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ABSTRACT: The objective was to evaluate ghrelin and growth hormone (GH) interactions and responses to a growth hormone-releasing hormone (GHRH)/arginine test in severe obesity before and after surgically-induced weight loss.
Our study population included 11 severely obese women 39 +/- 12 years of age, with a mean BMI of 48.6 +/- 2.4 kg/m2, re-studied in a phase of stabilized body weight, with a BMI of 33.4 +/- 1.2 kg/m2, 18 months after having successfully undergone biliopancreatic diversion (BPD). A GHRH/arginine test was performed before and 18 months after BPD to evaluate ghrelin and GH interactions. Active ghrelin, measured by radioimmunoassay (RIA), and GH, measured by chemiluminescence assay, were assayed before and after the GHRH/arginine test.
Fasting serum GH levels and GH area under the curve (AUC) significantly increased from 0.2 +/- 0.05 ng/mL to 1 +/- 0.3 ng/mL (p < 0.05) and from 514.76 +/- 98.7 ng/mL for 120 minutes to 1957.3 +/- 665.1 ng/mL for 120 minutes after bariatric surgery (p < 0.05), respectively. Although no significant change in fasting ghrelin levels was observed (573 +/- 77.9 before BPD vs. 574.1 +/- 32.7 after BPD), ghrelin AUC significantly increased from -3253.9 +/- 2180.9 pg/mL for 120 minutes to 1142.3 +/- 916.4 pg/mL for 120 minutes after BPD (p < 0.05). Fasting serum insulin-like growth factor (IGF)-1 concentration did not change significantly (133.6 +/- 9.9 ng/mL before vs. 153.3 +/- 25.2 ng/mL after BPD).
Our study demonstrates that the mechanisms involved in ghrelin and GH secretion after the secretagogue stimulus (GHRH/arginine) are consistent with patterns observed in other populations.
Obesity 09/2007; 15(8):2012-8. · 4.28 Impact Factor
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ABSTRACT: To investigate the effect of fat mass (FM) reduction on adipose tissue gene expression in terms of lipid synthesis [sterol regulatory binding protein 1c (SREBP-1c)] and lipid oxidation [uncoupling protein 2 (UCP-2)] 2 years after lipid malabsorption and to assess the influence of lipid malabsorption on fat-free mass (FFM) maintenance evaluating the expression of genes related to glycolysis [hexokinase (HKII)] and glucose storage [glycogen synthase (GS)]. Research Method and Procedures: SREBP-1c, UCP-2, HKII, and GS mRNA expression were studied by reverse transcriptase-competitive polymerase chain reaction in 10 massively obese subjects before and 2 years after bilio-pancreatic diversion (BPD). Body composition was assessed by isotopic dilution method and insulin sensitivity by euglycemic-hyperinsulinemic clamp.
FM decrease was approximately 60%, whereas FFM remained at normal physiological levels. In adipose tissue, SREBP-1c mRNA reduction (-39%, p < 0.005) was related only to FM changes after BPD, and UCP-2 decrease (-37%, p < 0.05) was dependent on free fatty acid (FFA) changes. No significant variations were observed in HKII and GS gene expression in skeletal muscle.
Lipid malabsorption induced by BPD altered the expression of genes involved in glucose and lipid metabolism, with different consequences on FM and FFM. The degree of FM loss seems to interfere with SREBP-1c gene suppression to preserve an adequate amount of fat storage, in accordance with the thrifty genotype hypothesis. The reduction of FFAs induced by BPD acts in inhibiting FFA transportation to the mitochondria (UCP-2), contributing to the decreased lipid oxidation inside the adipose tissue.
Obesity research 03/2005; 13(3):567-73. · 4.95 Impact Factor
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ABSTRACT: To verify whether Infliximab could modify insulin sensitivity and TNF-alpha and GLUT4 mRNA expression in muscle and adipose tissue of morbidly obese subjects. Soluble TNF receptors I and II (TNFR-I and TNFR-II) were also assayed.
Six obese subjects were investigated before and 2 weeks after a single intravenous administration of 5 mg/kg Infliximab; insulin sensitivity was evaluated by euglycemic hyperinsulinemic clamp, and TNF-alpha and GLUT4 mRNA expression were assessed by reverse-transcriptase polymerase chain reaction on muscle and adipose tissue. TNF-alpha, TNFR-I, and TNFR-II were determined using the ELISA technique.
Infliximab infusion did not affect fasting plasma insulin or fasting plasma glucose levels; whole body glucose uptake did not change significantly. TNF-alpha and GLUT4 mRNA did not show any significant change in muscle or adipose tissue. Serum TNF-alpha was undetectable before and after treatment, whereas TNFR-I and TNFR-II concentrations significantly decreased (p < 0.01).
An explanation for the absence of effect of Infliximab on insulin resistance in morbidly obese subjects may be the paracrine way of action of this cytokine. Because Infliximab is predominantly distributed within the vascular compartment, its effectiveness in penetrating muscle and adipose tissue is potentially low. The significant decrease of TNFR-I and TNFR-II might be ascribed to a targeted effect of Infliximab on the immune system.
Obesity research 04/2004; 12(4):734-9. · 4.95 Impact Factor
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ABSTRACT: A relationship between free fatty acids, intramuscular triglycerides (TG(M)s), and insulin resistance is widely accepted. The intracellular level of malonyl-coenzyme A (CoA) was suggested to be the possible link. Acetyl-CoA carboxylase (ACC) is a key enzyme in fatty acid metabolism, catalyzing the synthesis of malonyl-CoA, a fatty acid acyl-chain elongation unit, from acetyl-CoA. We assessed ACC2 mRNA expression variations in skeletal muscle of subjects who have undergone biliopancreatic diversion (BPD) operation. BPD, in fact inducing a massive lipid malabsorption, leads to a reversion of insulin resistance.
Twelve obese women (BMI > 40 kg/m(2)) were enrolled in the study. Body composition, euglycemic-hyperinsulinemic clamp, and muscle biopsies for lipid analysis and reverse transcription-competitive polymerase chain reaction were performed before and 3 years after BPD.
The average weight loss was around 37%. A significant inverse linear relation was observed between glucose uptake and TG(M) (y = -5.62x - 142.82, R(2) = 0.50, p = 0.01). The reduced amount of ACC2 mRNA directly correlated with both TG(M) (y = 2.11x +69.85, R(2) = 0.70, p = 0.01) and fasting insulin (y = 1.49x + 57.17, R(2) = 0.69, p < 0.01) concentrations.
In conclusion, down-regulation of ACC2 mRNA, induced by the lowering of plasma insulin concentration, is related to improvement of insulin sensitivity. We hypothesize that reduced amount of malonyl-CoA, consequent to reduced ACC2 mRNA, enhancing fatty acid oxidation, causes lowering of the intramyocitic triglyceride depot.
Obesity research 12/2003; 11(11):1306-12. · 4.95 Impact Factor
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ABSTRACT: To examine the muscular uncoupling protein expression 2 (UCP2) and UCP3 gene expression in morbid obese subjects before and after bariatric surgery [bilio-pancreatic diversion (BPD)].
Eleven obese subjects (BMI = 49 +/- 2 kg/m(2)) were studied before BPD and 24 months after BPD. Skeletal muscle UCP2 and UCP3 mRNA was measured using reverse transcriptase-competitive polymerase chain reaction and UCP3 protein by Western blotting. Intramyocytic triglycerides were quantified by high-performance liquid chromatography. Twenty-four-hour energy expenditure and respiratory quotient (RQ) were measured in a respiratory chamber.
After BPD, the average weight loss was approximately 38%. Nonprotein RQ was increased in the postobese subjects (0.73 +/- 0.00 vs. 0.83 +/- 0.02, p < 0.001). The intramyocytic triglyceride level dropped (3.66 +/- 0.16 to 1.60 +/- 0.29 mg/100 mg of fresh tissue, p < 0.0001) after BPD. Expression of UCP2 and UCP3 mRNA was significantly reduced (from 35.9 +/- 6.1% to 18.6 +/- 4.5% of cyclophilin, p = 0.02; from 60.2 +/- 14.0% to 33.4 +/- 8.5%, p = 0.03; respectively). UCP3 protein content was also significantly reduced (272.19 +/- 84.13 vs. 175.78 +/- 60.31, AU, p = 0.04). A multiple regression analysis (R(2) = 0.90) showed that IMTG levels (p = 0.007) represented the most powerful independent variable for predicting UCP3 variation.
The strong correlation of UCP expression and decrease in IMTG levels suggests that triglyceride content plays an even more important role in the regulation of UCP gene expression than the circulating levels of free fatty acids or the achieved degree of weight loss.
Obesity research 05/2003; 11(5):632-40. · 4.95 Impact Factor
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ABSTRACT: The aim of this study was to verify whether changes in PDK4 mRNA expression in skeletal muscle in formerly obese subjects who underwent malabsorptive bariatric surgery [bilio-pancreatic diversion (BPD)] might be related to insulin sensitivity improvement, and if these possible modifications might correlate with a reduction of the intramyocytic lipid level.
Six obese women (body mass index 46.6 +/- 8.2 kg/m(2)) were enrolled in the study. Body composition, euglycemic-hyperinsulinemic clamp and muscle biopsies for skeletal muscle lipid analysis, and semiquantitative reverse transcriptase-polymerase chain reaction were performed before and 3 years after BPD.
The average weight loss observed after surgery was approximately 42%. Increased glucose uptake was accompanied by a significant decrease of PDK4 mRNA (R(2) = 0.71, p < 0.001). The amounts of intramyocytic triglycerides correlate directly with PDK4 mRNA (R(2) = 0.87, p = 0.005) and inversely with glucose uptake values (R(2) = 0.75, p < 0.001).
Our results support the concept that a reduced tissue availability of fatty acids consequent to a massive lipid malabsorption influences glucose metabolism acting through the regulation of PDH complex. In fact, as shown in animals, a higher level of FFA availability is likely to induce overexpression of PDK4 also in humans.
Obesity research 03/2003; 11(2):176-82. · 4.95 Impact Factor
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ABSTRACT: Our aim was to investigate the regulation of the gene expression of leptin in subcutaneous adipose tissue biopsies in morbid obesity before and after biliopancreatic diversion (BPD).
Longitudinal study in morbidly obese subjects investigated twice: before and 6 months after BPD. Fourteen morbidly obese women, 37+/-13 years old and with a body mass index of 51.6+/-8.2 kg/m2, were studied before and 6 months after BPD (40.6+/-8.0 kg/m2). Using reverse transcriptase polymerase chain reaction analysis, the mRNA expression of leptin was investigated in adipose tissue. Plasma leptin was measured by radioimmunoassay; plasma insulin was measured by microparticle enzyme immunoassay. Free fatty acids (FFA) were measured using a colorimetric kit.
A significant decrease in leptin mRNA level was observed in comparison with pretreatment in BPD patients (59+/-34 vs 143+/-85 arbitrary units, P<0.01). A strict relationship between adipose tissue leptin mRNA and plasma leptin either before (R2=0.80, P<0.0001) or after BPD (R2=0.86, P<0.0001) and between plasma FFA concentration and insulin either before (R2=0.65, P<0.001) or after BPD (R2=0.92, P<0.0001) was observed. Finally, a significant correlation was found between changes in FFA and insulin (R2=0.64, P<0.001), insulin and leptin (R2=0.88, P<0.0001), and insulin and leptin mRNA (R2=0.83, P<0.0001).
These data demonstrate a high correlation between leptin mRNA expression in adipose tissue and plasma leptin in postobese subjects after BPD. The significant relationship between both leptin mRNA and plasma leptin with insulin suggests that circulating insulin might regulate leptin expression. It might be hypothesized that plasma FFA concentration can act on the insulin secretion and subsequently on the leptin secretory pathway.
Journal of Investigative Medicine 06/2002; 50(3):207-13. · 1.96 Impact Factor
