Bianca K. Itariu

Long-chain n−3 PUFAs reduce adipose tissue and systemic inflammation in severely obese nondiabetic patients: a randomized controlled trial

BACKGROUND Chronic adipose tissue inflammation is a hallmark of obesity, triggering the development of associated pathologies, particularly type 2 diabetes. Long-chain n-3 PUFAs reduce cardiovascular events and exert well-established antiinflammatory effects, but their effects on human adipose tissue inflammation are unknown. OBJECTIVE We investigated whether n-3 PUFAs reduce adipose tissue inflammation in severely obese nondiabetic patients. DESIGN We treated 55 severely obese nondiabetic patients, scheduled to undergo elective bariatric surgery, with 3.36 g long-chain n-3 PUFAs/d (EPA, DHA) or an equivalent amount of butterfat as control, for 8 wk, in a randomized open-label controlled clinical trial. The primary efficacy measure was inflammatory gene expression in visceral and subcutaneous adipose tissue samples (subcutaneous adipose tissue and visceral adipose tissue), collected during surgery after the intervention. Secondary efficacy variables were adipose tissue production of antiinflammatory n-3 PUFA-derived eicosanoids, plasma concentrations of inflammatory markers, metabolic control, and the effect of the Pro12Ala PPARG polymorphism on the treatment response. RESULTS Treatment with n-3 PUFAs, which was well tolerated, decreased the gene expression of most analyzed inflammatory genes in subcutaneous adipose tissue (P < 0.05) and increased production of antiinflammatory eicosanoids in visceral adipose tissue and subcutaneous adipose tissue (P < 0.05). In comparison with control subjects who received butterfat, circulating interleukin-6 and triglyceride concentrations decreased significantly in the n-3 PUFA group (P = 0.04 and P = 0.03, respectively). The Pro12Ala polymorphism affected the serum cholesterol response to n-3 PUFA treatment. CONCLUSIONS Treatment with long-chain n-3 PUFAs favorably modulated adipose tissue and systemic inflammation in severely obese nondiabetic patients and improved lipid metabolism. These effects may be beneficial in the long-term treatment of obesity. This trial was registered at clinicaltrials.gov as NCT00760760.

Impaired Local Production of Proresolving Lipid Mediators in Obesity and 17-HDHA as a Potential Treatment for Obesity-Associated Inflammation

Obesity-induced chronic low-grade inflammation originates from adipose tissue and is crucial for obesity-driven metabolic deterioration, including insulin resistance and type 2 diabetes. Chronic inflammation may be a consequence of a failure to actively resolve inflammation and could result from a lack of local specialized proresolving lipid mediators (SPMs), such as resolvins and protectins, which derive from the n-3 polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). We assessed obesity-induced changes of n-3–derived SPMs in adipose tissue and the effects of dietary EPA/DHA thereon. Moreover, we treated obese mice with SPM precursors and investigated the effects on inflammation and metabolic dysregulation. Obesity significantly decreased DHA-derived 17-hydroxydocosahexaenoic acid (17-HDHA, resolvin D1 precursor) and protectin D1 (PD1) levels in murine adipose tissue. Dietary EPA/DHA treatment restored endogenous biosynthesis of n-3–derived lipid mediators in obesity while attenuating adipose tissue inflammation and improving insulin sensitivity. Notably, 17-HDHA treatment reduced adipose tissue expression of inflammatory cytokines, increased adiponectin expression, and improved glucose tolerance parallel to insulin sensitivity in obese mice. These findings indicate that impaired biosynthesis of certain SPM and SPM precursors, including 17-HDHA and PD1, contributes to adipose tissue inflammation in obesity and suggest 17-HDHA as a novel treatment option for obesity-associated complications.

Severe obesity increases adipose tissue expression of interleukin-33 and its receptor ST2, both predominantly detectable in endothelial cells of human adipose tissue

Objective:Obesity is associated with chronic inflammation of the adipose tissue, which contributes to obesity-associated complications such as insulin resistance and type 2 diabetes. Interleukin (IL)-33 acts via its receptor ST2 and is involved in the pathogenesis of inflammatory disorders including atherosclerosis and heart disease. IL-33 has been demonstrated to promote endothelial cell inflammatory response, but also anti-inflammatory and protective actions such as TH2 and M2 polarization of T cells and macrophages, respectively. IL-33 and ST2 have been shown to be expressed in human and murine adipose tissue. Our objective was to investigate alterations in obesity and a possible role of IL-33 in adipose tissue inflammation.Subjects and methods:We investigated severely obese patients (BMI>40 kg m−2, n=20) and lean to overweight controls (BMI<30 kg m−2; n=20) matched for age and sex, as well as diet-induced obese and db/db mice, in order to determine the impact of obesity on IL-33 and ST2 gene and protein expression levels in adipose tissue and blood, and their correlation with inflammatory and metabolic parameters. Furthermore, we examined the cellular source and location of IL-33 and ST2 in situ.Results:IL-33 and ST2 expression levels were markedly elevated in omental and subcutaneous adipose tissue of severely obese humans and in diet-induced obese mice, but not in leptin receptor-deficient db/db mice. In addition, soluble ST2, but not IL-33 serum levels, were elevated in obesity. The main source for IL-33 in adipose tissue were endothelial cells, which, in humans, exclusively expressed ST2 on their surface. IL-33 expression strongly correlated with leptin expression in human adipose tissue.Conclusions:Expression of IL-33 and its receptor ST2 in human adipose tissue is predominantly detectable in endothelial cells and increased by severe obesity indicating an autocrine action. Thus, the adipose tissue microvasculature could participate in obesity-associated inflammation and related complications via IL-33/ST2.

Insulin-Like Growth Factor 1 Predicts Post-Load Hypoglycemia following Bariatric Surgery: A Prospective Cohort Study

Postprandial hypoglycemia is a complication following gastric bypass surgery, which frequently remains undetected. Severe hypoglycemic episodes, however, put patients at risk, e.g., for syncope. A major cause of hypoglycemia following gastric bypass is hyperinsulinemic nesidioblastosis. Since pancreatic islets in nesidioblastosis overexpress insulin-like growth factor 1 (IGF-1) receptor α and administration of recombinant IGF-1 provokes hypoglycemia, our main objective was to investigate the occurrence of post-load hypoglycemia one year after bariatric surgery and its relation to pre- and post-operative IGF-1 serum concentrations. We evaluated metabolic parameters including 2 h 75 g oral glucose tolerance test (OGTT) and measured IGF-1 serum concentration in thirty-six non-diabetic patients (29 f/7 m), aged 41.3±2.0 y with a median (IQR) BMI of 30.9 kg/m2 (27.5–34.3 kg/m2), who underwent elective bariatric surgery (predominantly gastric bypass, 83%) at our hospital. Post-load hypoglycemia as defined by a 2 h glucose concentration <60 mg/dl was detected in 50% of patients. Serum insulin and C-peptide concentration during the OGTT and HOMA-IR (homeostatic model assessment–insulin resistance) were similar in hypoglycemic and euglycemic patients. Strikingly, pre- and post-operative serum IGF-1 concentrations were significantly higher in hypoglycemic patients (p = 0.012 and p = 0.007 respectively). IGF-1 serum concentration before surgery negatively correlated with 2 h glucose concentration during the OGTT (rho = −0.58, p = 0.0003). Finally, IGF-1 serum concentrations before and after surgery significantly predicted post-load hypoglycemia with odds ratios of 1.28 (95%CI:1.03–1.55, p = 0.029) and 1.18 (95%CI:1.03–1.33, p = 0.015), respectively, for each 10 ng/ml increment. IGF-1 serum concentration could be a valuable biomarker to identify patients at risk for hypoglycemia following bariatric surgery independently of a diagnostic OGTT. Thus, IGF-1 testing could help to prevent a significant complication of gastric bypass surgery.

Treatment with n-3 polyunsaturated fatty acids overcomes the inverse association of vitamin D deficiency with inflammation in severely obese patients: a randomized controlled trial.

Obesity affects the vitamin D status in humans. Vitamin D and long-chain n-3 polyunsaturated fatty acids (PUFA) provide benefit for the prevention of fractures and cardiovascular events, respectively, and both are involved in controlling inflammatory and immune responses. However, published epidemiological data suggest a potential interference of n-3 PUFA supplementation with vitamin D status. Therefore, we aimed to investigate in a randomized controlled clinical trial whether treatment with long chain n-3 PUFA affects vitamin D status in severely obese patients and potential interrelations of vitamin D and PUFA treatment with inflammatory parameters. Fifty-four severely obese (BMI≥40 kg/m2) non-diabetic patients were treated for eight weeks with either 3.36 g/d EPA and DHA or the same amount of butter fat as control. Changes in serum 25-hydroxy-vitamin D [25(OH)D] concentrations, plasma fatty acid profiles and circulating inflammatory marker concentrations from baseline to end of treatment were assessed. At baseline 43/54 patients were vitamin D deficient (serum 25(OH)D concentration <50 nmol/l). Treatment with n-3 PUFA did not affect vitamin D status (P = 0.91). Serum 25(OH)D concentration correlated negatively with both IL-6 (P = 0.02) and hsCRP serum concentration (P = 0.03) at baseline. Strikingly, the negative correlations of 25(OH)D with IL-6 and hsCRP were lost after n-3 PUFA treatment. In conclusion, vitamin D status of severely obese patients remained unaffected by n-3 PUFA treatment. However, abrogation of the inverse association of 25(OH)D concentration with inflammatory markers indicated that n-3 PUFA treatment could compensate for some detrimental consequences of vitamin D deficiency. Trial Registration ClinicalTrials.gov NCT00760760

A protein-enriched low glycemic index diet with omega-3 polyunsaturated fatty acid supplementation exerts beneficial effects on metabolic control in type 2 diabetes

AIMS The current study aims to investigate practicability and effects of a combined dietary intervention with increased relative protein content supplemented with omega-3 polyunsaturated fatty acids (PUFA) on metabolic control and inflammatory parameters in a real life situation in type 2 diabetes patients. METHODS In this observational study we advised thirty mostly obese patients with type 2 diabetes to follow a protein-enriched diet with carbohydrates of low glycemic index (low GI) and moderate fat reduction supplemented with omega-3 PUFA for 24 weeks. Primary efficacy parameter was the change in HbA1c; secondary parameters included changes in systemic inflammation (measured by ultrasensitive C-reactive protein, usCRP), body weight, waist circumference, fat mass. The study is registered at clinicaltrials.gov (NCT01474603). RESULTS The dietary intervention significantly reduced the primary efficacy variable HbA1c from a baseline value of 63±11mmol/mol to 59±14mmol/mol (P=0.033) and 56±12mmol/mol (P=0.001) after 12 and 24 weeks, respectively. In addition, usCRP decreased significantly at 24 weeks (P=0.039). Waist circumference, an important indicator for cardiometabolic-risk and silent inflammation, decreased from baseline 116.0±14.1cm to 114.9±13.5cm (P=0.019), 114.0±14.4cm (P=0.001), and 112.7±13.4cm (P=0.049), after 3, 12 and 24 weeks, respectively. CONCLUSION Counseling a protein enriched and low glycemic index diet supplemented with long-chain omega-3 PUFA in a real-life clinical setting improves glycemic control and also reduces waist circumference and silent inflammation in overweight or obese patients with type 2 diabetes.

Adiponectin regulates aquaglyceroporin expression in hepatic stellate cells altering their functional state

Obesity is a major risk factor for liver fibrosis and tightly associated with low levels of adiponectin. Adiponectin has antifibrogenic activity protecting from liver fibrosis, which is mainly driven by activated hepatic stellate cells (HSC). Aquaporins are transmembrane proteins that allow the movement of water and, in case of aquaglyceroporins (AQPs), of glycerol that is needed in quiescent HSC for lipogenesis. Expression of various AQPs in liver is altered by obesity; however, the mechanisms through which obesity influences HSCs activation and AQPs expression remain unclear. This study aimed to identify obesity‐associated factors that are related to HSC AQPs expression activation and lipid storage.

Immunological blockade of adipocyte inflammation caused by increased matrix metalloproteinase-cleaved osteopontin in obesity.

Osteopontin (OPN) is upregulated in adipose tissue (AT) in obesity and contributes to subclinical inflammation, adipocyte dysfunction, and insulin resistance. OPN effects can be increased by cleavage by matrix metalloproteinases (MMP). This study aimed at investigating the presence of OPN cleavage products in human AT in obesity and their impact on adipocyte function and immunological blockade of these effects.

Mast cells are not associated with systemic insulin resistance

Infiltration of white adipose tissue (WAT) by inflammatory cells in obesity is considered to be a key event in the development of insulin resistance. Recently, mast cells (MCs) have been identified as new players in the pathogenesis of obesity. We aimed to investigate the relationship between MCs and various inflammatory markers in serum and WAT and to determine the role of MCs in the aetiology of insulin resistance.

Osteopontin promotes aromatase expression and estradiol production in human adipocytes.

Breast and endometrial cancer are often estrogen dependent, and their incidence and mortality are increased by obesity in postmenopausal women. Osteopontin (OPN) is a cytokine strongly upregulated in adipose tissue (AT) in obesity. OPN function is potentiated by cleavage by matrix metalloproteinases (MMP). OPN and MMPs play a role in cancer development and are prognostic markers in breast cancer progression. While induction of the estrogen-synthesizing enzyme aromatase by TNFa and IL1 has been shown in preadipocytes, an impact of OPN on aromatase expression in AT has not been investigated yet. Gene expression was determined in AT samples of 21 morbidly obese and matched non-obese subjects. Primary human adipocytes were treated with full-length OPN or MMP-cleaved OPN (cOPN). Protein and mRNA expressions were analyzed from cell lysates, or cells were subsequently supplied with testosterone to determine estradiol production and for indirect co-culture with the estrogen-dependent MCF-7 cell line. Aromatase expression strongly correlated with gene expression of OPN and various MMPs in visceral and MMPs in subcutaneous AT, but not with TNFα expression in both tissues. In vitro, cOPN more effectively than full-length OPN upregulated aromatase mRNA in adipocytes and significantly increased aromatase protein level and estradiol production, leading to increased MCF-7 growth in indirect co-culture. OPN and MMPs are upregulated in AT in obesity, and MMP-cleaved OPN is particularly effective in inducing aromatase activity in human adipocytes. Thereby, obesity-induced OPN expression in AT may contribute to estradiol production and thus to the association of obesity with estrogen-dependent cancers.