Trunk fat and leg fat have independent and opposite associations with fasting and postload glucose levels: the Hoorn study

Trunk fat and leg fat have independent and opposite associations with fasting and postload glucose levels: the Hoorn study. Snijder MB, Dekker JM, Visser M, Bouter LM, Stehouwer CD, Yudkin JS, Heine RJ, Nijpels G, Seidell JC; Hoorn study. Institute for Research in Extramural Medicine, VU University Medical Center, Amsterdam, The Netherlands. [email protected] OBJECTIVE: Waist and hip circumferences have been shown to have independent and opposite associations with glucose levels. Waist circumference is positively associated with glucose levels, whereas hip circumference is negatively associated. It is unclear which tissues are involved in the pathophysiological mechanism causing these associations. The main goal was to determine which tissue in the trunk and legs, fat or lean tissue, is associated with measures of glucose metabolism. RESEARCH DESIGN AND METHODS: In 623 participants of the third examination of the Hoorn Study, whole-body dual-energy X-ray absorptiometry was performed to determine fat and lean soft-tissue mass in the trunk and legs. Fasting and 2-h postload glucose levels after 75-g oral glucose tolerance test (OGTT) were determined. After exclusion of known diabetic patients, cross-sectional analyses were performed in 275 men aged 60-87 years (140 with normal glucose metabolism, 92 with impaired glucose metabolism; and 43 with diabetes) and in 281 women (148 with normal glucose metabolism, 90 with impaired glucose metabolism, and 43 with diabetes). RESULTS: Greater trunk fat mass was associated with higher glucose levels after adjustment for age, trunk lean mass, leg lean mass, and leg fat mass. Standardized beta (95% CI) in men were 0.44 (0.25-0.64) for fasting and 0.41 (0.22-0.60) for postload glucose. For women, these values were 0.49 (0.35-0.63) and 0.47 (0.33-0.61), respectively. In contrast, in the same regression models, a larger leg fat mass was associated with lower glucose levels. Standardized beta in men were -0.24 (-0.43 to -0.05) and -0.12 (-0.31 to 0.07) and in women -0.24 (-0.37 to -0.10) and -0.27 (-0.40 to -0.13) for fasting and postload glucose, respectively. In these models, larger leg lean mass was also associated with lower glucose levels but was only statistically significant in men. CONCLUSIONS: If trunk fat is taken into account, accumulation of fat in the legs seems to be protective against a disturbed glucose metabolism, particularly in women. Further research is needed to unravel underlying pathophysiological mechanism

Decrease of miR-146b-5p in Monocytes during Obesity Is Associated with Loss of the Anti-Inflammatory but Not Insulin Signaling Action of Adiponectin

Background: Low adiponectin, a well-recognized antidiabetic adipokine, has been associated with obesity-related inflammation, oxidative stress and insulin resistance. Globular adiponectin is an important regulator of the interleukin-1 receptor-associated kinase (IRAK)/NFkB pathway in monocytes of obese subjects. It protects against inflammation and oxidative stress by inducing IRAK3. microRNA (miR)-146b-5p inhibits NFkB-mediated inflammation by targeted repression of IRAK1 and TNF receptor-associated factor-6 (TRAF6). Therefore, we measured the expression of miR-146b-5p in monocytes of obese subjects. Because it was low we determined the involvement of this miR in the anti-inflammatory, antioxidative and insulin signaling action of globular adiponectin. Methods: miR-146b-5p expression in monocytes of obese subjects was determined by qRT-PCR. The effect of miR-146b-5p silencing on molecular markers of inflammation, oxidative stress and insulin signaling and the association with globular adiponectin was assessed in human THP-1 monocytes. Results: miR-146b-5p was downregulated in monocytes of obese persons. Low globular adiponectin decreased miR-146b-5p and IRAK3 in THP-1 monocytes, associated with increased mitochondrial reactive oxygen species (ROS). Intracellular ROS and insulin receptor substrate-1 (IRS1) protein were unchanged. Silencing of miR-146b-5p with an antisense inhibitor resulted in increased expression of IRAK1 and TRAF6 leading to more NFkB p65 DNA binding activity and TNFa. As

Moderate alcohol consumption increases insulin sensitivity and ADIPOQ expression in postmenopausal women: a randomised, crossover trial

Aims/hypothesis To determine whether 6 weeks of daily, moderate alcohol consumption increases expression of the gene encoding adiponectin (ADIPOQ) and plasma levels of the protein, and improves insulin sensitivity in postmenopausal women. Methods In a randomised, open-label, crossover trial conducted in the Netherlands, 36 apparently healthy postmenopausal women who were habitual alcohol consumers, received 250 ml white wine (~25 g alcohol/day) or 250 ml of white grape juice (control) daily during dinner for 6 weeks. Randomisation to treatment allocation occurred according to BMI. Insulin sensitivity and ADIPOQ mRNA and plasma adiponectin levels were measured at the end of both periods. Insulin sensitivity was estimated using the homeostasis model assessment of insulin resistance (HOMA-IR). Levels of ADIPOQ mRNA in subcutaneous adipose tissue were determined by RT-PCR. Results All subjects completed the study. Six weeks of white wine consumption reduced fasting insulin (mean¿±¿SEM 40.0¿±¿3.4 vs 46.5¿±¿3.4 pmol/l; p

Risk Factors for Acquisition of Fluoroquinolone or Aminoglycoside Resistance in Addition to Carbapenem Resistance in Pseudomonas aeruginosa

Background: Carbapenems, fluoroquinolones (FQs), and aminoglycosides (AGs) are key drugs for treating Pseudomonas aeruginosa infections, and accumulation of drug resistances make antibiotic therapy difficult.Methods: We evaluated 169 patients with imipenem (IPM)-resistant P. aeruginosa and compared patient background and microbiological characteristics between groups with or without FQ resistance. Similar analyses were performed for AG. Results: Of the 169 IPM-resistant strains, 39.1% showed resistance to FQs and 7.1% to AGs. The frequency of exposure to FQs within 90 days previously was higher in the group with FQ resistance (45.5%) than in the group without FQ resistance (13.6%). Similarly, 33.3% of patients in the group with AG resistance had been previously administered AGs, higher than the 7.6% of patients without AG resistance. Frequencies of metallo-β-lactamase (MBL) production were higher in the group with FQ or AG resistance (16.7% or 33.3%) than in the group without FQ or AG resistance (2.9% or 6.4%). Multivariate analyses showed exposures to FQs or AGs were related to the respective resistances. MBL production was a common factor for resistance to FQs or AGs, in addition to IPM-resistant P. aeruginosa. Conclusion: As well as promoting appropriate use of antibiotics, MBL production should be detected as a target of intervention for infection control

Adiponectin in relation to childhood myeloblastic leukaemia

Adiponectin, an adipocyte-specific secretory protein known to induce apoptosis, has been reported to be inversely related to breast and endometrial cancers and recently found to inhibit proliferation of myeloid but not lymphoid cell lines. We hypothesised that adiponectin may be inversely associated with acute myeloblastic leukaemia (AML), but not with acute lymphoblastic leukaemia of B (ALL-B) or T (ALL-T) cell origin in children. Blood samples and clinical information were collected over the period 1996–2000 from 201 children (0–14 years old) with leukaemia (22 AML, 161 ALL-B and 18 ALL-T cases) through a national network of childhood Hematology-Oncology units in Greece and from 201 controls hospitalised for minor pediatric ailments. Serum adiponectin levels were measured under code, at the Beth Israel Deaconess Medical Center, Boston, MA, USA using a radioimmunoassay procedure. Each of the three leukaemia groups was compared with the control group through multiple logistic regression. Odds ratios (OR) and 95% confidence intervals (95% CI) for an increase of adiponectin equal to 1 s.d. among controls were estimated controlling for gender, age, as well as for height and weight, expressed in age–gender-specific centiles of Greek growth curves. Adiponectin was inversely associated with AML (OR=0.56; 95% CI, 0.34–0.94), whereas it was not significantly associated with either ALL-B (OR=0.88; 95% CI, 0.71–1.10) or ALL-T (OR=1.08; 95% CI, 0.67–1.72). Biological plausibility and empirical evidence point to the importance of this hormone in the pathogenesis of childhood AML

Serum from Calorie-Restricted Rats Activates Vascular Cell eNOS through Enhanced Insulin Signaling Mediated by Adiponectin

eNOS activation resulting in mitochondrial biogenesis is believed to play a central role in life span extension promoted by calorie restriction (CR). We investigated the mechanism of this activation by treating vascular cells with serum from CR rats and found increased Akt and eNOS phosphorylation, in addition to enhanced nitrite release. Inhibiting Akt phosphorylation or immunoprecipitating adiponectin (found in high quantities in CR serum) completely prevented the increment in nitrite release and eNOS activation. Overall, we demonstrate that adiponectin in the serum from CR animals increases NO• signaling by activating the insulin pathway. These results suggest this hormone may be a determinant regulator of the beneficial effects of CR

Acadesine Kills Chronic Myelogenous Leukemia (CML) Cells through PKC-Dependent Induction of Autophagic Cell Death

CML is an hematopoietic stem cell disease characterized by the t(9;22) (q34;q11) translocation encoding the oncoprotein p210BCR-ABL. The effect of acadesine (AICAR, 5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranoside) a compound with known antileukemic effect on B cell chronic lymphoblastic leukemia (B-CLL) was investigated in different CML cell lines. Acadesine triggered loss of cell metabolism in K562, LAMA-84 and JURL-MK1 and was also effective in killing imatinib-resistant K562 cells and Ba/F3 cells carrying the T315I-BCR-ABL mutation. The anti-leukemic effect of acadesine did not involve apoptosis but required rather induction of autophagic cell death. AMPK knock-down by Sh-RNA failed to prevent the effect of acadesine, indicating an AMPK-independent mechanism. The effect of acadesine was abrogated by GF109203X and Ro-32-0432, both inhibitor of classical and new PKCs and accordingly, acadesine triggered relocation and activation of several PKC isoforms in K562 cells. In addition, this compound exhibited a potent anti-leukemic effect in clonogenic assays of CML cells in methyl cellulose and in a xenograft model of K562 cells in nude mice. In conclusion, our work identifies an original and unexpected mechanism by which acadesine triggers autophagic cell death through PKC activation. Therefore, in addition to its promising effects in B-CLL, acadesine might also be beneficial for Imatinib-resistant CML patients

Low Adiponectin Levels Are an Independent Predictor of Mixed and Non-Calcified Coronary Atherosclerotic Plaques

Atherosclerosis is the primary cause of coronary artery disease (CAD). There is increasing recognition that lesion composition rather than size determines the acute complications of atherosclerotic disease. Low serum adiponectin levels were reported to be associated with coronary artery disease and future incidence of acute coronary syndrome (ACS). The impact of adiponectin on lesion composition still remains to be determined. We measured serum adiponectin levels in 303 patients with stable typical or atypical chest pain, who underwent dual-source multi-slice CT-angiography to exclude coronary artery stenosis. Atherosclerotic plaques were classified as calcified, mixed or non-calcified. In bivariate analysis adiponectin levels were inversely correlated with total coronary plaque burden (r = -0.21, p = 0.0004), mixed (r = -0.20, p = 0.0007) and non-calcified plaques (r = -0.18, p = 0.003). No correlation was seen with calcified plaques (r = -0.05, p = 0.39). In a fully adjusted multivariate model adiponectin levels remained predictive of total plaque burden (estimate: -0.036, 95%CI: -0.052 to -0.020, p<0.0001), mixed (estimate: -0.087, 95%CI: -0.132 to -0.042, p = 0.0001) and non-calcified plaques (estimate: -0.076, 95%CI: -0.115 to -0.038, p = 0.0001). Adiponectin levels were not associated with calcified plaques (estimate: -0.021, 95% CI: -0.043 to -0.001, p = 0.06). Since the majority of coronary plaques was calcified, adiponectin levels account for only 3% of the variability in total plaque number. In contrast, adiponectin accounts for approximately 20% of the variability in mixed and non-calcified plaque burden. Adiponectin levels predict mixed and non-calcified coronary atherosclerotic plaque burden. Low adiponectin levels may contribute to coronary plaque vulnerability and may thus play a role in the pathophysiology of ACS

A Combined Transcriptomics and Lipidomics Analysis of Subcutaneous, Epididymal and Mesenteric Adipose Tissue Reveals Marked Functional Differences

Depot-dependent differences in adipose tissue physiology may reflect specialized functions and local interactions between adipocytes and surrounding tissues. We combined time-resolved microarray analyses of mesenteric- (MWAT), subcutaneous- (SWAT) and epididymal adipose tissue (EWAT) during high-fat feeding of male transgenic ApoE3Leiden mice with histology, targeted lipidomics and biochemical analyses of metabolic pathways to identify differentially regulated processes and site-specific functions. EWAT was found to exhibit physiological zonation. De novo lipogenesis in fat proximal to epididymis was stably low, whereas de novo lipogenesis distal to epididymis and at other locations was down-regulated in response to high-fat diet. The contents of linoleic acid and α-linolenic acid in EWAT were increased compared to other depots. Expression of the androgen receptor (Ar) was higher in EWAT than in MWAT and SWAT. We suggest that Ar may mediate depot-dependent differences in de novo lipogenesis rate and propose that accumulation of linoleic acid and α-linolenic acid in EWAT is favored by testosterone-mediated inhibition of de novo lipogenesis and may promote further elongation and desaturation of these polyunsaturated fatty acids during spermatogenesis

Interleukin-1 Receptor-Associated Kinase-3 Is a Key Inhibitor of Inflammation in Obesity and Metabolic Syndrome

BACKGROUND: Visceral obesity is associated with the rising incidence of type 2 diabetes and metabolic syndrome. Low-grade chronic inflammation and oxidative stress synergize in obesity and obesity-induced disorders. OBJECTIVE: We searched a cluster of molecules that support interactions between these stress conditions in monocytes. METHODS: RNA expressions in blood monocytes of two independent cohorts comprising 21 and 102 obese persons and 46 age-matched controls were determined by microarray and independently validated by quantitative RT-PCR analysis. The effect of three-month weight loss after bariatric surgery was determined. The effect of RNA silencing on inflammation and oxidative stress was studied in human monocytic THP-1 cells. RESULTS: Interleukin-1 receptor-associated kinase-3 (IRAK3), key inhibitor of IRAK/NFκB-mediated chronic inflammation, is downregulated in monocytes of obese persons. Low IRAK3 was associated with high superoxide dismutase-2 (SOD2), a marker of mitochondrial oxidative stress. A comparable expression profile was also detected in visceral adipose tissue of the same obese subjects. Low IRAK3 and high SOD2 was associated with a high prevalence of metabolic syndrome (odds ratio: 9.3; sensitivity: 91%; specificity: 77%). By comparison, the odds ratio of high-sensitivity C-reactive protein, a widely used marker of systemic inflammation, was 4.3 (sensitivity: 69%; specificity: 66%). Weight loss was associated with an increase in IRAK3 and a decrease in SOD2, in association with a lowering of systemic inflammation and a decreasing number of metabolic syndrome components. We identified the increase in reactive oxygen species in combination with obesity-associated low adiponectin and high glucose and interleukin-6 as cause of the decrease in IRAK3 in THP-1 cells in vitro. CONCLUSION: IRAK3 is a key inhibitor of inflammation in association with obesity and metabolic syndrome. Our data warrant further evaluation of IRAK3 as a diagnostic and prognostic marker, and as a target for intervention