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.

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.

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.

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)

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 lovastatin on the secretion of very low density lipoprotein lipids and apolipoprotein B in the hypertriglyceridemic Zucker obese rat.

Recent studies demonstrated that inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase lower plasma triglyceride primarily by decreasing hepatic secretion of very low density lipoproteins (VLDL). A possible mechanism is that inhibition of cholesterol synthesis interferes with the assembly of VLDL particles. Since one molecule of apolipoprotein (apo) B is required for the proper assembly and secretion of each VLDL and secretion of apo B may be regulated by various lipid components of the lipoproteins, question arises whether HMG-CoA reductase inhibitors also decrease the secretion of apo B. To address this issue, we investigated the effect of lovastatin on the secretion rate of VLDL-apo B and on the composition of VLDL in the Zucker obese rat; a model for genetic hypertriglyceridemia. Lovastatin treatment (4 mg/kg day x 13 days), as compared with placebo, decreased the concentrations of fasting plasma triglyceride (1740 +/- 170 vs. 3130 +/- 790 micrograms/ml) and VLDL-triglyceride (1379 +/- 59 vs. 3082 +/- 715 micrograms/ml). There was a small but non-significant decrease in VLDL-apo B (19 +/- 2 micrograms/ml vs. 26 +/- 7 micrograms/ml). Thus, lovastatin significantly decreased the ratio of triglyceride to apo B in VLDL (76 in lovastatin vs. 124 in placebo group). Secretion rates of VLDL-lipids and VLDL-apo B were measured after intravenous injection of Triton WR-1339.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term exercise training and retirement in genetically obese rats: effects on food intake, feeding efficiency and carcass composition.

Short-term physical exercise (EX) can reduce body weight and fat gain in obese humans and animals. However, the beneficial effects of physical exercise are not long-lasting. In this study, the effects of long-term physical exercise and retirement from exercise (R) on body weight, body composition and fat distribution were examined in genetically obese (OB) and lean (LE) female rats. Fifty OB and 45 LE rats, four weeks old, were divided into EX (swimming, 2h/day, 5 days/week) or sedentary (SD) groups. At the end of the 28th week of treatment, EX groups were further divided into continued EX or R groups for another 11-12 weeks. It was found that at the end of the 28th week EX had reduced the rate of weight gain in OB and LE rats. Percentage body fat was only reduced in OBEX rats and this was achieved by a significant reduction of subcutaneous fat mass. At the end of the 40th week, EX had further reduced the weight gain, fat mass and body fat percentage in OBEX rats while only body fat percentage was reduced in the LEEX group. Retirement from exercise reversed these phenomena. Thus there were no differences between OBSD and OBEX-R rats in body weight, fat mass and percentage body fat. However, the OBEX-R group had a significantly higher amount of internal fat than the other two OB groups. Therefore, exercise, even long-term to cover the entire fat cell proliferation period, still only exerted temporary beneficial effects in OB rats. After retirement, the beneficial effects all disappeared rapidly.(ABSTRACT TRUNCATED AT 250 WORDS)

Repeated pregnancy without lactation: effects on maternal glycemic control, pregnancy outcome, carcass composition, and fat distribution in rats.

Repeated pregnancy without lactation in rats has been reported to produce permanently elevated carcass fat mass and hyperplasia in subcutaneous fat depot. In the present study, the pregnancy outcome, intravenous glucose tolerance ability (IVGTT), and carcass composition were further examined in Osborne-Mendel rats. Female rats were divided into pregnancy-lactation (PL), pregnancy-no lactation (PNL), and control (CON) groups. Half of the rats were killed after three pregnancy/lactation cycles, whereas the rest were given a 12-week rest period before killing. It was found that rats in PNL group had fasting hyperglycemia and insulin insensitivity during the third pregnancy (P less than or equal to .05), elevated spontaneous abortion rate (P less than or equal to .05), and elevated subcutaneous fat content (P less than or equal to .01) relative to that of PL rats or CON rats. After a 12-week rest period, a significant increase in subcutaneous fat cell number was also observed in PNL rats. PL rats, on the other hand, have significantly elevated internal/subcutaneous fat ratios (P less than or equal to .05), both immediately after weaning and after the 12-week rest period. The significance of this change is not yet known.