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NF-κBp65 and Expression of Its Pro-Inflammatory Target Genes Are Upregulated in the Subcutaneous Adipose Tissue of Cachectic Cancer Patients.
Camargo, RG, Riccardi, DM, Ribeiro, HQ, Carnevali, LC, de Matos-Neto, EM, Enjiu, L, Neves, RX, Lima, JD, Figuerêdo, RG, de Alcântara, PS, et al
Nutrients. 2015;(6):4465-79
Abstract
Cancer cachexia, of which the most notable symptom is severe and rapid weight loss, is present in the majority of patients with advanced cancer. Inflammatory mediators play an important role in the development of cachexia, envisaged as a chronic inflammatory syndrome. The white adipose tissue (WAT) is one of the first compartments affected in cancer cachexia and suffers a high rate of lipolysis. It secretes several cytokines capable of directly regulating intermediate metabolism. A common pathway in the regulation of the expression of pro-inflammatory cytokines in WAT is the activation of the nuclear transcription factor kappa-B (NF-κB). We have examined the gene expression of the subunits NF-κBp65 and NF-κBp50, as well as NF-κBp65 and NF-κBp50 binding, the gene expression of pro-inflammatory mediators under NF-κB control (IL-1β, IL-6, INF-γ, TNF-α, MCP-1), and its inhibitory protein, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκB-α). The observational study involved 35 patients (control group, n = 12 and cancer group, n = 23, further divided into cachectic and non-cachectic). NF-κBp65 and its target genes expression (TNF-α, IL-1β, MCP-1 and IκB-α) were significantly higher in cachectic cancer patients. Moreover, NF-κBp65 gene expression correlated positively with the expression of its target genes. The results strongly suggest that the NF-κB pathway plays a role in the promotion of WAT inflammation during cachexia.
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Abdominal visceral and subcutaneous fat increase, insulin resistance and hyperlipidemia in testicular cancer patients treated with cisplatin-based chemotherapy.
Willemse, PM, van der Meer, RW, Burggraaf, J, van Elderen, SG, de Kam, ML, de Roos, A, Lamb, HJ, Osanto, S
Acta oncologica (Stockholm, Sweden). 2014;(3):351-60
Abstract
BACKGROUND Testicular cancer survivors treated with chemotherapy are at increased risk for metabolic syndrome (MetS) and cardiovascular disease (CVD). We explored acute effects of chemotherapy by assessing metabolic factors, abdominal fat volume, hepatic triglyceride content (HTC) and aortic wall stiffness. MATERIAL AND METHODS We studied 19 testicular cancer patients (age 20-54 years) before, at three and nine months after the start of chemotherapy. Blood serum was analyzed for lipids, glucose and insulin. Abdominal visceral and subcutaneous fat volume and aortic pulse wave velocity were assessed by magnetic resonance imaging (MRI) techniques; HTC was measured by proton MR spectroscopy. RESULTS Three months after start of chemotherapy visceral abdominal fat volume had significantly increased from 202 ± 141 to 237 ± 153 ml (p = 0.009) whereas body mass index and subcutaneous fat volume significantly increased nine months after treatment from 24.4 ± 4.0 to 26.4 ± 4.1 kg/m(2) (p = 0.01) and from 556 ± 394 to 668 ± 460 ml (p = 0.002) respectively. Serum total cholesterol, low-density lipoprotein cholesterol and insulin also significantly increased three months after start of treatment from 4.88 ± 1.1 to 5.61 ± 1.50 mmol/l (p = 0.002), 3.31 ± 1.16 to 3.73 ± 1.41 mmol/l (p = 0.02) and 5.7 ± 4.4 to 9.6 ± 6.3 mU/ml (p = 0.03), respectively. Nine months after start of chemotherapy serum lipid and insulin concentrations had returned to baseline. HTC increased in seven of the 19 patients (36.8%) during follow-up. Aortic pulse wave velocity remained unchanged at the three time points measured. CONCLUSION Cisplatin-based chemotherapy was associated with acute insulin resistance, dyslipidemia and an immediate increase in abdominal visceral adipose tissue and abdominal subcutaneous adipose tissue in testicular cancer patients. A large prospective cohort study with long follow-up is warranted to characterize the time course and relationship between acutely induced obesity and hypercholesterolemia and the development of metabolic syndrome and CVD years later in individual testicular cancer survivors.
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Effect of dietary fat modification on subcutaneous white adipose tissue insulin sensitivity in patients with metabolic syndrome.
Jimenez-Gomez, Y, Cruz-Teno, C, Rangel-Zuñiga, OA, Peinado, JR, Perez-Martinez, P, Delgado-Lista, J, Garcia-Rios, A, Camargo, A, Vazquez-Martinez, R, Ortega-Bellido, M, et al
Molecular nutrition & food research. 2014;(11):2177-88
Abstract
SCOPE To determine whether the insulin resistance that exists in metabolic syndrome (MetS) patients is modulated by dietary fat composition. METHODS AND RESULTS Seventy-five patients were randomly assigned to one of four diets for 12 wk: high-saturated fatty acids (HSFAs), high-MUFA (HMUFA), and two low-fat, high-complex carbohydrate (LFHCC) diets supplemented with long-chain n-3 (LFHCC n-3) PUFA or placebo. At the end of intervention, the LFHCC n-3 diet reduced plasma insulin, homeostasis model assessment of insulin resistance, and nonsterified fatty acid concentration (p < 0.05) as compared to baseline Spanish habitual (BSH) diet. Subcutaneous white adipose tissue (WAT) analysis revealed decreased EH-domain containing-2 mRNA levels and increased cbl-associated protein gene expression with the LFHCC n-3 compared to HSFA and HMUFA diets, respectively (p < 0.05). Moreover, the LFHCC n-3 decreased gene expression of glyceraldehyde-3-phosphate dehydrogenase with respect to HMUFA and BSH diets (p < 0.05). Finally, proteomic characterization of subcutaneous WAT identified three proteins of glucose metabolism downregulated by the LFHCC n-3 diet, including annexin A2. RT-PCR analysis confirmed the decrease of annexin A2 (p = 0.027) after this diet. CONCLUSION Our data suggest that the LFHCC n-3 diet reduces systemic insulin resistance and improves insulin signaling in subcutaneous WAT of MetS patients compared to HSFA and BSH diets consumption.
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Adipose triglyceride lipase and hormone-sensitive lipase protein expression in subcutaneous adipose tissue is decreased after an isoenergetic low-fat high-complex carbohydrate diet in the metabolic syndrome.
van Hees, AM, Jocken, JW, Essers, Y, Roche, HM, Saris, WH, Blaak, EE
Metabolism: clinical and experimental. 2012;(10):1404-12
Abstract
The objective was to determine the contribution of dietary fat quantity and composition to lipolysis and lipolytic gene expression in humans in relation to obesity, insulin resistance, and the metabolic syndrome (MetS). Men and women with the MetS were randomly assigned to one of four isoenergetic diets: a high-fat saturated fat diet (n=10), a high-fat monounsaturated fat diet (n=7), and two low-fat high-complex carbohydrate (LFHCC) diets, one supplemented with 1.24 g/day long-chain n-3 PUFA (LFHCC n=7, LFHCCn-3: n=8). Subcutaneous adipose tissue biopsies were taken before and after the 12-week dietary intervention period. ATGL and HSL mRNA and protein expression was determined. Whole body rate of appearance of free fatty acids (Ra(FFA)) was determined by intravenous infusion of [(2)H(2)]-palmitate in a subgroup of men (n=20). Adipose tissue ATGL and HSL mRNA and protein expression was not affected by alterations in dietary fat composition. Pooled analysis comparing the low- and high-fat diets showed that ATGL and HSL protein expression was significantly reduced after the LFHCC diets (P=.04), irrespective of long-chain n-3 PUFA. Moreover, LFHCC diets lowered fasting insulin, HOMA(IR), and (LDL)-cholesterol concentrations (P≤.05). Changes in ATGL and HSL protein expression was positively associated with changes in whole body Ra(FFA) (P<.03). The low-fat high-complex carbohydrate diets reduced ATGL and HSL protein expression and significantly improved circulating lipids and insulin sensitivity. Under isoenergetic conditions, dietary fat quantity, rather than composition, may be most important for modulating subcutaneous adipose tissue ATGL and HSL protein expression.
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Ethnic and sex differences in body fat and visceral and subcutaneous adiposity in children and adolescents.
Staiano, AE, Katzmarzyk, PT
International journal of obesity (2005). 2012;(10):1261-9
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Abstract
Body fat and the specific depot where adipose tissue (AT) is stored can contribute to cardiometabolic health risks in children and adolescents. Imaging procedures including magnetic resonance imaging and computed tomography allow for the exploration of individual and group differences in pediatric adiposity. This review examines the variation in pediatric total body fat (TBF), visceral AT (VAT) and subcutaneous AT (SAT) due to age, sex, maturational status and ethnicity. TBF, VAT and SAT typically increase as a child ages, though different trends emerge. Girls tend to accumulate more TBF and SAT during and after puberty, depositing fat preferentially in the gynoid and extremity regions. In contrast, pubertal and postpubertal boys tend to deposit more fat in the abdominal region, particularly in the VAT depot. Sexual maturation significantly influences TBF, VAT and SAT. Ethnic differences in TBF are mixed. VAT tends to be higher in white and Hispanic youth, whereas SAT is typically higher in African American youth. Asian youth typically have less gynoid fat but more VAT than whites. Obesity per se may attenuate sex and ethnic differences. Particular health risks are associated with high amounts of TBF, VAT and SAT, including insulin resistance, hepatic steatosis, metabolic syndrome and hypertension. These risks are affected by genetic, biological and lifestyle factors including physical activity, nutrition and stress. Synthesizing evidence is difficult as there is no consistent methodology or definition to estimate and define depot-specific adiposity, and many analyses compare SAT and VAT without controlling for TBF. Future research should include longitudinal examinations of adiposity changes over time in representative samples of youth to make generalizations to the entire pediatric population and examine variation in organ-specific body fat.
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Inflammation markers are modulated by responses to diets differing in postprandial insulin responses in individuals with the metabolic syndrome.
Kallio, P, Kolehmainen, M, Laaksonen, DE, Pulkkinen, L, Atalay, M, Mykkänen, H, Uusitupa, M, Poutanen, K, Niskanen, L
The American journal of clinical nutrition. 2008;(5):1497-503
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Abstract
BACKGROUND Inflammation may be a mechanism by which high postprandial insulin and glucose responses increase the risk of type 2 diabetes mellitus. OBJECTIVE We hypothesized that dietary carbohydrates characterized by different postprandial insulin responses may differentially modify cytokine concentrations in plasma and gene expression in subcutaneous adipose tissue. DESIGN Individuals (n = 47) with the metabolic syndrome were randomly assigned to a 12-wk diet with oat and wheat bread and potato (high postprandial insulin response) or rye bread and pasta (low postprandial insulin response). Postprandial glucose and insulin responses to the oat and wheat bread meal and to the rye bread meal were determined in 19 individuals before intervention. RESULTS During the 12-wk diet, the change in the gene expression of interleukin (IL)-10 receptor alpha and tumor necrosis factor-alpha in subcutaneous adipose tissue differed between the groups (P = 0.002 and P = 0.083, respectively). Moreover, the change in fasting plasma concentrations of IL-1beta and IL-6 differed between the groups (P = 0.020 and P = 0.055, respectively). In the postprandial challenge, the insulin response to the rye bread meal was lower than that to the oat and wheat bread meal (P < 0.001), whereas there were no differences in the mean blood glucose response. In contrast, plasma glucose concentrations decreased more below fasting concentrations 2.5-3 h after the oat and wheat bread meal than after the rye bread meal. A late postprandial rebound of free fatty acids was detected after the oat and wheat bread meal (P = 0.048). CONCLUSIONS Long-term intake of cereal foods with differing postprandial insulin responses may be a factor that modulates the inflammatory status in individuals with the metabolic syndrome.