Hospital-diagnosed overweight and obesity related to cancer risk: a 40-year Danish cohort study.

BACKGROUND: Obesity is associated with metabolic abnormalities that predispose patients to increased cancer risk. Contemporary data on the long-term risk of specific cancers are sparse among patients with hospital-diagnosed overweight and obesity. OBJECTIVES: To examine the overall cancer incidence and specific site-related cancer incidences among patients with overweight and obesity, compared to the general Danish population. METHODS: For this 40-year (1977-2016), nationwide, Danish cohort study, we reviewed medical databases to identify individuals with hospital-based overweight and obesity diagnoses. We computed age- and gender-standardized incidence ratios (SIRs) for subsequent cancer compared to the general population. RESULTS: We observed 20 706 cancers among 313 321 patients diagnosed with overweight and obesity (median age 43 years; median follow-up 6.7 years, range 1-40 years) compared to the 18 480 cancers expected; thus, the SIR was 1.12 [95% confidence interval (95% CI): 1.11-1.14]. The SIR associated with overweight and obesity was increased with concomitant comorbidities, like type 2 diabetes (SIR: 1.18; 95% CI: 1.13-1.23) and alcoholism-related diseases (SIR: 1.62; 95% CI: 1.45-1.82). The SIR was 1.31 (95% CI: 1.28-1.34) for cancers previously identified as obesity-related, including pancreatic (SIR: 1.38; 95% CI; 1.27-1.49) and postmenopausal breast cancer (SIR: 1.14; 95% CI: 1.09-1.19). Obesity/overweight status also elevated the SIRs for haematological (SIR: 1.24; 95% CI: 1.18-1.29) and neurological cancers (SIR: 1.19; 95% CI: 1.11-1.27]. In contrast, SIRs were 1.01 (95% CI: 0.97-1.05) for immune-related cancers, 0.88 (95% CI: 0.82-0.95) for malignant melanoma, and 0.88 (95% CI: 0.85-0.92) for hormone-related cancers, other than postmenopausal breast cancer. CONCLUSION: In this large cohort study, overweight and obesity was associated with increased risk of several common cancers.

Changes in Circulating BDNF in relation to Sex, Diet, and Exercise: A 12-Week Randomized Controlled Study in Overweight and Obese Participants.

Circulating BDNF is higher in women than in men and suggested to be affected by changes in food intake, body weight, and exercise. The purpose of this study was to compare BDNF concentrations in women and men during a 12-week weight loss intervention. Using a previously published 12-week randomized study, serum BDNF was assessed at baseline and after 12 weeks using an enzyme-linked immunosorbent assay method. Fifty overweight or obese but healthy individuals (26 women, mean age of 36.4 ± 7.9 years; 24 men, mean age of 38.0 ± 5.9 years) were included and allocated into three groups: exercise-only (EXO; 12 weeks of aerobic exercise and isocaloric diet), diet-only (DIO; 8 weeks of very low energy diet (VLED 600 kcal/day) followed by a 4-week weight maintenance diet), or diet and exercise (DEX; 12 weeks of aerobic exercise in parallel with 8 weeks of VLED (800 kcal/day) followed by a 4-week weight maintenance diet). At baseline, BDNF levels were 25% higher in women compared to men (p=0.006). Body weight was reduced in all intervention groups (p < 0.006). Exercise (EXO group) induced a 22% reduction in circulating BDNF in men (p=0.037) and women (p=0.080). In the DIO and DEX groups, a significant reduction in BDNF levels (29.9%; p=0.035 and 32.5%; p=0.003, respectively) was observed in women but not in men. In conclusion, circulating BDNF was significantly changed by diet alone or combined with exercise in women and only by exercise alone in men. This suggests that changes in circulating BDNF depend on weight loss methods (diet/exercise) as well as sex.

Early changes in vitamin B12 uptake and biomarker status following Roux-en-Y gastric bypass and sleeve gastrectomy.

BACKGROUND & AIMS: Bariatric surgery increases the risk of micronutrient deficiencies, including vitamin B12 (B12) deficiency. We analysed early changes in biomarkers of B12 status following bariatric surgery. METHODS: We prospectively included adult patients (n = 27) referred for either Roux-en-Y Gastric Bypass (RYGB) (n = 19) or Sleeve Gastrectomy (SG) (n = 8). Blood samples were drawn before surgery and 2 and 6 months following surgery for measurement of B12, holotranscobalamin (holoTC), and methylmalonic acid (MMA). The B12 absorption capacity was estimated from the increase in plasma holoTC two days after a standardised oral B12 challenge. RESULTS: B12 status decreased following both RYBG and SG. While a decrease in plasma B12 was not evident until 6 months postoperatively, we observed a statistically significant decrease in plasma holoTC and increase in MMA already 2 months postoperatively. These changes were more pronounced at 6 months post surgery. Correspondingly, the B12 absorption capacity was decreased following surgery. CONCLUSIONS: HoloTC and MMA were superior to B12 to detect early changes in B12 status following bariatric surgery. Our data challenge the current concept that liver B12 stores secure long-term maintenance of B12 status. They indicate that B12 treatment in pharmacological doses may be warranted immediately after surgery.

Diabetic retinopathy in people with Type 2 diabetes and obesity treated by Roux-en-Y gastric bypass compared with non-operated controls: with focus on the role of diabetes remission in a cross-sectional and a 6-year follow-up study.

AIM: Whether or not Roux-en-Y gastric bypass (RYGB) and the derived metabolic improvements are beneficial to diabetic retinopathy is controversial. We aimed to determine the presence and development of retinopathy in individuals with obesity and Type 2 diabetes treated by RYGB compared with non-operated controls, and to determine the role of diabetes remission. METHODS: We graded fundus photography using the Wisconsin Epidemiologic Study of Diabetic Retinopathy in 96 individuals with obesity and Type 2 diabetes treated by RYGB 6 years after surgery compared with 48 non-operated controls. In a subsample, we investigated the development of retinopathy over time. In the secondary analysis, we divided the RYGB group according to diabetes remission. RESULTS: RYGB surgery was not statistically associated with less retinopathy [relative risk (RR) 0.82, 95% CI 0.59 to 1.14], when adjusted for diabetes duration, sex, age and BMI. During 5.9 years of follow-up, retinopathy grading in the RYGB group was unchanged, whereas the control group displayed worse grading by 0.69 steps (95% CI 0.18 to 1.19). The RYGB group with diabetes remission (52%) showed a trend towards less retinopathy [adjusted RR (aRR) 0.45; 95% CI 0.19 to 1.06] than controls, and less retinopathy (aRR 0.33; 95% CI 0.11 to 0.94) than the RYGB group without remission in the cross-sectional data. CONCLUSIONS: In a cross-sectional setting, individuals with Type 2 diabetes treated by RYGB showed a tendency towards less retinopathy than non-operated controls, in particular diabetes remission following RYGB was associated with less retinopathy. Moreover after 5.9 years, retinopathy in the RYGB group had progressed less than in the control group. (Clinical Trial Registry No: NCT02625649).

Amino acid supplementation is anabolic during the acute phase of endotoxin-induced inflammation: A human randomized crossover trial.

BACKGROUND & AIMS: Inflammation is catabolic and causes muscle loss. It is unknown if amino acid supplementation reverses these effects during the acute phase of inflammation. The aim was to test whether amino acid supplementation counteracts endotoxin-induced catabolism. METHODS: Eight young, healthy, lean males were investigated three times in randomized order: (i) normal conditions (Placebo), (ii) endotoxemia (LPS), and (iii) endotoxemia with amino acid supplementation (LPS + A). Protein kinetics were determined using phenylalanine, tyrosine, and urea tracers. Each study day consisted of a four-hour non-insulin stimulated period and a two-hour hyperinsulinemic euglycemic clamp period. Muscle biopsies were collected once each period. RESULTS: Endotoxin administration created a significant inflammatory response (cytokines, hormones, and vital parameters) without significant differences between LPS and LPS + A. Whole body protein breakdown was elevated during LPS compared with Placebo and LPS + A (p < 0.05). Whole body protein synthesis was higher during LPS + A than both Placebo and LPS (p < 0.003). Furthermore, protein synthesis was higher during LPS than during Placebo (p < 0.02). Net muscle phenylalanine release was markedly decreased during LPS + A (p < 0.004), even though muscle protein synthesis and breakdown rates did not differ significantly between interventions. LPS + A increased mammalian target of rapamycin (mTOR) phosphorylation (p < 0.05) and eukaryotic translation factor 4E-binding protein 1 (4EBP1) phosphorylation (p = 0.007) without activating AMPK or affecting insulin signaling through Akt. During insulin stimulation net muscle phenylalanine release and protein degradation were further reduced. CONCLUSIONS: Amino acid supplementation in the acute phase of inflammation reduces whole body and muscle protein loss, and this effect is associated with activation of mTOR and downstream signaling to protein synthesis through mTORC1, suggesting a therapeutic role for intravenous amino acids in inflammatory states. CLINICAL TRIAL REGISTRY: The Central Denmark Region Ethics Commitee (1-10-71-410-12) www.clinicaltrials.gov (identification number NCT01705782).

Consumption of sucrose-sweetened soft drinks increases plasma levels of uric acid in overweight and obese subjects: a 6-month randomised controlled trial.

BACKGROUND/OBJECTIVES: Sucrose-sweetened soft drinks (SSSDs) are associated with the development of metabolic disorders. Fructose is a major component of SSSDs and is demonstrated to induce uric acid (UA) production and stimulate fat accumulation independent of excess caloric intake. UA induce insulin resistance and low-grade inflammation, suggesting that UA may have a causal role in the development of metabolic complications. The objective of this study is to investigate the long-term effects of consuming SSSDs on circulating levels of UA in overweight and obese subjects. SUBJECTS/METHODS: Using a previously published study, circulating UA levels were assessed at baseline and after 6 months using chromogenic enzymatic absorptiometry. The study included 47 overweight and obese subjects without diabetes, randomised to consume 1 l daily of either SSSD (regular cola), isocaloric semi-skimmed milk, diet cola or water for 6 months. RESULTS: Circulating UA levels increased ~15% (P = 0.02) after the 6-month intervention in the SSSD group with no change in the other groups. In the SSSD group, circulating UA levels increased significantly after the intervention in both absolute (P = 0.005) and relative values (P = 0.004). The change in UA after the intervention correlated with changes in liver fat (P = 0.005), triglycerides (P = 0.02) and insulin (P = 0.002). CONCLUSIONS: In this secondary analysis daily intake of 1 l SSSD for 6 months was found to increase circulating UA levels compared with isocaloric milk, diet cola and water. Thus, a high daily intake of SSSDs in overweight and obese subjects without overt diabetes may increase the risk of developing metabolic complications through the elevation of UA. This trial is registered at ClinicalTrials.gov as NCT00777647.

Effects of LPS and dietary free fatty acids on MCP-1 in 3T3-L1 adipocytes and macrophages in vitro.

BACKGROUND: High levels of free fatty acids (FFA) have been suggested to be one of the underlying mechanisms for adipose tissue (AT) inflammation and dysfunction in obesity. Human AT produces several adipokines including monocyte chemoattractant protein-1 (MCP-1), which are involved in the pathogenesis of obesity-mediated inflammation. OBJECTIVE: In this study, we investigated the effects of lipopolysaccharide (LPS) and a panel of dietary FFA on MCP-1 gene and protein expression in adipocytes and macrophages. Furthermore, we investigated whether the effect of LPS and FFA were mediated through the toll-like receptor 4 (TLR4). METHODS: 3T3-L1 adipocytes and THP-1 macrophages were incubated for 24 h with the following FFA: monounsaturated fatty acid (oleic acid), saturated fatty acid (palmitic acid) and trans fatty acid (elaidic acid; 500 µM) with and without LPS (2 ng ml(-1)), and MCP-1 and TLR4 mRNA expression and MCP-1 protein secretion was determined. RESULTS: The results showed that LPS significantly increased MCP-1 and TLR4 expression and MCP-1 secretion in 3T3-L1 adipocytes, and that the MCP-1 expression was blocked by a TLR4 inhibitor (CLI095). The effects of the various FFA on MCP-1 mRNA expression and protein secretion in the adipocytes showed no significant changes either alone or in combination with LPS. In macrophages, palmitic acid increased MCP-1 mRNA expression by 1.8-fold (P<0.05), but oleic acid and elaidic acid had no effects. CONCLUSIONS: In conclusion, in 3T3-L1 adipocyte, the TLR4-agonist, LPS, stimulates the proinflammatory chemokine MCP-1. The different classes of FFA did not induce MCP-1 mRNA expression or protein secretion in the adipocytes, but the saturated FFA, palmitic acid, induced MCP-1 mRNA expression in macrophages, possibly because of the higher expression level of TLR4 in the macrophages than the adipocytes. Our results indicate that FFA may induce AT inflammation through proinflammatory stimulation of macrophages.

Strength training and testosterone treatment have opposing effects on migration inhibitor factor levels in ageing men.

BACKGROUND: The beneficial effects of testosterone treatment (TT) are debated. METHODS: Double-blinded, placebo-controlled study of six months TT (gel) in 54 men aged 60-78 with bioavailable testosterone (BioT) <7.3 nmol/L and waist >94 cm randomized to TT (50-100 mg/day, n = 20), placebo (n = 18), or strength training (ST) (n = 16) for 24 weeks. Moreover, the ST group was randomized to TT (n = 7) or placebo (n = 9) after 12 weeks. OUTCOMES: Chemokines (MIF, MCP-1, and MIP-1 α ) and lean body mass (LBM), total, central, extremity, visceral, and subcutaneous (SAT) fat mass established by DXA and MRI. Results. From 0 to 24 weeks, MIF and SAT decreased during ST + placebo versus placebo, whereas BioT and LBM were unchanged. TT decreased fat mass (total, central, extremity, and SAT) and increased BioT and LBM versus placebo. MIF levels increased during TT versus ST + placebo. ST + TT decreased fat mass (total, central, and extremity) and increased BioT and LBM versus placebo. From 12 to 24 weeks, MCP-1 levels increased during TT versus placebo and MCP-1 levels decreased during ST + placebo versus placebo. CONCLUSION: ST + placebo was associated with decreased MIF levels suggesting decreased inflammatory activity. TT may be associated with increased inflammatory activity.

Effects of vitamin D supplementation on body fat accumulation, inflammation, and metabolic risk factors in obese adults with low vitamin D levels - results from a randomized trial.

BACKGROUND: Low plasma 25-hydroxy-vitamin D (25OHD) is associated with obesity. Vitamin D (VD) may be implicated in obesity and its complications such as insulin resistance, hypertension, and low-grade inflammation. We investigated the effects of VD supplementation on fat distribution and on obesity complications in obese adults with low plasma levels of 25OHD. METHODS: In a double-blind design 52 subjects aged 18 to 50years with BMI>30kg/m(2) and plasma 25OHD <50nmol/l were randomized to 26weeks of treatment with 7000IU of VD daily or placebo. Body composition was assessed by DXA and subcutaneous (SAT) and visceral adipose tissue (VAT), intrahepatic (IHL) and intramyocellular lipids (IMCL) were evaluated by magnetic resonance imaging and magnetic resonance spectroscopy. Insulin resistance (HOMA-IR), blood pressure, plasma lipids, and circulating inflammatory markers were also investigated. RESULTS: VD treatment increased mean plasma levels of 25OHD from 33nmol/l to 110nmol/l (P<0.0001) and decreased median parathyroid hormone levels from 5.3 to 4.5pmol/l (P<0.01) in the intervention group. Treatment did not change body fat, SAT, VAT, IHL, or IMCL compared with placebo. Neither did treatment affect HOMA, blood pressure, plasma lipids or any of several inflammatory markers investigated including hsCRP. CONCLUSION: Increasing 25OHD levels by VD treatment for 26weeks have no effects on obesity complications in obese adults with low baseline plasma 25OHD.

Effect of weight loss and exercise on angiogenic factors in the circulation and in adipose tissue in obese subjects.

BACKGROUND: Vascular growth is a prerequisite for adipose tissue (AT) development and expansion. Some AT cytokines and hormones have effects on vascular development, like vascular endothelial growth factor (VEGF-A), angiopoietin (ANG-1), ANG-2 and angiopoietin-like protein-4 (ANGPTL-4). METHODS: In this study, the independent and combined effects of diet-induced weight loss and exercise on AT gene expression and proteins levels of those angiogenic factors were investigated. Seventy-nine obese males and females were randomized to: 1. Exercise-only (EXO; 12-weeks exercise without diet-restriction), 2. Hypocaloric diet (DIO; 8-weeks very low energy diet (VLED) + 4-weeks weight maintenance diet) and 3. Hypocaloric diet and exercise (DEX; 8-weeks VLED + 4-weeks weight maintenance diet combined with exercise throughout the 12 weeks). Blood samples and fat biopsies were taken before and after the intervention. RESULTS: Weight loss was 3.5 kg in the EXO group and 12.3 kg in the DIO and DEX groups. VEGF-A protein was non-significantly reduced in the weight loss groups. ANG-1 protein levels were significantly reduced 22-25% after all three interventions (P < 0.01). The ANG-1/ANG-2 ratio was also decreased in all three groups (P < 0.05) by 27-38%. ANGPTL-4 was increased in the EXO group (15%, P < 0.05) and 9% (P < 0.05) in the DIO group. VEGF-A, ANG-1, and ANGPTL-4 were all expressed in human AT, but only ANGPTL-4 was influenced by the interventions. CONCLUSIONS: Our data show that serum VEGF-A, ANG-1, ANG-2, and ANGPTL-4 levels are influenced by weight changes, indicating the involvement of these factors in the obese state. Moreover, it was found that weight loss generally was associated with a reduced angiogenic activity in the circulation.

Investigations of the anti-inflammatory effects of vitamin D in adipose tissue: results from an in vitro study and a randomized controlled trial.

Inflammation is a key feature of obesity and type 2 diabetes. The active vitamin D metabolite, 1,25-dihydroxyvitamin D [1,25(OH)2D], modulates the inflammation in vitro. We studied whether inflammation in adipose tissue (AT) cultures could be reduced by incubation with 1,25(OH)2D in vitro, or by oral treatment with vitamin D in vivo in obese subjects with low plasma levels of 25-hydroxyvitamin D. Samples of subcutaneous AT were stimulated with IL-1ß to induce inflammation. In the in vitro study, samples were concomitantly incubated with or without 1,25(OH)2D, and analyzed for mRNA and protein levels of inflammatory markers IL-6, IL-8, and MCP-1. In the in vivo study, samples of subcutaneous AT from obese subjects obtained before and after treatment with 7,000 IU of vitamin D daily or placebo in a randomized controlled trial were stimulated with IL-1ß. The samples were analyzed for AT gene expression and compared with plasma markers of inflammation. In the in vitro study, concomitant incubation with 1,25(OH)2D reduced mRNA levels of MCP-1 by 45% (p=0.01), of IL-6 by 32% (p=0.002), and of IL-8 by 34% (p=0.03), and reduced secretion of IL-8 protein by 18% (p=0.005). In vivo treatment with vitamin D did not reduce AT expression or circulating levels of MCP-1, IL-6, or IL-8. 1,25(OH)2D has significant anti-inflammatory effects in AT in vitro. However, a similar reduction in AT and systemic inflammation cannot be obtained by oral treatment with vitamin D in obese subjects.

Expression of vitamin D-metabolizing enzymes in human adipose tissue -- the effect of obesity and diet-induced weight loss.

OBJECTIVE: Low vitamin D (VD) levels are common in obesity. We hypothesized that this may be due to metabolism of VD in adipose tissue (AT). Thus, we studied (1) whether the VD-metabolizing enzymes were expressed differently in AT of lean and obese individuals and in visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT), and (2) whether their expression was influenced by weight loss. METHODS: Samples of SAT and VAT were analyzed for expression of the vitamin-D-25-hydroxylases CYP2R1, CYP2J2, CYP27A1 and CYP3A4, the 25-vitamin-D-1α-hydroxylase CYP27B1, the catabolic vitamin-D-24-hydroxylase CYP24A1, and the vitamin D receptor, using reverse transcriptase-PCR. Moreover, plasma 25-hydroxy-vitamin D (25OHD) level was measured and related to the expression of these enzymes. Samples of SAT and VAT from 20 lean women and 20 obese women, and samples of SAT from 17 obese subjects before and after a 10% weight loss were analyzed. RESULTS: A plasma 25OHD level <50 nmol l(-1) was highly prevalent in both lean (45%) and obese (90%) women (P<0.01). Plasma 25OHD increased by 27% after weight loss in the obese individuals (P<0.05). Expression levels of the 25-hydroxylase CYP2J2 and the 1α-hydroxylase CYP27B1 were decreased by 71% (P<0.0001) and 49% (P<0.05), respectively, in SAT of the obese. CYP24A1 did not differ between lean and obese women, but the expression was increased by 79% (P<0.05) after weight loss. CONCLUSION: Obesity is characterized by a decreased expression of the 25-hydroxylase CYP2J2 and the 1α-hydroxylase CYP27B1 in SAT, whereas the catabolic CYP24A1 does not differ between lean and obese women. However, the expression of CYP24A1 is increased after weight loss. Accordingly, AT has the capacity to metabolize VD locally, and this can be dynamically altered during obesity and weight loss.

The effect of weight loss on serum mannose-binding lectin levels.

BACKGROUND: Serum levels of the mannose-binding lectin (MBL), which is an activator of the complement system, have been considered as a pathogenic factor in a broad range of diseases, and means of modulating MBL are therefore being evaluated. In this study we examine the effects of weight loss on MBL levels, and in continuation of this if MBL is synthesized in human adipose tissue. METHODS: 36 nondiabetic obese subjects received a very low-calorie diet (VLCD) of 800 kcal/day for 8 weeks. Blood samples were collected at baseline and after VLCD. Furthermore, we measured MBL mRNA levels by the real-time RT-PCR on human adipose tissue compared to liver tissue. RESULTS: The mean body weight was reduced from 106.3 ± 2.6 kg to 92.8 ± 2.4 kg, P < 0.0001. Median MBL at baseline was 746 µg/L (IQR 316-1190) versus 892 µg/L (IQR 336-1511) after 8 weeks, P = 0.23. No correlations were found between weight loss and changes in MBL (r = -0.098, P = 0.57). MBL real-time RT-PCR showed no expression of mRNA in adipose tissue, but as expected a good expression in liver tissue was seen. CONCLUSIONS: MBL levels are not affected by weight loss and MBL is not synthesized in human adipose tissue.

Satiety scores and satiety hormone response after sucrose-sweetened soft drink compared with isocaloric semi-skimmed milk and with non-caloric soft drink: a controlled trial.

BACKGROUND/OBJECTIVES: Observational studies indicate that sugar-sweetened soft drinks (SSSD) may promote obesity, among other factors, owing to low-satiating effects. The effect of energy in drinks on appetite is still unclear. We examined the effect of two isocaloric, but macronutrient, different beverages (SSSD versus semi-skimmed milk) and two non-energy-containing beverages (aspartame-sweetened soft drink (ASSD) and water) on appetite, appetite-regulating hormones and energy intake (EI). SUBJECTS/METHODS: In all, 24 obese individuals were included in a crossover trial. Each subject was served either 500 ml of SSSD (regular cola: 900 kJ), semi-skimmed milk (950 kJ), ASSD (diet cola: 7.5 kJ), or water. Subjective appetite scores, ghrelin, GLP-1, and GIP concentrations were measured at baseline and continuously 4-h post intake. Ad libitum EI was measured 4 h after intake of the test drinks. RESULTS: Milk induced greater subjective fullness and less hunger than regular cola (P<0.05). Also, milk led to 31% higher GLP-1 (95% CI: 20, 44; P<0.01) and 45% higher GIP (95% CI: 23, 72; P<0.01) concentrations compared with SSSD. Ghrelin was equally 20% lower after milk and SSSD compared with water. The total EI (ad libitum EI+EI from the drink) was higher after the energy-containing drinks compared with diet cola and water (P<0.01). CONCLUSIONS: Milk increased appetite scores and GLP-1 and GIP responses compared with SSSD. The energy containing beverages were not compensated by decreased EI at the following meal, emphasizing the risk of generating a positive energy balance by consuming energy containing beverages. Furthermore, there were no indications of ASSD increased appetite or EI compared with water.

Investigations of the human endocannabinoid system in two subcutaneous adipose tissue depots in lean subjects and in obese subjects before and after weight loss.

CONTEXT: Endocannabinoids (ECs) have a role in obesity by affecting appetite and through peripheral effects. Obesity is associated with a dysregulation of the endocannabinoid system (ECS). OBJECTIVE: We aimed to determine the ECS in subcutaneous adipose tissue (AT) in obese subject and investigate the influence of diet-induced weight loss on this system. DESIGN: The obese study participants underwent a 12 weeks diet regimen resulting in 10-12% weight loss. All study participants underwent fasting blood samples and AT biopsies from abdomen and gluteal region, the obese subjects both before and after weight loss. SETTING AND PARTICIPANTS: A total of 21 healthy obese individuals (10 men/11 women, age 39.5 ± 1.6 years, body mass index (BMI): 37.5 ± 0.8 kg m(-2)) and 21 age- and gender-matched lean subjects (BMI: 23.8 ± 0.4 kg m(-2)) were studied. MAIN OUTCOME MEASURES: The activity of ECS in AT was determined by measuring arachidonoyl glycerol (2-AG) and N-arachidonoylethanolamine/anandamide in AT by mass spectrometry and gene expressions of enzymes and receptors involved in the ECS. RESULTS: The EC, 2-AG was reduced in obese individuals in the gluteal AT depot (P<0.01). Moreover, 2-AG increased in both depots in the obese subjects following weight loss (P<0.05). The gene expression of the CB1 was either not affected by the obese state (in the gluteal AT depot) or reduced (in the abdominal depot, P<0.05) and significantly affected by weight loss. The expression of the degrading enzymes FAAH, FAAH2, MGL and MGL2 was differently affected by obesity, AT depot and weight loss. CONCLUSION: We found reduced levels of 2-AG in subcutaneous AT in obesity, which increased after weight loss. In abdominal AT, the low CB1 expression was normalised after weight loss, whereas in gluteal AT the CB1 expression was reduced after weight loss. These findings support the concept of a dysregulated ECS in AT in association with obesity.

Improved glucose tolerance after intensive life style intervention occurs without changes in muscle ceramide or triacylglycerol in morbidly obese subjects.

AIM: This study investigated the effect of a 15-week life style intervention (hypocaloric diet and regular exercise) on glucose tolerance, skeletal muscle lipids and muscle metabolic adaptations in 14 female and 9 male morbidly obese subjects (age: 32.5±2.3 years, body mass index: 46.1±1.9 kg m(-2) ). METHOD: Before and after the life style intervention, an oral glucose tolerance test was performed and a muscle biopsy was obtained in the fasted state. Maximal oxygen uptake was measured by an indirect test. RESULTS: After the intervention, body weight was decreased (P<0.05) by 11±1%, maximal oxygen uptake increased (P<0.05) by 18±5% and glucose tolerance increased (P<0.05) by 12±3%. Muscle glycogen was significantly increased by 47±14%, but muscle ceramide and triacylglycerol content remained completely unchanged. No sex difference was observed for any of these parameters, but during submaximal exercise a marked decrease (P<0.05) of 15±2% in respiratory exchange ratio was seen only in females indicating an enhanced fat oxidation. CONCLUSION: Despite a marked weight loss and an improved aerobic capacity muscle ceramide and triacylglycerol remained unchanged after intensive life style intervention, and muscle lipids hence do not seem to play a major role for the improved glucose tolerance in these morbidly obese subjects. Interestingly, only the females improved fat oxidation during submaximal exercise after the intervention implying the presence of a sex-dependent response to intensive life style adaptation.

Anti-inflammatory effect of resveratrol on adipokine expression and secretion in human adipose tissue explants.

OBJECTIVE: Human obesity is closely associated with a state of chronic low-grade inflammation, which also involves the adipose tissue with enhanced production of bioactive substances (adipokines). Calorie restriction (CR) reduces adipocytokine production and improves metabolic profile in rodents. Some of these effects are mediated through activation of the sirtuin 1 (Sirt1) enzyme, and in this study, we investigate whether the natural phytoalexin, resveratrol (RSV), which is a potent Sirt1 activator, has anti-inflammatory effects in human adipose tissue explants. DESIGN: The effect of RSV on interleukin 1ß (IL1ß)-induced change of adipokine mRNA gene expression and secretion were measured in human adipose tissue explants. RESULTS: Exposure of human adipose tissue in vitro to IL1ß for 24 h increased secretion of the proinflammatory adipokines IL6, IL8 and monocyte chemoattractant protein 1 (MCP-1) 3-7.7-fold (P<0.05) and increased IL6, IL8, MCP-1, IL1ß and PAI-1 mRNA expression 1.3-7.2-fold (P<0.05) accordingly. Concomitant incubations with RSV reversed the IL1ß-stimulated secretion (16-36%) and gene expression (25-48%) of these adipokines. IL1ß reduced adiponectin mRNA expression (40%), a decrement that was reversed by RSV treatment. Similar effects were observed in differentiated human preadipocytes in primary culture, indicating that human adipocytes are a potential target for RSV effects. Finally, the effects were neutralized by sirtinol, a Sirt1 inhibitor. CONCLUSION: This study is the first to show anti-inflammatory effects of RSV on adipokine expression and secretion in human adipose tissue in vitro through the SIRT1 pathway. Thus, RSV is hypothesized to possess beneficial effects and might improve the metabolic profile in human obesity.

Reduced cannabinoid receptor 1 protein in subcutaneous adipose tissue of obese.

BACKGROUND: Cannabinoid 1 receptors are identified in various tissues involved in the internal metabolism including adipose tissue and the endocannabinoid system is claimed to be overactive in the obese state. To study the potential involvement of cannabinoid receptor 1 in the endocannabinoid system over-activity in adipose tissue in the obese state, we investigated the cannabinoid receptor 1 levels in adipose tissue from different fat depots in lean and obese humans. MATERIALS AND METHODS: The adipose tissue samples were analysed by Western blot and by RT-PCR. RESULTS: Both the gene expression and the protein of cannabinoid receptor 1 were lower in subcutaneous abdominal adipose tissue from obese subjects as compared with lean subjects (P < 0.01 and P = 0.058). Moreover, in lean subjects, the level of cannabinoid receptor 1 was significantly higher in subcutaneous adipose tissue compared with visceral adipose tissue (P < 0.05) for both gene expression and protein. The level of cannabinoid receptor 1 was similar between the two depots in obese subjects. The expression of cannabinoid receptor 1 was higher in subcutaneous gluteal adipose tissue as compared with subcutaneous abdominal adipose tissue (P < 0.05). CONCLUSION: We found in lean subjects, a robust lower level of cannabinoid receptor 1 in visceral adipose tissue compared with subcutaneous adipose tissue (both RNA and protein levels), but similar levels of cannabinoid receptor 1 between the two depots in obese subjects. Our present findings do not indicate that cannabinoid receptor 1 is directly involved in the endocannabinoid system over-activity in adipose tissue in obesity.

Weight history of patients with newly diagnosed Type 2 diabetes.

AIMS: To estimate and illustrate how the 10 years of weight change immediately preceding diabetes diagnosis vary with weight at the age of 20 years and with socio-demographic variables, risk factors and comorbidities at diagnosis. METHODS: Data were from a population-based cohort of 1320 persons newly diagnosed with diabetes aged > or = 40 years. Patients' weight at diagnosis was measured by the doctor, while patients recalled their weight approximately 1, 5 and 10 years prior to diagnosis and at age 20 years. RESULTS: Median weight gain from age 20 years to diabetes diagnosis at median age 65.3 years was 14.7 kg (interquartile range 6.0-23.0). Women gained weight more than men, and the lower the weight at age 20 years, the greater the weight gain. The average weight gain from 10 years prior to diabetes diagnosis until diagnosis, however, was only 1 kg and decreased markedly with age. These 10 years of weight change were also associated with sex and the following baseline characteristics: diagnostic plasma glucose, urinary glucose, urinary albumin, fasting triglycerides, systolic blood pressure, smoking habits, and presence of diabetic retinopathy. CONCLUSIONS: The results add to the evidence that it is important to advise young patients in particular, especially women, who have gained and sustained considerable weight to curb this upward weight trend in order to prevent the development of diabetes.