Biomedical subjects

Philip G McTernan

Publications and source records attributed to Philip G McTernan.

10 recordsLinked to original sources

PubMed2007

Adiponectin and resistin in human cerebrospinal fluid and expression of adiponectin receptors in the human hypothalamus.

CONTEXT: The adipokine leptin has critical importance in central appetite regulation. In contrast to some suggestion of adiponectin influencing energy homeostasis in rodents, there is no evidence for adiponectin or resistin entering the human blood-brain barrier. OBJECTIVE: The objective was to establish the presence of adiponectin or resistin in human cerebrospinal fluid (CSF) and to compare their distribution with leptin. Furthermore, we wished to examine the expression of the adiponectin receptors 1 and 2 (AdipR1, AdipR2) in the human hypothalamus. METHODS: For this purpose, serum and CSF samples were collected from 20 men and 19 women matched for age [men, 69.8 +/- 8.6 yr (mean +/- SD); women, 69.4 +/- 4.3 yr] and BMI (men, 29.4 +/- 3.4 kg/m(2); women, 27.3 +/- 4.8 kg/m(2)) undergoing elective surgery under spinal anesthesia. RESULTS: Adiponectin was identified in CSF with levels 1000-fold less than serum, whereas resistin and leptin levels were 100-fold less. Unlike their serum levels, adiponectin CSF levels showed no gender difference or correlation with insulin resistance, which is similar to resistin CSF levels. The adiponectin and leptin CSF/serum ratios in our study exhibit the same pattern of gender-specific BMI association with inverse correlation in women (r = -0.61; P = 0.02) and no correlation in men (r = 0.026; P = not significant). Furthermore, immunostaining established AdipR1 and -2 in the hypothalamus and increased AdipR2 expression in the paraventricular nucleus, which is involved in energy regulation. CONCLUSION: In summary, our findings show both the presence of adiponectin and resistin in human CSF, with no effect of insulin resistance on CSF levels. The CSF entry of adiponectin and leptin in women appears to be impaired in obesity.

Adiponectin↗

PubMed2006

The in vitro effects of resistin on the innate immune signaling pathway in isolated human subcutaneous adipocytes.

CONTEXT: Obesity-associated inflammation is a contributory factor in the pathogenesis of type 2 diabetes mellitus (T2DM); the mechanisms underlying the progression to T2DM are unclear. The adipokine resistin has demonstrated proinflammatory properties in relation to obesity and T2DM. OBJECTIVES: The objectives of this study were to characterize resistin expression in human obesity and address the role of resistin in the innate immune pathway; to examine the influence of lipopolysaccharide, recombinant human resistin (rhResistin), insulin, and rosiglitazone in human adipocytes; and, finally, to analyze the effect of rhResistin on the expression of components of the nuclear factor-kappaB pathway and insulin signaling cascade. METHODS: Abdominal sc adipose tissue was obtained from patients undergoing elective liposuction surgery (n = 35; age, 36-49 yr; body mass index, 26.5 +/- 5.9 kg/m2). Isolated adipocytes were cultured with rhResistin (10-50 ng/ml). The level of cytokine secretion from isolated adipocytes was examined by ELISA. The effect of rhResistin on protein expression of components of the innate immune pathway was examined by Western blot. RESULTS: In vitro studies demonstrated that antigenic stimuli increase resistin secretion (P < 0.001) from isolated adipocytes. Proinflammatory cytokine levels were increased in response to rhResistin (P < 0.001); this was attenuated by rosiglitazone (P < 0.01). When examining components of the innate immune pathway, rhResistin stimulated Toll-like receptor-2 protein expression. Similarly, mediators of the insulin signaling pathway, phosphospecific c-Jun NH2-terminal kinase (JNK) 1 and JNK2, were up-regulated in response to rhResistin. CONCLUSION: Resistin may participate in more than one mechanism to influence proinflammatory cytokine release from human adipocytes, potentially via the integration of nuclear factor-kappaB and JNK signaling pathways.

Adipocytes↗

PubMed2006

Adiponectin is a candidate marker of metabolic syndrome in obese children and adolescents.

The aim of this study was to compare the use of several biomarkers to identify obese children and adolescents with increased metabolic risk. One hundred sixty-two Caucasian obese children and adolescents (41% males, 9-18 years old) referred to the Istituto Auxologico Italiano between 2003 and 2004 underwent an oral glucose tolerance test. Circulating levels of adiponectin (AD), plasminogen activator inhibitor 1 (PAI-1), interleukin 18 (IL-18), C-reactive protein (CRP), fibrinogen, uric acid, lipids and insulin were measured. Twenty five percent of obese children had the MS defined using World Health Organization-derived child specific criteria. MS subjects had significantly lower AD (p<0.01) and higher log-PAI-1 (p<0.001), uric acid (p<0.0001), and IL-18 (p<0.001). Subjects with AD levels </=median value had a significantly increased risk of having the MS (p<0.0001), as did subjects with uric acid and PAI-1 levels greater than the median. There was no increased risk with elevated IL-18, CRP, or fibrinogen. Hypoadiponectinemia was independently associated with the MS risk (p<0.0001). In conclusion in obese children and adolescents AD is the best predictor of MS and thus of higher cardiovascular disease risk.

Adiponectin↗

PubMed2006

Human epicardial adipose tissue expresses a pathogenic profile of adipocytokines in patients with cardiovascular disease.

INTRODUCTION: Inflammation contributes to cardiovascular disease and is exacerbated with increased adiposity, particularly omental adiposity; however, the role of epicardial fat is poorly understood. METHODS: For these studies the expression of inflammatory markers was assessed in epicardial fat biopsies from coronary artery bypass grafting (CABG) patients using quantitative RT-PCR. Further, the effects of chronic medications, including statins, as well as peri-operative glucose, insulin and potassium infusion, on gene expression were also assessed. Circulating resistin, CRP, adiponectin and leptin levels were determined to assess inflammation. RESULTS: The expression of adiponectin, resistin and other adipocytokine mRNAs were comparable to that in omental fat. Epicardial CD45 expression was significantly higher than control depots (p < 0.01) indicating significant infiltration of macrophages. Statin treated patients showed significantly lower epicardial expression of IL-6 mRNA, in comparison with the control abdominal depots (p < 0.001). The serum profile of CABG patients showed significantly higher levels of both CRP (control: 1.28 +/- 1.57 microg/mL vs CABG: 9.11 +/- 15.7 microg/mL; p < 0.001) and resistin (control: 10.53 +/- 0.81 ng/mL vs CABG: 16.8 +/- 1.69 ng/mL; p < 0.01) and significantly lower levels of adiponectin (control: 29.1 +/- 14.8 microg/mL vs CABG: 11.9 +/- 6.0 microg/mL; p < 0.05) when compared to BMI matched controls. CONCLUSION: Epicardial and omental fat exhibit a broadly comparable pathogenic mRNA profile, this may arise in part from macrophage infiltration into the epicardial fat. This study highlights that chronic inflammation occurs locally as well as systemically potentially contributing further to the pathogenesis of coronary artery disease.

Adiponectin↗

PubMed2006

Resistin.

PURPOSE OF REVIEW: Resistin, a cysteine-rich 12.5 kDa polypeptide, is a recently discovered adipocytokine with a controversial history regarding its role in the pathogenesis of obesity-mediated insulin resistance and type 2 diabetes mellitus. Whilst current studies appear to re-affirm the role of resistin on glucose homeostasis in rodent systems, we are still unravelling the functionality of resistin in human biology in respect to glucose metabolism and insulin signalling. This review will summarize the current knowledge, put into context the developments to date and discuss the controversial points. RECENT FINDINGS: Current evidence appears to suggest that resistin is a pro-inflammatory cytokine. Thus, like many other adipocytokines, resistin may possess a dual role in contributing to metabolic disease: first through its direct effects on substrate metabolism and second, through regulating inflammation within its target tissues. The chemistry of resistin has also been the subject of investigation and like adiponectin, the homo-oligomerization of this protein has a bearing on its function. SUMMARY: The most recent advances include the identification of circulating higher molecular weight structures of resistin in both rodent and human serum. This has been complemented by work casting light on the function and purpose of multimeric resistin in mice. Resistin appears to have effects on substrate metabolism through impairment of insulin action, particularly in the liver, but in addition, also has effects on insulin independent pathways.

Animals↗

PubMed2005

Role of resistin in obesity, insulin resistance and Type II diabetes.

Resistin is a member of a class of cysteine-rich proteins collectively termed resistin-like molecules. Resistin has been implicated in the pathogenesis of obesity-mediated insulin resistance and T2DM (Type II diabetes mellitus), at least in rodent models. In addition, resistin also appears to be a pro-inflammatory cytokine. Taken together, resistin, like many other adipocytokines, may possess a dual role in contributing to disease risk. However, to date there has been considerable controversy surrounding this 12.5 kDa polypeptide in understanding its physiological relevance in both human and rodent systems. Furthermore, this has led some to question whether resistin represents an important pathogenic factor in the aetiology of T2DM and cardiovascular disease. Although researchers still remain divided as to the role of resistin, this review will place available data on resistin in the context of our current knowledge of the pathogenesis of obesity-mediated diabetes, and discuss key controversies and developments.

Amino Acid Sequence↗

PubMed2003

Resistin and type 2 diabetes: regulation of resistin expression by insulin and rosiglitazone and the effects of recombinant resistin on lipid and glucose metabolism in human differentiated adipocytes.

Resistin, an adipocyte secreted factor, has been suggested to link obesity with type 2 diabetes in rodent models, but its relevance to human diabetes remains uncertain. Although previous studies have suggested a role for this adipocytokine as a pathogenic factor, its functional effects, regulation by insulin, and alteration of serum resistin concentration by diabetes status remain to be elucidated. Therefore, the aims of this study were to analyze serum resistin concentrations in type 2 diabetic subjects; to determine the in vitro effects of insulin and rosiglitazone (RSG) on the regulation of resistin, and to examine the functional effects of recombinant human resistin on glucose and lipid metabolism in vitro. Serum concentrations of resistin were analyzed in 45 type 2 diabetic subjects and 34 nondiabetic subjects. Subcutaneous human adipocytes were incubated in vitro with insulin, RSG, and insulin in combination with RSG to examine effects on resistin secretion. Serum resistin was increased by approximately 20% in type 2 diabetic subjects compared with nondiabetic subjects (P = 0.004) correlating with C-reactive protein. No other parameters, including adiposity and fasting insulin levels, correlated with serum resistin in this cohort. However, in vitro, insulin stimulated resistin protein secretion in a concentration-dependent manner in adipocytes [control, 1215 +/- 87 pg/ml (mean +/- SEM); 1 nM insulin, 1414.0 +/- 89 pg/ml; 1 microM insulin, 1797 +/- 107 pg/ml (P < 0.001)]. RSG (10 nM) reduced the insulin-mediated rise in resistin protein secretion (1 nM insulin plus RSG, 971 +/- 35 pg/ml; insulin, 1 microM insulin plus RSG, 1019 +/- 28 pg/ml; P < 0.01 vs. insulin alone). Glucose uptake was reduced after treatment with 10 ng/ml recombinant resistin and higher concentrations (P < 0.05). Our in vitro studies demonstrated a small, but significant, reduction in glucose uptake with human recombinant resistin in differentiated preadipocytes. In human abdominal sc adipocytes, RSG blocks the insulin-mediated release of resistin secretion in vitro. In conclusion, elevated serum resistin in human diabetes reflects the subclinical inflammation prevalent in type 2 diabetes. Our in vitro studies suggest a modest effect of resistin in reducing glucose uptake, and suppression of resistin expression may contribute to the insulin-sensitizing and glucose-lowering actions of the thiazolidinediones.

Adipocytes↗

PubMed2002

Glucocorticoid regulation of p450 aromatase activity in human adipose tissue: gender and site differences.

The distinct gender-specific patterns of fat distribution in men and women (android and gynoid) suggest a role for sex steroids. In keeping with these observations, it has been suggested that estrogens can promote preadipocyte cell proliferation and/or differentiation. The enzyme aromatase P450 is responsible for the conversion of androgen precursor steroids to estrogens and may, therefore, have a role in regulating adipose tissue mass and its distribution. We have investigated the glucocorticoid regulation of aromatase expression in human adipose tissue, specifically to define any site- and gender-specific differences. Abdominal subcutaneous (Sc) and omental (Om) adipose tissue was obtained from male and female patients undergoing elective surgery. After collagenase digestion, preadipocytes were cultured in serum-free medium, for 6-10 d, until confluent with either cortisol (10(-6) M, 10(-7) M) or insulin (500 nM) or a combination of both treatments. Adipocytes were studied in suspension cultures. Aromatase activity was assessed using tritiated [1 beta-(3)H]-androstenedione as substrate. In Sc preadipocytes, basal aromatase activity increased in females from 11.5 +/- 1.4 (mean plus minus SEM) to 28.0 +/- 1.8 pmol/mg x h (n = 17, P < 0.05) with 10(-6) M cortisol. By contrast, in males, aromatase activity was inhibited by 10(-6) M cortisol (19.4 +/- 2.4 pmol/mg x h vs. 7.5 +/- 1.3, n = 9, P < 0.01; men vs. women, P < 0.005). These data were endorsed through Western blot analysis using an in-house antihuman aromatase antibody, which recognized a specific 55-kDa species. Aromatase activity was less at Om sites in preadipocytes, increasing in females from 1.1 +/- 0.2 to 3.2 +/- 0.7 pmol/mg x h with 10(-6) M cortisol (P < 0.05) and in males from 2.6 +/- 0.1 pmol/mg x h to 7.8 +/- 0.3 pmol/mg x h after cortisol (men vs. women, P < 0.001). Cortisol-induced aromatase activity in Om adipocytes from postmenopausal females was higher than that in premenopausal females (P < 0.001). Insulin had no independent effect on aromatase expression, but coincubation of preadipocytes with cortisol and insulin eliminated both gender- and site-specific differences. In conclusion, in women, but not men, cortisol increased aromatase activity at Sc sites, and this may facilitate predilection for Sc adiposity in females. The observed site-, gender-, and menopausal-specific differences in the glucocorticoid regulation of this enzyme may contribute to the gender- and menopausal-specific patterns of fat distribution.

Adipose Tissue↗

PubMed2002

Increased resistin gene and protein expression in human abdominal adipose tissue.

Resistin, a novel signalling molecule isolated in mice has been suggested to be the putative hormone thought to link obesity with type 2 diabetes. The aim of this study was to examine resistin protein expression in human adipose tissue depots and resistin secretion in isolated adipose cells, to characterize resistin expression in human adipose tissue. Both resistin mRNA and protein expression were analysed from human adipose tissue (n = 5 adipose tissue samples: abdominal subcutaneous (Sc) n = 19, abdominal omental adipose tissue (Om) n = 10, thigh n = 9, breast n = 7). Resistin protein expression levels were similar in both the abdominal Sc and Om adipose tissue depots, and expression in abdominal fat depots were increased compared with thigh (p < 0.001) and breast tissue depots (p < 0.001). These findings were consistent with the mRNA expression studies. Resistin was secreted from both pre-adipocytes and adipocytes cells. Thus, resistin resides within isolated adipose cells and is expressed and secreted in human adipose tissue. In conclusion, this study confirms the expression of resistin in human adipose tissue and increased expression in abdominal fat, this suggests a potential role in linking central obesity to type 2 diabetes and/or cardiovascular disease.

Abdomen↗

PubMed2002

Insulin and rosiglitazone regulation of lipolysis and lipogenesis in human adipose tissue in vitro.

Lipolysis is an important process determining fuel metabolism, and insulin regulates this process in adipose tissue. The aim of this study was to investigate the long-term effects of insulin, an insulin enhancer (rosiglitazone [RSG]), and insulin in combination with RSG on the regulation of lipolysis and lipogenesis in human abdominal subcutaneous fat. Lipolysis and lipogenesis were assessed by protein expression studies of hormone-sensitive lipase (HSL) (84 kDa) and lipoprotein lipase (LPL) (56 kDa), respectively. In addition, lipolytic rate was assessed by glycerol release assay and tumor necrosis factor (TNF)-alpha release measured by enzyme-linked immunosorbent assay (n = 12). In subcutaneous adipocytes, increasing insulin doses stimulated LPL expression, with maximal stimulation at 100 nmol/l insulin (control, 1.0 +/- 0.0 [mean +/- SE, protein expression relative to control]; 1 nmol/l insulin, 0.87 +/- 0.13; 100 nmol/l insulin, 1.68 +/- 0.19; P < 0.001). In contrast, insulin at the 100 nmol/l dose reduced the expression of HSL (100 nmol/l insulin, 0.49 +/- 0.05; P < 0.05), while no significant reduction was observed at other doses. Higher doses of insulin stimulated both HSL (1,000 nmol/l insulin, 1.4 +/- 0.07; P < 0.01) and LPL (control 1.00 +/- 0.0; 1,000 nmol/l insulin, 2.66 +/- 0.27; P < 0.01) protein expression. Cotreatment with RSG induced an increased dose response to insulin for LPL and HSL (P < 0.05); RSG alone also increased LPL and HSL expression (P < 0.05). Insulin stimulated TNF-alpha secretion in a dose-dependent manner (P < 0.01); the addition of RSG (10(-8) mol/l) reduced TNF-alpha secretion (P < 0.05). In summary, chronic treatment of human adipocytes with insulin stimulates lipolysis and LPL protein expression. The addition of RSG reduced the lipolytic rate and TNF-alpha secretion. The increase in lipolysis is not explained by changes in HSL expression. These data, therefore, may explain in part why hyperinsulinemia coexists with increased circulating nonesterified free fatty acids and increased adiposity in obese and/or type 2 diabetic patients.

Adipocytes↗