Roles of circulating WNT-signaling proteins and WNT-inhibitors in human adiposity, insulin resistance, insulin secretion, and inflammation.

Wingless-type MMTV integration site family member (WNT) signaling and WNT-inhibitors have been implicated in regulation of adipogenesis, insulin resistance, pancreatic function, and inflammation. Our goal was to determine serum proteins involved in WNT signaling (WNT5 and WISP2) and WNT inhibition (SFRP4 and SFRP5) as they relate to obesity, serum adipokines, insulin resistance, insulin secretion, and inflammation in humans. Study population comprised 57 insulin resistant women with polycystic ovary syndrome (PCOS) and 27 reference women. In a cross-sectional study, blood samples were obtained at fasting, during oral, and frequently sampled intravenous glucose tolerance tests. Serum WNT5, WISP2, and SFRP4 concentrations did not differ between PCOS vs. reference women. Serum WNT5 correlated inversely with weight both in PCOS and reference women, and correlated directly with insulin response during oral glucose tolerance test in PCOS women. Serum WISP2 correlated directly with fatty acid binding protein 4. Serum SFRP5 did not differ between obese (n=32) vs. nonobese (n=25) PCOS women, but reference women had lower SFRP5 (p<5×10(-6) as compared to both PCOS groups). Serum SFRP5 correlated inversely with IL-1ß, TNF-α, cholesterol, and apoprotein B. These findings demonstrated that WNT5 correlated inversely with adiposity and directly with insulin response, and the WNT-inhibitor SFRP5 may be anti-inflammatory. Better understanding of the role of WNT signaling in obesity, insulin resistance, insulin secretion, lipoprotein metabolism, and inflammation is important for prevention and treatment of metabolic syndrome, diabetes and cardiovascular disease.

The effects of weight loss on FABP4 and RBP4 in obese women with metabolic syndrome.

Fat accumulation is associated with the release of many novel adipokines such as retinol-binding protein 4 and fatty acid-binding protein 4. These adipokines have been linked to insulin resistance, metabolic syndrome, type 2 diabetes and cardiovascular disease. Since weight loss is the first step for the treatment of metabolic syndrome, which increases the risks for both type 2 diabetes and cardiovascular disease, we have investigated the effects of weight loss on serum retinol-binding protein 4 and fatty acid-binding protein 4 in obese individuals with this syndrome. Twenty-nine obese female subjects with metabolic syndrome, aged 18-62 years completed a 2-month weight loss diet plan. Data were collected from dual-energy X-ray absorptiometry and indirect calorimetry. Blood was taken at baseline and at 2 months and assayed for adipokines, lipids, and insulin resistance parameters. The change in circulating fatty acid-binding protein 4 levels were inversely correlated with total weight loss (p<0.02) and lean mass loss (p<0.01), but not with fat mass loss. Retinol-binding protein 4 levels did not track with any measure of body composition. Changes in leptin levels were found to correlate with weight loss (p<0.02), fat loss (p<0.03), and lean mass loss (p<0.05). Fatty acid-binding protein 4 levels increased and retinol-binding protein 4 levels did not change during moderate weight loss in obese women with metabolic syndrome; however, several other risk factors for type 2 diabetes and cardiovascular disease did improve with weight loss.

Differential effects of walnuts vs almonds on improving metabolic and endocrine parameters in PCOS.

BACKGROUND/OBJECTIVES: Polycystic ovary syndrome (PCOS) is commonly associated with insulin resistance, dyslipidemia and increased inflammation, which all benefit from dietary intake of monounsaturated and n-3 polyunsaturated fatty acids (MUFA and n-3 PUFA). Our goal was to compare the effects of MUFA-rich almonds vs n-3/n-6 PUFA-rich walnuts on metabolic and endocrine parameters in PCOS. SUBJECTS/METHODS: Thirty-one PCOS patients randomly received either walnuts or almonds containing 31 g of total fat per day for 6 weeks. At the beginning and at the end, anthropometric parameters, fasting lipids, phospholipid-fatty acids, inflammatory markers, androgens, oral glucose tolerance tests (OGTT) and frequently sampled intravenous-GTT were obtained. RESULTS: Weight remained stable. Within group, walnuts increased the n-3/n-6 essential PUFA in the diet and plasma phospholipids. Walnuts decreased low-density lipoprotein-cholesterol by 6% from 3.76 ± 0.27 to 3.38 ± 0.22 mmol/l (P = 0.05) and apoprotein B by 11% from 0.72 ± 0.04 to 0.64 ± 0.05 g/l (P < 0.03). Although almonds also reduced low-density lipoprotein-cholesterol by 10% and apoprotein B by 9%, these were not significant. Walnuts increased insulin response during OGTT by 26% (P < 0.02). Both walnuts and almonds increased adiponectin (walnuts from 9.5 ± 1.6 to 11.3 ± 1.8 µg per 100 ml, P = 0.0241; almonds from 10.1 ± 1.5 to 12.2 ± 1.4 µg/dl, P = 0.0262). Walnuts decreased HgBA1 from 5.7 ± 0.1 to 5.5 ± 0.1% (P = 0.0006) with significant intergroup difference from almonds (P=0.0470). Walnuts increased sex hormone-binding globulin from 38.3 ± 4.1 to 43.1 ± 4.3 nmol/l (P=0.0038) and almonds reduced free androgen index from 2.6 ± 0.4 to 1.8 ± 0.3 (P = 0.0470). CONCLUSION: Nut intake exerted beneficial effects on plasma lipids and androgens in PCOS.

Effects of walnut consumption on plasma fatty acids and lipoproteins in combined hyperlipidemia.

BACKGROUND: Epidemiologic studies show an inverse relation between nut consumption and coronary heart disease. OBJECTIVE: We determined the effects of walnut intake on plasma fatty acids, lipoproteins, and lipoprotein subclasses in patients with combined hyperlipidemia. DESIGN: Participants sequentially adhered to the following diets: 1) a habitual diet (HD), 2) a habitual diet plus walnuts (HD+W), 3) a low-fat diet (LFD), and 4) a low-fat diet plus walnuts (LFD+W). RESULTS: In 13 postmenopausal women and 5 men ( +/- SD age 60 +/- 8 y), walnut supplementation did not increase body weight despite increased energy intake and the LFD caused weight loss (1.3 +/- 0.5 kg; P < 0.01). When comparing the HD with the HD+W, linoleic acid concentrations increased from 29.94 +/- 1.14% to 36.85 +/- 1.13% and alpha-linolenic acid concentrations increased from 0.78 +/- 0.04% to 1.56 +/- 0.11%. During the LFD+W, plasma total cholesterol concentrations decreased by 0.58 +/- 0.16 mmol/L when compared with the HD and by 0.46 +/- 0.14 mmol/L when compared with the LFD. LDL-cholesterol concentrations decreased by 0.46 +/- 0.15 mmol/L when compared with the LFD. Measurements of lipoprotein subclasses and particle size suggested that walnut supplementation lowered cholesterol preferentially in small LDL (46.1 +/- 1.9% compared with 33.4 +/- 4.3%, HD compared with HD+W, respectively; P < 0.01). HDL-cholesterol concentrations decreased from 1.27 +/- 0.07 mmol/L during the HD to 1.14 +/- 0.07 mmol/L during the HD+W and to 1.11 +/- 0.08 mmol/L during the LFD. The decrease was seen primarily in the large HDL particles. CONCLUSIONS: Walnut supplementation may beneficially alter lipid distribution among various lipoprotein subclasses even when total plasma lipids do not change. This may be an additional mechanism underlying the antiatherogenic properties of nut intake.

Risk factors for early-onset, ventilator-associated pneumonia in critical care patients: selected multiresistant versus nonresistant bacteria.

BACKGROUND: Ventilator-associated pneumonia is the leading nosocomial infection in critically ill patients. The frequency of ventilator-associated pneumonia caused by multidrug-resistant bacteria has increased in recent years, and these pathogens cause most of the deaths attributable to pneumonia. The authors, therefore, evaluated factors associated with selected multidrug-resistant ventilator-associated pneumonia in critical care patients. METHODS: The authors prospectively recorded potential risk factors at the time of intensive care unit admission. An endotracheal aspirate was obtained in all patients who met clinical criteria for pneumonia. Patients were considered to have ventilator-associated pneumonia only when they met the clinical criteria and aspirate culture was positive for bacteria 48 h or more after initiation of mechanical ventilation. Pediatric patients were excluded. Adult patients with ventilator-associated pneumonia were first grouped as "early-onset" (< 5 days) and "late-onset," determined by episodes of ventilator-associated pneumonia, and then, assigned to four groups based on the bacteria cultured from their tracheal aspirates: Pseudomonas aeruginosa, Acinetobacter baumanii, methicillin-resistant staphylococci, and all others. The first three bacteria were considered to be multidrug resistant, whereas the others were considered to be antibiotic susceptible. Potential risk factors were evaluated with use of univariate statistics and multivariate regression. RESULTS: Among 486 consecutive patients admitted during the study, 260 adults underwent mechanical ventilation for more than 48 h. Eighty-one patients (31%) experienced 99 episodes of ventilator-associated pneumonia, including Pseudomonas(33 episodes), methicillin-resistant staphylococci (17 episodes), Acinetobacter(9 episodes), and nonresistant bacteria (40 episodes). Sixty-six of these episodes were early onset and 33 episodes were late onset. Logistic regression analysis identified three factors significantly associated with early-onset ventilator-associated pneumonia caused by any one of the multidrug-resistant bacterial strains: emergency intubation (odds ratio, 6.4; 95% confidence interval, 2.0-20.2), aspiration (odds ratio, 12.7; 95% confidence interval, 2.4-64.6), and Glasgow coma score of 9 or less (odds ratio, 3.9; 95% confidence interval, 1.3-11.3). A. baumanii-related pneumonia cases were found to be significantly associated with two of these factors: aspiration (odds ratio, 14.2; 95% confidence interval, 1.5-133.8) and Glasgow coma score (odds ratio, 6.0; 95% confidence interval, 1.1-32.6). CONCLUSIONS: The authors recommend that patients undergoing emergency intubation or aspiration or who have a Glasgow coma score of 9 or less be monitored especially closely for early-onset multidrug-resistant pneumonia. The occurrence of aspiration and a Glasgow coma score of 9 or less are especially associated with pneumonia caused by A. baumanii.

Changes in plasma lipoproteins during low-fat, high-carbohydrate diets: effects of energy intake.

BACKGROUND: Low-fat diets can increase plasma triacylglycerol and reduce HDL cholesterol. Changes in energy intake and body weight can influence the lipoprotein response. OBJECTIVE: We sought to prospectively examine the effects of euenergetic and ad libitum dietary fat restriction on plasma lipoproteins in healthy postmenopausal women. DESIGN: Participants first received a controlled euenergetic diet in which dietary fat was reduced stepwise from 35% to 25% to 15% over 4 mo. Thereafter, participants followed an ad libitum 15%-fat diet for 8 mo; 54 women completed the intervention. RESULTS: During the controlled euenergetic diet, plasma triacylglycerol increased from 1.70 +/- 0.10 to 2.30 +/- 0.16 mmol/L, total cholesterol decreased from 5.87 +/- 0.13 to 5.53 +/- 0. 13 mmol/L, LDL cholesterol decreased from 3.41 +/- 0.10 to 2.87 +/- 0.10 mmol/L, HDL cholesterol decreased from 1.76 +/- 0.08 to 1.50 +/- 0.08 mmol/L, and apolipoprotein (apo) A-I decreased from 5.11 +/- 0.14 to 4.78 +/- 0.14 mmol/L (P < 0.0001 for all changes). Hormone replacement therapy did not affect the relative change in HDL cholesterol. Plasma glucose, insulin, hemoglobin A(1C,) free fatty acid, and apo B concentrations did not change significantly. During the ad libitum 15%-fat diet, participants lost 4.6 +/- 0.4 kg. Plasma triacylglycerol and LDL cholesterol returned to baseline values (1.77 +/- 0.12 and 3.31 +/- 0.08 mmol/L, respectively), whereas HDL cholesterol and apo A-I remained low (1.40 +/- 0.08 and 4.82 +/- 0.18 mmol/L, respectively). HDL cholesterol and apo A-I concentrations stabilized in subjects who were not receiving hormone replacement therapy but continued to decline in women who were receiving hormone therapy. CONCLUSIONS: The ad libitum 15%-fat diet resulted in significant weight loss. The euenergetic but not the ad libitum diet caused hypertriacylglycerolemia. HDL cholesterol decreased during both low-fat diets.

(+)-Catechin in human plasma after ingestion of a single serving of reconstituted red wine.

BACKGROUND: Red wine consumption may decrease the risk of coronary heart disease through the actions of its constituent flavonoids. (+)-Catechin is an abundant flavonoid in red wine. OBJECTIVE: The objective was to determine changes in plasma (+)-catechin concentrations after ingestion of a single, moderate serving of dealcoholized red wine reconstituted with either water (DRW) or water and alcohol (ARW). DESIGN: Nine subjects (5 men, 4 women) ingested, in random order, 120 mL DRW on one day and 120 mL ARW on another day. Both the DRW and ARW contained 35 mg (121 micromol) free (+)-catechin. Blood samples were collected at 0, 0.5, 1, 2, 3, 4, and 8 h. Plasma was analyzed by gas chromatography-mass spectrometry for (+)-catechin after enzymatic release of sulfate and glucuronide conjugates. RESULTS: Calcium ions were needed to effectively hydrolyze (+)-catechin conjugates in plasma containing EDTA. Neither the ARW or DRW nor sex affected the area under the curve at 8 h, the maximum concentration (c(max)), or the time it took for plasma total (+)-catechin to reach maximum concentration (t(max)). Pooled mean (+/-SEM) values for the ARW and DRW were as follows: area under the curve, 306.1 +/- 29.5 nmol*h/L; c(max), 76.7 +/- 7.5 nmol/L; and t(max), 1.44 +/- 0.13 h. The half-life of (+)-catechin in plasma was significantly less (P = 0.038) after ingestion of the ARW (3.17 h) than after ingestion of the DRW (4.08 h). CONCLUSIONS: Increases in plasma total (+)-catechin concentrations were not significantly different after single moderate servings of either the ARW or DRW. Alcohol in the ARW hastened the elimination of (+)-catechin from the plasma compartment. (+)-Catechin elimination may represent excretion or conversion to methylated derivatives.

Effects of dietary fat restriction on particle size of plasma lipoproteins in postmenopausal women.

Hypertriglyceridemia is an independent risk factor for coronary artery disease (CAD) and is also commonly associated with other coronary risk factors, ie, small, dense low-density lipoprotein (LDL) particles and low plasma levels of high-density lipoprotein cholesterol (HDL-C). Dietary fat restriction is recommended for the prevention of nutrition-related cancers. Low-fat, high-carbohydrate intake can increase plasma triglyceride (TG) and decrease HDL-C. In general, plasma TG levels are inversely related to the particle size of LDL. We investigated the effects of dietary fat restriction on the concentration and particle size of plasma lipoproteins in 14 healthy postmenopausal women (aged 61 +/- 11 years). During a 4-month period of eucaloric controlled feeding, dietary fat was reduced stepwise from a habitual intake of 33% +/- 8% to 23% and then to 14% of daily energy. Changes in the plasma lipid level and particle size of very-low-density lipoprotein (VLDL), LDL, and HDL were determined at the end of each dietary phase. Increasing carbohydrate intake without weight loss was associated with an increase in plasma TG (1.86 +/- 0.30 v 2.47 +/- 0.37 mmol/L) and decreases in total cholesterol (5.82 +/- 0.25 v 5.40 +/- 0.21 mmol/L), LDL-C (3.07 +/- 0.18 v 2.61 +/- 0.21 mmol/L), HDL-C (1.42 +/- 0.1 v 1.24 +/- 0.1 mmol/L), and apolipoprotein (apo) A1 (5.14 +/- 0.25 v 4.61 +/- 0.36 mmol/L), whereas plasma apo B did not change. The particle size of VLDL increased (42.7 +/- 1.4 v 47.0 +/- 0.9 nm). However, there was no change in either LDL (25.1 +/- 0.2 v 25.3 +/- 0.2 nm) or HDL particle size. Although at each level of dietary fat intake LDL particle size correlated inversely with plasma TG and apo B, there was no relationship between the increase in plasma TG and LDL particle size. These results show that hypertriglyceridemia caused by a eucaloric high-carbohydrate intake is not associated with a decrease in LDL particle size. Therefore, carbohydrate-induced hypertriglyceridemia may not have the same atherogenic potential as genetic hypertriglyceridemias.

Effects of dietary carbohydrates on glucose and lipid metabolism in golden Syrian hamsters.

Frequent coexistence of insulin resistance, central obesity, and hypertriglyceridemia in the same individual suggests an underlying common pathogenesis. Insulin resistance and hypertriglyceridemia can be induced by carbohydrate feeding in rats. Golden Syrian hamsters are believed to be resistant to the metabolic effects of dietary carbohydrates. We investigated the effects of diets containing 60% fructose or sucrose on glucose and lipid metabolism in hamsters, both in the fasting state and during an intravenous glucose tolerance test. Fructose caused obesity (weight after treatment: 131 +/- 7 gm in the control group, 155 +/- 5 gm in the fructose group, 136 +/- 7 gm in sucrose group, p < 0.04). Fructose also reduced glucose disappearance rate (KG: 2.69% +/- 0.39% in the control group, 1.45% +/- 0.18% in the fructose group, p < 0.02). Sucrose caused a marginal decrease in glucose disappearance (KG: 1.93% +/- 0.21%, p = 0.08 vs the control group). Only fructose feeding increased fasting plasma nonesterified fatty acids (0.645 +/- 0.087 mEq/L in the control group, 1.035 +/- 0.083 mEq/L in the fructose group, 0.606 +/- 0.061 mEq/L in the sucrose group, p < 0.002), plasma triglycerides (84 +/- 6 mg/dl in the control group, 270 +/- 65 mg/dl in the fructose group, 94 +/- 16 mg/dl in the sucrose group, p < 0.0002), and liver triglycerides (1.88 +/- 0.38 mg/gm liver weight in the control group, 2.35 =/- 0.24 mg/gm in the fructose group, 1.41 +/- 0.13 mg/gm in the sucrose group, p < 0.04). Previous studies in the rat have suggested that dietary carbohydrates induce insulin resistance by increasing plasma nonesterified fatty acids and triglycerides, which are preferentially used by the muscles. The present report shows that sucrose also can cause some decrease in glucose disappearance in the hamster without causing hypertriglyceridemia or increasing plasma nonesterified fatty acids. Thus other mechanisms may also contribute to the insulin resistance in the hamster. These findings suggest that hamsters provide a good model for investigation of hormonal and nutritional regulation of glucose and lipid metabolism.

Effects of omega-3 fatty acids on intravascular lipolysis of very-low-density lipoproteins in humans.

Very-low-density lipoproteins (VLDLs) are the major carriers of fasting plasma triglyceride (TG). TG-enriched VLDLs become cholesterol (C)-enriched low-density lipoproteins (LDLs) through hydrolysis facilitated by lipoprotein lipase (LPL). Omega-3 fatty acid (n-3 FA) supplementation may increase LDL-C while decreasing plasma TG in hypertriglyceridemic patients. It has been proposed that n-3 FAs increase LDL-C by promoting production of TG-poor VLDL and accelerating conversion of VLDL to LDL. To study the effects of n-3 FA supplementation on in vivo lipolysis of VLDL directly, we treated 11 hypertriglyceridemic subjects with n-3 FA (3.3 g/d). Each participant was studied three times: at baseline, after a 1-month period of run-in olive oil placebo, and after 1 more month of n-3 FA supplementation. Lipolysis was induced by intravenous infusion of heparin for 2 hours. Plasma samples were obtained every 30 minutes for determination of lipids and apoproteins (apos), separation of individual lipoproteins by fast protein liquid chromatography (FPLC), and measurement of LPL and hepatic TG lipase (HTGL) levels. n-3 FA supplementation decreased fasting plasma TG (2.51 +/- 0.23 v 3.97 +/- 0.46 mmol/L), VLDL-TG (1.08 +/- 0.18 v 2.35 +/- 0.35 mmol/L), and VLDL-C (0.39 +/- 0.05 v 0.72 +/- 0.13 mmol/L) while increasing LDL-C (3.59 +/- 0.21 v 3.00 +/- 0.23 mmol/L) and plasma apo B (3.31 +/- 0.19 v 2.90 +/- 0.17 mmol/L). The absolute rate of TG lipolysis correlated with fasting TG (r = .74, P < .005) and was lower after n-3 FA supplementation (0.11 +/- 0.01 mmol/mL/min) as compared with placebo (0.19 +/- 0.01, P < .01), whereas percent decreases from baseline TG levels were similar at entry onto the study (57.4% +/- 2.5%), after placebo (58.8% +/- 2.7%), and after n-3 FA (52% +/- 3.6%).(ABSTRACT TRUNCATED AT 250 WORDS)

Impact of n-3 fatty acids on lipoprotein metabolism.

The n-3 fish oils initially attracted the attention of the research community because of their protective actions against coronary artery disease. However, since then, research in this field has contributed to the basic understanding of several aspects of lipid and lipoprotein metabolism.

Changes in plasma lipoproteins during lipolysis in vivo in the hypertriglyceridemic state.

We investigated the effects of the severity of the hypertriglyceridemic state on lipolysis of very-low-density lipoproteins (VLDLs) in vivo. In six patients with mild (Mild, fasting triglyceride 2.54 +/- 0.27 mmol/L) and six with moderate hypertriglyceridemia (Mod, fasting triglyceride 4.63 +/- 0.47 mmol/L), heparin infusion decreased plasma triglycerides in direct correlation with the baseline triglyceride (r = 0.92 in Mild, r = 0.96 in Mod) concentration. Fasting VLDL-triglyceride correlated inversely with postheparin lipoprotein lipase (LPL) (r = -0.85). A decrease in VLDL-triglyceride correlated with baseline VLDL-triglyceride (r = 0.93), but not with postheparin LPL. In the Mild group, low-density-lipoprotein (LDL) cholesterol steadily increased (baseline, 2.90 +/- 0.18 mmol/L; 30 min, 3.03 +/- 0.23 mmol/L; 2 h, 3.15 +/- 0.18 mmol/L) in correlation with the decrease in VLDL-triglyceride (r = 0.89). In the Mod group, LDL cholesterol initially decreased (baseline, 2.51 +/- 0.34 mmol/L; 30 min, 2.30 +/- 0.23 mmol/L) and then increased (2 h, 2.82 +/- 0.28 mmol/L). These results demonstrate a delay in conversion of VLDLs into LDLs in pronounced hypertriglyceridemia, which may contribute to the etiology of low plasma LDL cholesterol.

Effect of growth hormone on epiphyseal growth plates in zinc deficiency.

This study was carried out on 18 albino rats. The control group, consisting of six rats, was fed a normal diet and tap water. The other rats were given a zinc-deficient diet and deionized water. Two weeks later the latter group was again divided into two into smaller groups. The first of these groups was given an given an additional 100 ppm of zinc acetate. From the fifteenth day onwards, the human growth hormone (Nanormon) was injected intra-peritoneally to each group at a dose of 80 micrograms/day for two weeks. At the end of the experiment, it was found that body weights were markedly increased in the control and zinc-added groups compared with the zinc-deficient rats. In the zinc-deficient group, serum zinc, hair zinc levels, alkaline phosphatase activity and serum protein levels were lower than those of the control and zinc-added groups. The zinc-deficient group had narrower tibial epiphyseal growth plates than those of the control group. The count of hypertrophied cells was also less in the zinc-deficient group. Based on these data, our conclusion was that the growth hormone becomes ineffective under conditions of zinc deficiency. This means that zinc deficiency has multidimensional effects on growth hormone activity.