Alterations of Serum Ser312-Phosphorylated Fetuin-A from Exercise-Induced Moderate Body Weight Loss in Individuals with Obesity.

OBJECTIVE: Phosphorylated fetuin-A (pFet-A) inhibits insulin action and has been shown to be associated with obesity and insulin resistance. The objective of this cohort study was to assess the effect of incremental body weight loss on alterations in serum pFet-A and indexes of insulin sensitivity. METHODS: A total of 16 men with obesity attained a targeted weight loss of 8% to 10% of their initial body weight by achieving an energy expenditure/deficit of 2,000 to 2,500 kcal/wk. Anthropometric assessments and blood samples were obtained every 4 weeks. Weight loss was calculated and partitioned as 2% to 4%, 4% to 6%, 6% to 8%, and 8% to 10% compared with initial body weight. RESULTS: Targeted body weight loss of 8% to 10% decreased serum pFet-A, pFet-A:Fet-A ratio, fasting insulin, log(homeostasis model assessment of insulin resistance), quantitative insulin sensitivity check index, adipose insulin resistance, and insulin resistance index significantly. Percent changes in serum pFet-A were associated with percent changes in indexes of insulin sensitivity. Unlike insulin sensitivity indexes, which were altered starting with 6% to 8% weight loss, serum pFet-A levels were significantly decreased by 19.6% starting with 2% to 4% weight loss and decreased by 25.6%, 36.8%, and 42.3% with 4% to 6%, 6% to 8%, and 8% to 10% weight loss, respectively. CONCLUSIONS: This study reports for the first time that the insulin-sensitizing effects of moderate weight loss are associated with a reduction in serum pFet-A levels.

Phosphorylation status of fetuin-A is critical for inhibition of insulin action and is correlated with obesity and insulin resistance.

Fetuin-A (Fet-A), a hepatokine associated with insulin resistance, obesity, and incident type 2 diabetes, is shown to exist in both phosphorylated and dephosphorylated forms in circulation. However, studies on fetuin-A phosphorylation status in insulin-resistant conditions and its functional significance are limited. We demonstrate that serum phosphofetuin-A (Ser312) levels were significantly elevated in high-fat diet-induced obese mice, insulin-resistant Zucker diabetic fatty rats, and in individuals with obesity who are insulin resistant. Unlike serum total fetuin-A, serum phosphofetuin-A was associated with body weight, insulin, and markers of insulin resistance. To characterize potential mechanisms, fetuin-A was purified from Hep3B human hepatoma cells. Hep3B Fet-A was phosphorylated (Ser312) and inhibited insulin-stimulated glucose uptake and glycogen synthesis in L6GLUT4 myoblasts. Furthermore, single (Ser312Ala) and double (Ser312Ala + Ser120Ala) phosphorylation-defective Fet-A mutants were without effect on glucose uptake and glycogen synthesis in L6GLUT4 myoblasts. Together, our studies demonstrate that phosphorylation status of Fet-A (Ser312) is associated with obesity and insulin resistance and raise the possibility that Fet-A phosphorylation may play a role in regulation of insulin action.

Paraoxonase responses to exercise and niacin therapy in men with metabolic syndrome.

Our purpose was to characterize changes in paraoxonase 1 (PON1) activity and concentration after single aerobic exercise sessions conducted before and after 6 weeks of niacin therapy in men with metabolic syndrome (MetS). Twelve men with MetS expended 500 kcal by walking at 65% of VO2max before and after a 6-week regimen of niacin. Niacin doses were titrated by 500 mg/week from 500 to 1500 mg/day and maintained at 1500 mg/day for the last 4 weeks. Fasting blood samples were collected before and 24 hours after each exercise session and analyzed for PON1 activity, PON1 concentration, myeloperoxidase (MPO), apolipoprotein A1, oxidized low-density lipoprotein (oLDL), lipoprotein particle sizes and concentrations. PON1 activity, PON1 concentration, MPO, and oLDL were unaltered following the independent effects of exercise and niacin (P > 0.05 for all). High-density lipoprotein particle size decreased by 3% (P = 0.040) and concentrations of small very low-density lipoprotein increased (P = 0.016) following exercise. PON1 activity increased 6.1% (P = 0.037) and PON1 concentrations increased 11.3% (P = 0.015) with the combination of exercise and niacin. Exercise and niacin works synergistically to increase PON1 activity and concentration with little or no changes in lipoproteins or markers of lipid oxidation.

Extended-release niacin decreases serum fetuin-A concentrations in individuals with metabolic syndrome.

BACKGROUND: Fetuin-A, a liver-secreted phosphoprotein and physiological inhibitor of insulin receptor tyrosine kinase, is associated with insulin resistance, metabolic syndrome (MetS), and an increased risk for type 2 diabetes. However, studies on the modulation of circulating levels of fetuin-A are limited. The goal of this study was to determine the effect of niacin administration on serum total- and phosphorylated fetuin-A (phosphofetuin-A) concentrations in individuals with MetS and correlate with changes in serum lipids, insulin sensitivity, and markers of inflammation. METHODS: Fifteen sedentary, obese, male participants, who met the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria for MetS, were treated with extended-release niacin (Niaspan) for 6 weeks. Blood samples were obtained before and after treatment with niacin. RESULTS: Serum fetuin-A and phosphofetuin-A concentrations were decreased following niacin administration (p < 0.005). Changes in fetuin-A concentrations were correlated with changes in triglyceride (r = 0.62, p = 0.01) and C-reactive protein (CRP) concentrations (r = 0.58, p < 0.05) after niacin treatment. Changes in high-density lipoproteins (HDL)-cholesterol following niacin intervention were negatively correlated with changes in serum fetuin-A (p < 0.05) and phosphofetuin-A concentrations (p < 0.05). Serum cortisol levels were significantly elevated after niacin administration. CONCLUSIONS: Niacin treatment lowers serum total- and phosphofetuin-A concentrations in individuals with MetS, and these changes correlate with the beneficial changes in serum lipids. Because niacin is known to induce insulin resistance, these findings suggest that fetuin-A may not be a mediator of niacin-induced insulin resistance but it may blunt the insulin resistance induced by niacin by decreasing its circulating concentrations.

Independent and combined effects of aerobic exercise and pharmacological strategies on serum triglyceride concentrations: a qualitative review.

Elevated fasting and postprandial serum triglyceride concentrations are associated with cardiovascular disease morbidity and mortality. Aerobic exercise reduces serum triglyceride concentrations in the presence or absence of weight loss. Although pharmacological interventions are often used in combination with aerobic exercise to achieve target triglyceride concentrations, information on the combined effects of aerobic exercise and lipid-modifying agents on serum triglycerides is limited. This review examines the independent and combined effects of both interventions on serum fasting and postprandial triglyceride concentrations from the available literature. Reductions in serum triglycerides after aerobic exercise are associated with an increase in skeletal muscle lipoprotein lipase activity and a decrease in hepatic triglyceride and very-low-density lipoprotein (VLDL) synthesis and secretion. Lipid-modifying agents such as niacin, omega-3 fatty acids, and statins also decrease fasting and postprandial triglycerides by increasing lipoprotein lipase (LPL) activity and/or decreasing VLDL synthesis. When combined, lipid-modifying agents may reduce fasting and postprandial triglyceride secretion to an extent in which aerobic exercise cannot provide any additional benefit. These observations indicate that aerobic exercise and pharmacological strategies reduce serum triglycerides by similar mechanisms, which may attenuate the triglyceride-lowering capacity of the concordant treatment.

Postprandial triglyceride responses to aerobic exercise and extended-release niacin.

BACKGROUND: Aerobic exercise and niacin are frequently used strategies for reducing serum triglycerides, and, yet, there is no information regarding the combined effects of these strategies on postprandial triglycerides. OBJECTIVE: We compared the effects of aerobic exercise and 6 wk of extended-release niacin on postprandial triglycerides in men with the metabolic syndrome. DESIGN: Fifteen participants underwent each of 4 conditions: control--high-fat meal only (100 g fat); exercise--aerobic exercise performed 1 h before a high-fat meal; niacin--high-fat meal consumed after 6 wk of niacin; and niacin + exercise--high-fat meal consumed after 6 wk of niacin and 1 h after aerobic exercise. Temporal responses for triglyceride and insulin concentrations were measured and total (AUC(T)) and incremental (AUC(I)) areas under the curve were calculated. Differences were determined by using a 2-factor repeated-measures analysis of variance (P < 0.05 for all). RESULTS: Exercise lowered the triglyceride AUC(I) by 32% compared with control (724 +/- 118 and 1058 +/- 137, respectively). Niacin had no influence on the triglyceride AUC(I) and attenuated the triglyceride-lowering effect of exercise when combined. Niacin + exercise had no effect on the triglyceride AUC(I) but decreased the insulin AUC(I) after niacin administration. CONCLUSIONS: Aerobic exercise lowers the postprandial triglyceride response to a high-fat meal. Niacin lowers fasting but not postprandial triglycerides and appears to influence the triglyceride-lowering effect of aerobic exercise when combined. However, exercise decreases postprandial insulin concentrations after niacin administration, which illustrates the potential metabolic benefits of exercise in persons taking niacin.