Effect of Massive Weight Loss on Inflammatory Adipocytokines and the Innate Immune System in Morbidly Obese Women

Manco, Melania; Fernández‐Real, José Manuel; Equitani, Francesco; Vendrell, Joan; Mora, Maria Elena Valera; Nanni, Giuseppe; Tondolo, Vincenzo; Calvani, Menotti; Ricart, Wifredo; Castagneto, Marco; Mingrone, Geltrude

doi:10.1210/jc.2006-0960

Cited by 146 publications

(118 citation statements)

References 53 publications

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“…In this study, we have segregated inflammatory and metabolic biomarkers specific for severe obesity and OSA. Severe obesity leads to chronic inflammation, which has been implicated in poor cardiovascular outcomes (13). OSA causes lowgrade inflammation and hypercytokinemia (6).…”

Section: Osa Systemic Inflammation and Metabolic Dysfunction In Sevmentioning

confidence: 99%

“…Insulin resistance, systemic inflammation, and OSA are particularly prevalent in patients with severe obesity defined as a body mass index (BMI) exceeding 40 kg/m 2 (2,(10)(11)(12). While obesity causes systemic inflammation, insulin resistance, and sleep apnea (12)(13)(14)(15), sleep apnea may further exacerbate the inflammatory and metabolic disturbances (2,3,6). Nevertheless, it is not known whether concomitant OSA is implicated in metabolic dysregulation and systemic inflammation in severe obesity.…”

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confidence: 99%

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Obstructive Sleep Apnea, Insulin Resistance, and Steatohepatitis in Severe Obesity

Polotsky

Patil

Savransky

et al. 2009

Am J Respir Crit Care Med

191

139

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Rationale: Obstructive sleep apnea is associated with insulin resistance and liver injury. It is unknown whether apnea contributes to insulin resistance and steatohepatitis in severe obesity. Objectives: To examine whether sleep apnea and nocturnal hypoxemia predict the severity of insulin resistance, systemic inflammation, and steatohepatitis in severely obese individuals presenting for bariatric surgery. Methods: We performed sleep studies and measured fasting blood glucose, serum insulin, C-reactive protein, and liver enzymes in 90 consecutive severely obese individuals, 75 women and 15 men, without concomitant diabetes mellitus or preexistent diagnosis of sleep apnea or liver disease. Liver biopsies (n 5 20) were obtained during bariatric surgery. Measurements and Main Results: Obstructive sleep apnea with a respiratory disturbance index greater than 5 events/hour was diagnosed in 81.1% of patients. The median respiratory disturbance index was 15 6 29 events/hour and the median oxygen desaturation during apneic events was 4.6 6 1.8%. All patients exhibited high serum levels of C-reactive protein, regardless of the severity of apnea, whereas liver enzymes were normal. Oxygen desaturation greater than 4.6% was associated with a 1.5-fold increase in insulin resistance, according to the homeostasis model assessment index. Histopathology data suggested that significant nocturnal desaturation might predispose to hepatic inflammation, hepatocyte ballooning, and liver fibrosis. Fasting blood glucose levels and steatosis scores were not affected by nocturnal hypoxia. There was no relationship between the respiratory disturbance index and insulin resistance or liver histopathology. Conclusions: Hypoxic stress of sleep apnea may be implicated in the development of insulin resistance and steatohepatitis in severe obesity.Keywords: hypoxemia; fatty liver disease; metabolic syndrome; sleepdisordered breathing; liver injury Obstructive sleep apnea (OSA) is a complex disorder consisting of upper airway obstruction, chronic intermittent hypoxia (CIH), and sleep fragmentation (1). Epidemiologic studies have demonstrated that OSA is associated with insulin resistance and glucose intolerance, independent of obesity (2-4). Clinical investigations have also shown that OSA results in low-grade systemic inflammation (5, 6). Both insulin resistance and systemic inflammation may contribute to the increased cardiovascular risk in patients with OSA (7-9). Insulin resistance, systemic inflammation, and OSA are particularly prevalent in patients with severe obesity defined as a body mass index (BMI) exceeding 40 kg/m 2 (2, 10-12). While obesity causes systemic inflammation, insulin resistance, and sleep apnea (12-15), sleep apnea may further exacerbate the inflammatory and metabolic disturbances (2, 3, 6). Nevertheless, it is not known whether concomitant OSA is implicated in metabolic dysregulation and systemic inflammation in severe obesity.One of the consequences of obesity and insulin resistance is nonalcoholic fatty liver disease (N...

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Section: Osa Systemic Inflammation and Metabolic Dysfunction In Sevmentioning

confidence: 99%

mentioning

confidence: 99%

Obstructive Sleep Apnea, Insulin Resistance, and Steatohepatitis in Severe Obesity

Polotsky

Patil

Savransky

et al. 2009

Am J Respir Crit Care Med

191

139

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“…Biliopancreatic diversion is able to affect both the degree of insulin resistance and circulating TNF-a. 40 We cannot exclude that the change in NGAL rhythm may be a consequence of the improvement of insulin sensitivity or due to the decrease in TNF-a after weight loss. 41 We hypothesize that these changes are synchronous and some how related to each other in a complex and still unclear network of signals.…”

Section: Discussionmentioning

confidence: 98%

Metabolic endotoxemia and saturated fat contribute to circulating NGAL concentrations in subjects with insulin resistance

et al. 2009

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Objective: Lipocalin-2 (neutrophil gelatinase-associated lipocalin, NGAL) is an innate immune system protein that has been linked to insulin resistance and obesity, but the mechanisms behind these associations are poorly known. We hypothesized that endotoxin (lipopolysaccharide, LPS) and fat intake were in the background of these associations. Design: We studied four cohorts: (1) a cross-sectional study in 194 subjects; (2) the changes in NGAL concentration induced by diet and weight loss in 36 obese women (with circadian rhythm in 8 of them); (3) the effects of acute fat intake on circulating NGAL concentration in 42 morbidly obese subjects; and (4) LPS-induced NGAL secretion ex vivo (whole blood and adipose tissue explants). Results: Serum NGAL concentration was significantly associated with fasting triglycerides and LPS-binding protein in patients with type 2 diabetes. In obese subjects, the intake of saturated fatty acids was the factor that best explained the variance of NGAL changes after weight loss (contributing independently to 14% of NGAL variance). In fact, weight loss significantly changed the circadian rhythm of NGAL. The acute increase in circulating NGAL after fat overload was significantly associated with fasting insulin (r ¼ 0.52, Po0.001), homeostasis model assessment of insulin resistance (HOMA-IR) (r ¼ 0.36, P ¼ 0.02) and post-load triglyceride concentrations (r ¼ 0.38, P ¼ 0.018). LPS-induced NGAL secretion from adipose tissue explants did not change significantly, but LPS led to a significant increase in NGAL concentration in the whole blood obtained from patients with type 2 diabetes. Conclusion: Metabolic endotoxemia and saturated fat might contribute to circulating NGAL concentration in patients with insulin resistance.

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“…Nevertheless, changes in hepatic CBG expression at the gene level might take place after surgery. Changes in CBG and FCI levels might also be related to the improvement of the low-grade inflammatory status (28) occurring in post BPD-patients (32), as suggested by the decrease of CRP. The observed dissociation between cortisol and DHEA response to the DEX-ST in post-BPD women also supports this hypothesis, with higher concentrations of DHEA (the biologically active form of the hormone) in postobese women compared with obese and control subjects.…”

Section: Figure 1-mean ϯ Sem Of Cortisol (A) Acth (B) and Dhea (C) mentioning

confidence: 99%

Massive Weight Loss Decreases Corticosteroid-Binding Globulin Levels and Increases Free Cortisol in Healthy Obese Patients

et al. 2007

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OBJECTIVE -Obesity, insulin resistance, and weight loss have been associated with changes in hypothalamic-pituitary-adrenal (HPA) axis. So far, no conclusive data relating to this association are available. In this study, we aim to investigate the effects of massive weight loss on cortisol suppressibility, cortisol-binding globulin (CBG), and free cortisol index (FCI) in formerly obese women.RESEARCH DESIGN AND METHODS -Ten glucose-normotolerant, fertile, obese women (BMI Ͼ40 kg/m 2 , aged 38.66 Ϯ 13.35 years) were studied before and 2 years after biliopancreatic diversion (BPD) when stable weight was achieved and were compared with age-matched healthy volunteers. Cortisol suppression was evaluated by a 4-mg intravenous dexamethasone suppression test (DEX-ST). FCI was calculated as the cortisol-to-CBG ratio. Insulin sensitivity was measured by an euglycemic-hyperinsulinemic clamp, and insulin secretion was measured by a C-peptide deconvolution method. RESULTS-No difference was found in cortisol suppression after DEX-ST before or after weight loss. A decrease in ACTH was significantly greater in control subjects than in obese (P ϭ 0.05) and postobese women (P Յ 0.01) as was the decrease in dehydroepiandrosterone (P Յ 0.05 and P Յ 0.01, respectively). CBG decreased from 51.50 Ϯ 12.76 to 34.33 Ϯ 7.24 mg/l (P Յ 0.01) following BPD. FCI increased from 11.15 Ϯ 2.85 to 18.16 Ϯ 6.82 (P Յ 0.05). Insulin secretion decreased (52.04 Ϯ 16.71 vs. 30.62 Ϯ 16.32 nmol/m Ϫ2 ; P Յ 0.05), and insulin sensitivity increased by 163% (P Յ 0.0001). Serum CBG was related to BMI (r 0 ϭ 0.708; P ϭ 0.0001), body weight (r 0 ϭ 0.643; P ϭ 0.0001), body fat percent (r 0 ϭ 0.462; P ϭ 0.001), C-reactive protein (r 0 ϭ 0.619; P ϭ 0.004), and leptin (r 0 ϭ 0.579; P ϭ 0.007) and negatively to M value (r 0 ϭ Ϫ0.603; P ϭ 0.005).CONCLUSIONS -After massive weight loss in morbidly obese subjects, an increase of free cortisol was associated with a simultaneous decrease in CBG levels, which might be an adaptive phenomenon relating to environmental changes. This topic, not addressed before, adds new insight into the complex mechanisms linking HPA activity to obesity. Diabetes Care 30:1494-1500, 2007N utritional status and activity of the hypothalamic-pituitary-adrenal (HPA) axis are strictly associated (1,2). However, little is known about the effect of starvation and intentional calorie deprivation on the HPA axis (3,4). The HPA axis controls the secretion of cortisol with excessive secretion being inhibited by negative feedback. Several studies suggest that abnormalities in cortisol action and HPA axis control may be a factor that links disturbances of carbohydrate metabolism (which characterize insulin resistance) and obesity (5-6). In obesity, estimation of plasma cortisol does not reflect the function of the HPA axis (7), and levels of cortisol in obese patients have been reported to be normal (8), low (9), or increased (10). On the contrary, response to different stimuli (high secretion of cortisol after laboratory stress tests or after different exo...

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Effect of Massive Weight Loss on Inflammatory Adipocytokines and the Innate Immune System in Morbidly Obese Women

Abstract: Surgically induced weight loss is capable of reversing low-grade inflammation, at least partially. The relationships between sCD14, MBL, BPI, and glucose sensitivity, and the role of TNF-alpha in obesity warrant further investigation.

Cited by 146 publications

References 53 publications

Obstructive Sleep Apnea, Insulin Resistance, and Steatohepatitis in Severe Obesity

Obstructive Sleep Apnea, Insulin Resistance, and Steatohepatitis in Severe Obesity

Metabolic endotoxemia and saturated fat contribute to circulating NGAL concentrations in subjects with insulin resistance

Massive Weight Loss Decreases Corticosteroid-Binding Globulin Levels and Increases Free Cortisol in Healthy Obese Patients

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