I and apoCIII, and the vast majority of their HDL cholesterol was packed in apoE-containing HDL particles. In the remaining 65% of patients (n = 13), HDL before surgery contained high levels of apoA-I and apoCIII, in addition to apoE. In both subgroups, surgical weight loss resulted in a switch from apoE to apoA-I-containing HDL. CONCLUSIONS: Rapid weight loss exerts a significant improvement in HDL structure and functionality that may contribute to the documented beneficial effect of malabsorptive bariatric procedures on cardiovascular health.

Neutrophil Gelatinase-Associated Lipocalin as a Biomarker of Acute Kidney Injury in Patients with Morbid Obesity Who Underwent Bariatric Surgery.

INTRODUCTION: Neutrophil gelatinase-associated lipocalin (NGAL) has been identified as a biomarker of acute kidney injury (AKI) that could contribute to early diagnosis and effective management of AKI. The purpose of this study was to evaluate NGAL as a predictive marker of AKI in patients with clinically severe obesity (BMI >50) who underwent biliopancreatic diversion surgery. PATIENTS AND METHODS: We prospectively studied 23 patients with clinically severe obesity who underwent biliopancreatic bypass surgery. NGAL was measured using chemiluminescent microparticle immunoassay in three urine samples collected from each patient before surgery (first sample), 2-6 h after surgery (second sample) and on the first postoperative day (third sample). RESULTS: Renal function was evaluated using serum creatinine values, which were 0.91 ± 0.26 mg/dl before surgery, 0.87 ± 0.31 mg/dl immediately after surgery and 0.92 ± 0.62 mg/dl on the fifth postoperative day. During the immediate postoperative period, AKI was observed in 2 patients, one of whom required renal replacement therapy with hemodialysis. In both patients, urine NGAL increased within the first postoperative hours before the values of serum creatinine increased. CONCLUSION: Urine NGAL in patients with clinically severe obesity, which was surgically treated, might be a potential biomarker of early AKI detection. Further research is required in order to confirm these results observed in a small number of patients who developed postoperative AKI and make recommendations for predictive NGAL values in patients who underwent bariatric surgery.

Improved levothyroxine pharmacokinetics after bariatric surgery.

BACKGROUND: The absorption of levothyroxine (LT4) is affected by many factors. Bariatric surgery is recommended in severely obese patients. The aim of this study was to determine the consequences of bariatric surgery on LT4 pharmacokinetic parameters, and to identify the regions of the gastrointestinal tract where LT4 is absorbed in patients with severe obesity before and after surgery. METHODS: We studied 32 severely obese nonhypothyroid patients who underwent sleeve gastrectomy (SG; n=10), Roux-en-Y gastric bypass (RYGBP; n=7), or biliopancreatic diversion with long limbs (BPD-LL; n=15). Before surgery, from 8:00 a.m., blood samples were collected before and every 30 minutes after the oral administration of a solution of 600 µg of LT4. The same procedure was repeated 35 days after surgery. We estimated the pharmacokinetic parameters of LT4 before and after surgery, including the area under the curve (AUC), the peak thyroxine concentration (Cmax), and the time to peak thyroxine concentration (Tmax). RESULTS: Following surgery, in the SG group, the mean AUC was higher than it was before surgery (18.97±6.01 vs. 25.048±6.47 [µg/dL]·h; p<0.01), whereas the values of Cmax and Tmax were similar to those before surgery. In the RYGBP group, mean AUC, Cmax, and Tmax were similar before and after surgery. In the BPD-LL group, mean AUC and Cmax were higher after surgery than before (14.18±5.64 vs. 25.51±9.1 [µg/dL]·h, p<0.001; 5.62±1.34 vs. 8.16±2.57 µg/dL, p<0.001, respectively), whereas Tmax was similar. CONCLUSIONS: The pharmacokinetic parameters of LT4 absorption are improved following SG and BPD-LL types of bariatric procedures. We conclude that the stomach, the duodenum, and the upper part of the jejunum are not sites for LT4 absorption, because in the above-mentioned bariatric procedures these are bypassed or removed.

Impaired pharmacokinetics of levothyroxine in severely obese volunteers.

BACKGROUND: Suppressive or replacement doses of levothyroxine (LT4) are affected by the rate and extent of the active ingredient absorbed, as well as by the lean body mass. Obesity has reached epidemic proportions worldwide and is related with many comorbidities. The aim of this study was to determine the pharmacokinetic parameters of LT4 in severely obese individuals and compared them with similar data in lean control subjects. METHODS: We studied 62 euthyroid subjects who had negative tests for anti-thyroid peroxidise antibodies (Ab-TPO). Thirty eight of these subjects were severely obese but otherwise healthy (severe obese subjects [SOS] group). Twenty-four were healthy control subjects (control group), with a body mass index of 23.3 ± 1.7 kg/m(2). Subjects received 600 µg oral sodium LT4 after an overnight fast. Serum triiodothyronine (T3), T4, and thyroid-stimulating hormone were measured at baseline. Serum T4 and T3 was measured 0.5, 1, 1.5, 2, 2.5, 3, and 4 hours after LT4 administration. RESULTS: Baseline serum T4 and thyroid-stimulating hormone concentrations were higher in the SOS group than in the control group; serum T3 was similar in the two groups. The corrected area under the curve and the maximum T4 concentration after LT4 administration were lower, whereas the time to maximum concentration from the baseline was higher in SOS than in the control group. The estimated plasma volume was higher in the SOS than in the control group. Mean serum T3 levels increased gradually during the four hours after LT4 administration in the control group. In contrast, they decreased gradually in the SOS group. CONCLUSIONS: Severely obese individuals may need higher LT4 suppressive or replacement doses than normal-weight individuals due, among other factors, to impaired LT4 pharmacokinetic parameters. The latter could be attributed to their higher plasma volume and/or to delayed gastrointestinal LT4 absorption. T4 conversion to T3 might be defective in severe obesity.

The alpha2B adrenergic receptor deletion/insertion polymorphism in morbid obesity.

The sympathetic nervous system participates in the regulation of the basal metabolic rate (BMR) and in the manifestation of the obesity-related metabolic syndrome. A deletion/insertion germline polymorphism of the alpha(2B) adrenergic receptor that is associated with reduced agonist-promoted desensitization has been linked to low BMR in obese subjects and to a predisposition to gain weight. This study investigated an association of the alpha(2B) polymorphism with the BMR and metabolic syndrome-related parameters of morbidly obese patients. Genotype frequencies were similar in patients and in a control group. The patients' BMR, adjusted for fat-free mass, fat mass, sex and age, did not differ between alpha(2B) genotypes. The polymorphism was also not associated with the patients' BMI, systolic and diastolic blood pressure, resting heart rate, total and HDL cholesterol, triglycerides, fasting glucose and uric acid levels. These findings do not support a major functional significance of the alpha(2B) adrenergic receptor polymorphism in the present sample of morbidly obese subjects.