Impact of Routine and Long-Term Follow-Up on Weight Loss after Bariatric Surgery.

BACKGROUND: Weight loss after bariatric surgery varies among patients. Patients who do not complete long-term follow-up are considered to loose less weight than those with regular follow-up visits. OBJECTIVE: To evaluate the influence of patients' follow-up compliance on long-term excess weight loss (%EWL) and total weight loss (%TWL) after bariatric surgery, comparing results between gastric bypass (GB) and sleeve gastrectomy (SG). METHODS: Patients with up to 5 years of follow-up data after bariatric surgery were included in this retrospective analysis. Patients were divided in 2 groups: those in group 1 who had attended every scheduled postoperative appointment and those in group 2 who had been lost to follow-up before 1 year and were later contacted by telephone. %EWL and %TWL were compared to determine the possible relationship between type of surgery and regularity of the follow-up. RESULTS: A total of 385 patients were included. A significant difference in EWL was observed at 5 years in the SG group (78% for group 1 versus 39% for group 2; p = 0.02) and GB group (75% for group 1 versus 62% for group 2; p = 0.01). No significant differences between surgeries were found when comparing long-term EWL in group 1 patients 77% for SG versus 75% for GB. For group 2 patients, GB achieved greater EWL than SG; p = 0.005. %TWL patients in group 2 showed significant differences in all periods of study (p < 0.05). CONCLUSION: Bariatric surgery patients who attended all scheduled follow-up appointments experienced significantly greater long-term EWL and TWL than those who did not. GB has apparent increased benefits for weight loss in long-term follow-up when compared with SG for patients who did not attend long-term follow-up. Therefore, continued long-term follow-up of bariatric patients should be encouraged to increase postoperative weight loss results.

Role of ghrelin isoforms in the mitigation of hepatic inflammation, mitochondrial dysfunction, and endoplasmic reticulum stress after bariatric surgery in rats.

BACKGROUND/OBJECTIVES: Bariatric surgery improves nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), but the underlying mechanisms remain elusive. We evaluated the potential role of ghrelin isoforms in the amelioration of hepatic inflammation after sleeve gastrectomy and Roux-en-Y gastric bypass (RYGB). SUBJECTS/METHODS: Plasma ghrelin isoforms were measured in male Wistar rats (n = 129) subjected to surgical (sham operation, sleeve gastrectomy, or RYGB) or dietary interventions [fed ad libitum a normal (ND) or a high-fat diet (HFD) or pair-fed diet]. The effect of acylated and desacyl ghrelin on markers of inflammation, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress in primary rat hepatocytes under palmitate-induced lipotoxic conditions was assessed. RESULTS: Plasma desacyl ghrelin was decreased after sleeve gastrectomy and RYGB, whereas the acylated/desacyl ghrelin ratio was augmented. Both surgeries diminished obesity-associated hepatic steatosis, CD68+- and apoptotic cells, proinflammatory JNK activation, and Crp, Tnf, and Il6 transcripts. Moreover, a postsurgical amelioration in the mitochondrial DNA content, oxidative phosphorylation (OXPHOS) complexes I and II, and ER stress markers was observed. Specifically, following bariatric surgery GRP78, spliced XBP-1, ATF4, and CHOP levels were reduced, as were phosphorylated eIF2α. Interestingly, acylated and desacyl ghrelin inhibited steatosis and inflammation of palmitate-treated hepatocytes in parallel to an upregulation of OXPHOS complexes II, III, and V, and a downregulation of ER stress transducers IRE1α, PERK, ATF6, their downstream effectors, ATF4 and CHOP, as well as chaperone GRP78. CONCLUSIONS: Our data suggest that the increased relative acylated ghrelin levels after bariatric surgery might contribute to mitigate obesity-associated hepatic inflammation, mitochondrial dysfunction, and ER stress.

Role of aquaporin-7 in ghrelin- and GLP-1-induced improvement of pancreatic ß-cell function after sleeve gastrectomy in obese rats.

BACKGROUND/OBJECTIVES: Glycerol is a key metabolite for lipid accumulation in insulin-sensitive tissues as well as for pancreatic insulin secretion. We examined the role of aquaporin-7 (AQP7), the main glycerol channel in ß-cells, and AQP12, an aquaporin related to pancreatic damage, in the improvement of pancreatic function and steatosis after sleeve gastrectomy in diet-induced obese rats. SUBJECTS/METHODS: Male Wistar obese rats (n=125) were subjected to surgical (sham operation and sleeve gastrectomy) or dietary (pair-fed to the amount of food eaten by sleeve-gastrectomized animals) interventions. The tissue distribution and expression of AQPs in the rat pancreas were analyzed by real-time PCR, western blotting and immunohistochemistry. The effect of ghrelin isoforms and glucagon-like peptide 1 (GLP-1) on insulin secretion, triacylglycerol (TG) accumulation and AQP expression was determined in vitro in RIN-m5F ß-cells. RESULTS: Sleeve gastrectomy reduced pancreatic ß-cell apoptosis, steatosis and insulin secretion. Lower ghrelin and higher GLP-1 concentrations were also found after bariatric surgery. Acylated and desacyl ghrelin increased TG content, whereas GLP-1 increased insulin release in RIN-m5F ß-cells. Sleeve gastrectomy was associated with an upregulation of AQP7 together with a normalization of the increased AQP12 levels in the rat pancreas. Interestingly, ghrelin and GLP-1 repressed AQP7 and AQP12 expression in RIN-m5F ß-cells. AQP7 protein was negatively correlated with intracellular lipid accumulation in acylated ghrelin-treated cells and with insulin release in GLP-1-stimulated ß-cells. CONCLUSIONS: AQP7 upregulation in ß-cells after sleeve gastrectomy contributes, in part, to the improvement of pancreatic steatosis and insulin secretion by increasing intracellular glycerol used for insulin release triggered by GLP-1 rather than for ghrelin-induced TG biosynthesis.

Dissociation of body mass index, excess weight loss and body fat percentage trajectories after 3 years of gastric bypass: relationship with metabolic outcomes.

BACKGROUND/OBJECTIVES: Body weight, body mass index (BMI) and excess weight loss (EWL) are the most frequently used measures to analyse bariatric surgery outcomes. However, these measurements do not provide accurate information on body composition (BC) with body fat (BF), importantly determining the levels of cardiometabolic risk factors. Our aim was to analyse the evolution of BC after Roux-en-Y Gastric Bypass (RYGB) and its influence on the changes of cardiometabolic risk factors in comparison to BMI and EWL. SUBJECTS/METHODS: A group of 81 obese Caucasian patients (19 males/62 females) aged 44.9±1.3 years undergoing RYGB between January 2006 and December 2011 was prospectively followed up for a period of 3 years. BC was determined by air-displacement plethysmography. Visceral adiposity, physical activity and cardiometabolic risk factors were measured. RESULTS: BF was markedly (P<0.001) reduced after the first year, increasing progressively during the second and third years after RYGB, following a different trajectory than body weight, BMI and EWL that decreased up to the second year post surgery. Markers of glucose homeostasis decreased during the first month and continued to decrease during the first year (P<0.05), remaining stabilised or slightly increased between the second and third years following RYGB. However, markers of lipid metabolism decreased (P<0.05) markedly during the first 12 months, increasing thereafter in parallel to the changes observed in BC, with the exception of high-density lipoprotein-cholesterol, which increased progressively throughout the whole period analysed. CONCLUSIONS: The adverse switch in the changes in BC between the first and the second years after RYGB may underlie the changes observed in cardiometabolic risk factors. Tracking of adiposity during the follow-up of bariatric/metabolic surgery yields clinically relevant information to better identify patients in need of increased lifestyle advice or treatment intensification.

Crosstalk between adipokines and myokines in fat browning.

Skeletal muscle is the largest organ determining whole-body insulin sensitivity and metabolic homoeostasis. Adaptive changes of skeletal muscle in response to physical activity include adjustments in the production and secretion of muscle-derived bioactive factors, known as myokines, such as myostatin, IL-4, IL-6, IL-7 and IL-15, myonectin, follistatin-like 1 or leukaemia inhibitory factor. These myokines not only act locally in the muscle in an autocrine/paracrine manner, but also are released to the bloodstream as endocrine factors to regulate physiological processes in other tissues. Irisin, derived from the cleavage of FNDC5 protein, constitutes a myokine that induces myogenesis and fat browning (switch of white adipocytes to brown fat-like cells) together with a concomitant increase in energy expenditure. Besides being a target for irisin actions, the adipose tissue also constitutes a production site of FNDC5. Interestingly, irisin secretion from subcutaneous and visceral fat depots is decreased by long-term exercise training and fasting, suggesting a discordant regulation of FNDC5/irisin in skeletal muscle and adipose tissue. Accordingly, our group has recently reported that the adipokine leptin differentially regulates FNDC5/irisin expression in skeletal muscle and fat, confirming the crosstalk between both tissues. Moreover, irisin secretion and function are regulated by other myokines, such as follistatin or myostatin, as well as by other adipokines, including fibroblast growth factor 21 and leptin. Taken together, myokines have emerged as novel molecular mediators of fat browning and their activity can be modulated by adipokines, confirming the crosstalk between skeletal muscle and adipose tissue to regulate thermogenesis and energy expenditure.

[Body weight- independent variations in HDL-cholesterol following gastric bypass]. / Las variaciones en cholesterol-HDL tras bypass gástrico proximal son independientes de la evolución ponderal.

BACKGROUND: Bariatric surgery has multiple beneficial effects on lipid profile in patients with morbid obesity. However, these changes can be attenuated by weight regain. This retrospective study was designed to assess the effects of gastric bypass(GBP) on different lipid fractions over a 6 year follow-up. PATIENTS AND METHODS: We studied 177 patients (135 women)with morbid obesity (BMI 44.2+0.4 kg/m2) aged 42.4+0.9 years before and 3, 6, 9, 12, 24, 36, 48, 60 and 72 months after laparoscopic proximal GBP. Anthropometry, body composition measurement (Bod-Pod) and fasting blood samples were taken in all evaluations to measure total cholesterol (TC),LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C), triglycerides(TG), glucose and insulin. RESULTS: GPB was followed by a significant BMI reduction (nadir BMI at 18 m 28.3+0.4 kg/m2 p<0,001) and fat mass decrease(p<0,001). Maximal percentage of excess BMI lost was 84.1%and that of body fat was 87% 18 months after GBP. These numbers decreased to 65.6% and 38.3% (p<0,005 vs nadir) respectively 72 months after the operation, indicating both weight and fat mass regain. TG and LDL-C values decreased 30% with respect to preoperative levels, while HDL-C increased 97%over initial values. This HDL-C increase was progressive even over the weight regain phase. Both TC/HDL-C and TG/HDL-Cratios normalized after GBP and values were sustained over the weight regain period until the end of the study. CONCLUSIONS: These results confirm the beneficial effects of GBP on all lipid fractions, which are maintained over 6 years of follow-up. Globally, the rise in HDL-C seems to be independent of weight or fat mass changes, since it increases even over the weight regain phase, so contributing to a reduction in the prevalence of dyslipidaemia and to cardiovascular risk reduction.

Physical activity in anorexia nervosa: How relevant is it to therapy response?

OBJECTIVE: Elevated physical activity has been observed in some patients with anorexia nervosa (AN) despite their emaciated condition. However, its effects on treatment outcome remain unclear. This study aimed to examine objectively measured physical activity in this clinical population and how it might be related to a partial hospitalization therapy response, after considering potential confounders. METHOD: The sample comprised 88 AN patients consecutively enrolled in a day hospital treatment program, and 116 healthy-weight controls. All participants were female and a baseline assessment took place using an accelerometer (Actiwatch AW7) to measure physical activity, the Eating Disorders Inventory-2 and the Depression subscale of the Symptom Checklist-Revised. Outcome was evaluated upon the termination of the treatment program by expert clinicians. RESULTS: Although AN patients and controls did not differ in the average time spent in moderate-to-vigorous physical activity (MVPA) (P=.21), nor daytime physical activity (P=.34), fewer AN patients presented a high physical activity profile compared to the controls (37% vs. 61%, respectively; P=.014). Both lower levels of MVPA and greater eating disorder severity had a direct effect on a poor treatment outcome. Depression symptoms in the patients were associated with lower MVPA, as well as with an older age, a shorter duration of the disorder and greater eating disorder psychopathology. CONCLUSIONS: There is a notable variation in the physical activity profile of AN patients, characterized by either low or very high patterns. Physical activity is a highly relevant issue in AN that must be taken into account during the treatment process.

[Interdisciplinary European guidelines on metabolic and bariatric surgery]. / Interdisciplinární Evropská doporucení metabolické a bariatrické chirurgie.

In 2012, an outstanding expert panel derived from IFSO-EC (International Federation for the Surgery of Obesity - European Chapter) and EASO (European Association for the Study of Obesity), composed by key representatives of both Societies including past and present presidents together with EASOs OMTF (Obesity Management Task Force) chair, agreed to devote the joint Medico-Surgical Workshop of both institutions to the topic of metabolic surgery as a pre-satellite of the 2013 European Congress on Obesity (ECO) to be held in Liverpool given the extraordinarily advancement made specifically in this field during the past years. It was further agreed to revise and update the 2008 Interdisciplinary European Guidelines on Surgery of Severe Obesity produced in cooperation of both Societies by focusing in particular on the evidence gathered in relation to the effects on diabetes during this lustrum and the subsequent changes that have taken place in patient eligibility criteria. The expert panel composition allowed the coverage of key disciplines in the comprehensive management of obesity and obesity-associated diseases, aimed specifically at updating the clinical guidelines to reflect current knowledge, expertise and evidence-based data on metabolic and bariatric surgery.

Reduced hepatic aquaporin-9 and glycerol permeability are related to insulin resistance in non-alcoholic fatty liver disease.

BACKGROUND/OBJECTIVES: Glycerol represents an important metabolite for the control of lipid accumulation and hepatic gluconeogenesis. We investigated whether hepatic expression and functionality of aquaporin-9 (AQP9), a channel mediating glycerol influx into hepatocytes, is impaired in non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) in the context of insulin resistance. SUBJECTS/METHODS: Liver biopsies were obtained from 66 morbid obese patients undergoing bariatric surgery (66% women, mean body mass index (BMI) 46.1±1.0 kg m(-2)) with available liver echography and pathology analysis of the biopsies in this cross-sectional study. Subjects were classified according to normoglycemia (NG), impaired glucose tolerance (IGT) or type 2 diabetes (T2D). Hepatic expression of AQP9 was analyzed by real-time PCR, western blotting and immunohistochemistry, while glycerol permeability (P(gly)) was measured by stopped-flow light scattering. RESULTS: AQP9 was the most abundantly (P<0.0001) expressed aquaglyceroporin in human liver (AQP9>>>AQP3>AQP7>AQP10). Obese patients with T2D showed increased plasma glycerol as well as lower P(gly) and hepatic AQP9 expression. The prevalence of NAFLD and NASH in T2D patients was 100 and 65%, respectively. Interestingly, AQP9 expression was decreased in patients with NAFLD and NASH as compared with those without hepatosteatosis, in direct relation to the degree of steatosis and lobular inflammation, being further reduced in insulin-resistant individuals. The association of AQP9 with insulin sensitivity was independent of BMI and age. Consistent with these data, fasting insulin and C-reactive protein contributed independently to 33.1% of the hepatic AQP9 mRNA expression variance after controlling for the effects of age and BMI. CONCLUSIONS: AQP9 downregulation together with the subsequent reduction in hepatic glycerol permeability in insulin-resistant states emerges as a compensatory mechanism whereby the liver counteracts further triacylglycerol accumulation within its parenchyma as well as reduces hepatic gluconeogenesis in patients with NAFLD.

Interdisciplinary European guidelines on metabolic and bariatric surgery.

In 2012, an expert panel composed of presidents of each of the societies, the European Chapter of the International Federation for the Surgery of Obesity (IFSO-EC), and of the European Association for the Study of Obesity (EASO), as well as of the chair of EASO Obesity Management Task Force (EASO OMTF) and other key representatives from IFSO-EC and EASO, devoted the joint Medico-Surgical Workshop of both institutions to the topic of metabolic surgery in advance of the 2013 European Congress on Obesity held in Liverpool. This meeting was prompted by the extraordinary advancement made in the field of metabolic and bariatric surgery during the past decade. It was agreed to revise and update the 2008 Interdisciplinary European Guidelines on Surgery of Severe Obesity produced by focusing in particular on the evidence gathered in relation to the effects on diabetes and the changes in the recommendations of patient eligibility criteria. The expert panel allowed the coverage of key disciplines in the comprehensive management of obesity and obesity-associated diseases, aimed specifically at updating the clinical guidelines to reflect current knowledge, expertise and evidence-based data on metabolic and bariatric surgery.

Inflammation and insulin resistance exert dual effects on adipose tissue tumor protein 53 expression.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: Inflammation and insulin resistance exert dual effects on adipose p53, which seems to be the final result of these opposing forces.

Liver, but not adipose tissue PEDF gene expression is associated with insulin resistance.

OBJECTIVE: Recent studies linked circulating pigment epithelium-derived factor (PEDF) to obesity-associated insulin resistance, but the main source of circulating PEDF is unknown. We aimed to investigate liver and adipose tissue PEDF gene expression in association with obesity and insulin resistance. DESIGN, SUBJECTS AND METHODS: Three (two cross-sectional and one longitudinal) independent cohorts have been studied, for adipose tissue (n=80 and n=30) and liver gene expression (n=32 and n=14). Effects of high glucose and cytokines on HepG2 cell line were also investigated. PEDF gene expression and circulating PEDF were analyzed using real-time PCR and ELISA, respectively. RESULTS: In a first cohort of subjects, PEDF relative gene expression was higher in subcutaneous (SC) than in omental (OM) adipose tissue (P<0.0001) being also higher in mature adipocytes compared with stromo-vascular cells (P<0.0001). However, OM PEDF relative gene expression was decreased in morbidly obese subjects (P=0.01). Both OM PEDF and OM PEDF receptor (PEDFR) correlated positively with lipogenic and lipolytic genes, and with genes implicated in the lipid vacuole formation. Circulating PEDF levels were not associated with fat PEDF gene expression. In the second cohort, SC PEDF was decreased in subjects with type 2 diabetes and did not change significantly after weight loss. We next explored circulating PEDF in association with markers of liver-related insulin resistance injury (alanine aminotransferase, r=0.59, P=0.001). Interestingly, liver PEDF gene expression increased with obesity and insulin resistance in men, being significantly associated with fasting glucose and glycated hemoglobin in two independent cohorts. In fact, high glucose led to increased PEDF in HepG2 cells, while inflammatory stimuli present in the adipose tissue environment downregulated PEDF. CONCLUSION: Liver, but not adipose tissue, might be the source of increased circulating PEDF linked to insulin resistance.

Role of extracellular matrix remodelling in adipose tissue pathophysiology: relevance in the development of obesity.

Adipose tissue responds dynamically to alterations in nutrient excess through adipocyte hypertrophy and hyperplasia, followed by increased angiogenesis, immune cell infiltration, extracellular matrix (ECM) overproduction, and thus, increased production of proinflammatory adipokines during the progression of chronic inflammation. Adipose tissue remodelling is an ongoing process that is pathologically accelerated in the obese state in large part mediated by ECM proteins and proteases. The ECM is subject to major modifications by adipocytes and other cell types that are infiltrated in the adipose tissue, such as macrophages and vascular cells. In obesity, unusual expression of ECM components and fragments derived from tissue-remodelling processes can influence immune cell recruitment and activation, actively contributing to inflammation. ECM turnover requires a tightly regulated balance between the synthesis of the components and their proteolysis, mainly by fibrinolytic systems and matrix metalloproteases (MMPs). In this review, we discuss the key cellular steps that lead to adipose tissue remodelling and the main molecular mechanisms and mediators in this process. We highlight the importance of hypoxia and angiogenesis in the adipose remodelling process, as well as the cross-talk between adipocytes, macrophages and ECM components.

The ghrelin O-acyltransferase-ghrelin system reduces TNF-α-induced apoptosis and autophagy in human visceral adipocytes.

AIMS/HYPOTHESIS: Proinflammatory and proapoptotic cytokines such as TNF-α are upregulated in human obesity. We evaluated the association between ghrelin isoforms (acylated and desacyl ghrelin) and TNF-α in obesity and obesity-associated type 2 diabetes, as well as the potential role of ghrelin in the control of apoptosis and autophagy in human adipocytes. METHODS: Plasma concentrations of the ghrelin isoforms and TNF-α were measured in 194 participants. Ghrelin and ghrelin O-acyltransferase (GOAT) levels were analysed by western-blot, immunohistochemistry and real-time PCR in 53 biopsies of human omental adipose tissue. We also determined the effect of acylated and desacyl ghrelin (10 to 1,000 pmol/l) on TNF-α-induced apoptosis and autophagy-related molecules in omental adipocytes. RESULTS: Circulating concentrations of acylated ghrelin and TNF-α were increased, whereas desacyl ghrelin levels were decreased in obesity-associated type 2 diabetes. Ghrelin and GOAT were produced in omental and subcutaneous adipose tissue. Visceral adipose tissue from obese patients with type 2 diabetes showed higher levels of GOAT, increased adipocyte apoptosis and increased expression of the autophagy-related genes ATG5, BECN1 and ATG7. In differentiating human omental adipocytes, incubation with acylated and desacyl ghrelin reduced TNF-α-induced activation of caspase-8 and caspase-3, and cell death. In addition, acylated ghrelin reduced the basal expression of the autophagy-related genes ATG5 and ATG7, while desacyl ghrelin inhibited the TNF-α-induced increase of ATG5, BECN1 and ATG7 expression. CONCLUSIONS/INTERPRETATION: Apoptosis and autophagy are upregulated in human visceral adipose tissue of patients with type 2 diabetes. Acylated and desacyl ghrelin reduce TNF-α-induced apoptosis and autophagy in human visceral adipocytes.

Short- and long-term changes in gastric morphology and histopathology following sleeve gastrectomy in diet-induced obese rats.

BACKGROUND: Sleeve gastrectomy (SG) has been used as a multipurpose surgical procedure for the treatment of morbid obesity. The aim of the study was to analyze gastric morphology and histology at two different time points after SG in rats. METHODS: Thirty-five male Wistar rats were fed ad libitum during 3 months on a high-fat diet to induce obesity. Subsequently, 25 diet-induced obese rats underwent either SG (n = 12) or a sham operation (n = 13). The remaining ten obese animals encompassed the nonoperated control group (Co). Four weeks postoperatively, 15 rats (n = 5 rats/experimental group) were sacrificed, while the remaining 20 rats were sacrificed after 16 weeks (animals/group; Co = 5, sham = 8, SG = 7) to compare the gastric morphological and histopathological changes over time. Body weight and food intake were regularly recorded. RESULTS: For both time periods, the Co groups exhibited the highest body weight, while the rats undergoing the SG showed the lowest weight gain (P < 0.05). Initially, significant differences (P < 0.005) in food intake relative to body weight were observed between the Co rats and animals undergoing surgery, which disappeared thereafter. The actual total stomach size after both experimental periods in the SG group was similar to that of non- and sham-operated rats mainly due to a forestomach enlargement, which was more pronounced after 16 weeks. Traits of gastritis cystica profunda characterized by gastric foveolae elongation with hyperplasia and cystic dilatation of the glands were observed in the residual stomachs of the sleeve-gastrectomized rats. These findings were mostly observed after 16 weeks of performing the SG, although they were also detected occasionally following 4 weeks postoperatively. No intestinal metaplasia was observed. CONCLUSION: After SG gastric macro- and microscopic changes with functional implications in both the short and long term take place.

Association of increased visfatin/PBEF/NAMPT circulating concentrations and gene expression levels in peripheral blood cells with lipid metabolism and fatty liver in human morbid obesity.

BACKGROUND AND AIMS: Nicotinamide phosphoribosyltransferase (NAMPT) is an adipokine with physiological effects on the control of glucose homeostasis as well as potentially involved in inflammation. The association of circulating NAMPT concentrations with obesity has not been clearly established. The aim of the present work was to evaluate the effect of obesity on circulating concentrations and gene expression levels of NAMPT in human peripheral blood cells (PBCs) as well as its involvement in inflammation, glucose and lipid metabolism. METHODS AND RESULTS: Forty-four serum samples obtained from 14 lean and 30 obese volunteers were used to analyse the circulating concentrations of NAMPT. In addition, PBC, omental adipose tissue (OM) and liver biopsy samples obtained from a subgroup of subjects were used to determine transcript levels of NAMPT by Real-time PCR. Glucose and lipid profile as well as several inflammatory factors and hepatic enzymes were analysed. NAMPT circulating concentrations (P<0.01) and gene expression levels in PBC (P<0.05) were significantly increased in obese patients as compared to lean subjects. Total-cholesterol (P=0.016), HDL-cholesterol (P=0.036) and triglycerides (P=0.050) were significant and independent determinants of circulating concentrations of NAMPT (P<0.01). Moreover, a positive correlation (P<0.01) was found with the hepatic enzymes alanine aminotransferase, aspartate aminotransferase, and γ-glutamyltransferase after BMI adjustment. CONCLUSION: Our work shows that NAMPT circulating concentrations and mRNA expression levels in PBC are increased in obese patients and that plasma NAMPT levels are related to inflammation, lipid metabolism and hepatic enzymes suggesting a potential involvement in fatty liver disease and in the obesity-associated inflammatory state.

Thyroid hormone responsive Spot 14 increases during differentiation of human adipocytes and its expression is down-regulated in obese subjects.

CONTEXT: Very limited information is available regarding the function of human thyroid hormone responsive Spot 14 (human S14, hS14) in adipogenesis and human adiposity. OBJECTIVE: To evaluate hS14 levels during differentiation of human pre-adipocytes, in human fat depots and isolated fat cells. DESIGN: This was a cross-sectional study. SUBJECTS: A total of 161 omental (OM) and 87 subcutaneous (SC) adipose tissue samples obtained during elective surgical procedures from a population who varied widely in terms of obesity. MEASUREMENTS: hS14 gene expression and protein levels during adipogenesis were assessed by RT-PCR, western blot, and using an automated confocal imaging approach. RESULTS: hS14 gene expression levels were decreased in OM adipose tissue from overweight (-42.0%) and obese subjects (-56.5%) compared with lean subjects (P<0.05 and P<0.0001, respectively). hS14 mRNA (but not hS14-related) was inversely associated with obesity measures such as body mass index (P=0.001), percent fat mass (P=0.001), waist-to-hip ratio (P=0.020), and systolic blood pressure (P=0.031). hS14 gene expression and protein levels were up-regulated at the early stages of differentiation of human pre-adipocytes as well as for 3T3-L1 cells. That observation was most prominent in those individual cells exhibiting the more marked differentiation features. hS14 gene expression levels increased by approximately 45 000-fold in mature adipocytes. Increased hS14 levels were also found in stromal-vascular cells/pre-adipocytes (3.8-fold, P<0.05) and in adipose tissue samples (1.9-fold, P<0.0001) from SC compared with OM fat depots. CONCLUSIONS: These results suggest that hS14 is involved in human adipogenesis, but inversely related to obesity and OM fat accumulation.

Increased adipose tissue expression of lipocalin-2 in obesity is related to inflammation and matrix metalloproteinase-2 and metalloproteinase-9 activities in humans.

Lipocalin-2 (LCN2) is a novel adipokine with potential roles in obesity, insulin resistance, and inflammation. The aim of the present work was to evaluate the effect of obesity on circulating concentrations and gene and protein expression levels of LCN2 in human visceral adipose tissue (VAT) as well as its involvement in inflammation. VAT biopsies from 47 subjects were used in the study. Real-time PCR and Western-blot analyses were performed to quantify levels of LCN2 in VAT as well as the association with other genes implicated in inflammatory pathways. Forty-four serum samples were used to analyze the circulating concentrations of LCN2. Zymography analysis was used to determine the activity of matrix metalloproteinase (MMP) in VAT. Obese patients exhibited increased mRNA (p < 0.0001) and protein (p = 0.017) expression levels of LCN2 compared to lean subjects. Although no differences in plasma LCN2 concentrations were observed, increased circulating LCN2/MMP-9 complex levels were found (p = 0.038) in the obese group. Moreover, obese individuals showed increased (p < 0.01) activity of MMP-2 and MMP-9/LCN2 complex, while a positive correlation (p < 0.01) between MMP-2 and MMP-9 activities and BMI was observed. Gene and protein expression levels of LCN2 in VAT were positively associated with inflammatory markers (p < 0.01). These findings represent the first observation that mRNA and protein levels of LCN2 are increased in human VAT of obese subjects. Furthermore, LCN2 is associated with MMP-2 and MMP-9 activities as well as with pro-inflammatory markers suggesting its potential involvement in the low-grade chronic inflammation accompanying obesity.

The bone-adipose axis in obesity and weight loss.

Body fat and lean mass are correlated with bone mineral density, with obesity apparently exerting protection against osteoporosis. The pathophysiological relevance of adipose tissue in bone integrity resides in the participation of adipokines in bone remodeling through effects on deposition and resorption. On the other hand, the skeleton has recently emerged as an endocrine organ with effects on body weight control and glucose homeostasis through the actions of bone-derived factors such as osteocalcin and osteopontin. The cross-talk between adipose tissue and the skeleton constitutes a homeostatic feedback system with adipokines and molecules secreted by osteoblasts and osteoclasts representing the links of an active bone-adipose axis. Given the impact of bariatric surgery on absorption and the adipokine secretory pattern, to focus on the changes taking place following surgical-induced weight loss on this dynamic system merits detailed consideration.