RESUMO
AIM: Insulin resistance induced by growth hormone (GH) is linked to promotion of lipolysis by unknown mechanisms. We hypothesized that suppression of the activity of pyruvate dehydrogenase in the active form (PDHa) underlies GH-induced insulin resistance similar to what is observed during fasting. METHODS: Eight healthy male subjects were studied four times in a randomized, single-blinded parallel design: Control, GH, Fasting (36 h) and GH + Fasting. GH (30 ng × kg(-1) × min(-1)) or saline was infused throughout the metabolic study day. Substrate metabolism and insulin sensitivity were assessed by indirect calorimetry and isotopically determined rates of glucose turnover before and after a hyperinsulinemic euglycemic clamp. PDHa activity, PDH-E1α phosphorylation, PDK4 expression and activation of insulin signalling proteins were assessed in skeletal muscle. RESULTS: Both fasting and GH promoted lipolysis, which was associated with ≈50% reduction in insulin sensitivity compared with the control day. PDHa activity was significantly reduced by GH as well as fasting. This was associated with increased inhibitory PDH-E1α phosphorylation on site 1 (Ser(293)) and 2 (Ser(300)) and up-regulation of PDK4 mRNA, while canonical insulin signalling to glucose transport was unaffected. CONCLUSION: Competition between intermediates of glucose and fatty acids seems to play a causal role in insulin resistance induced by GH in human subjects.
Assuntos
Hormônio do Crescimento Humano/farmacologia , Resistência à Insulina/fisiologia , Lipólise/fisiologia , Piruvato Desidrogenase (Lipoamida)/metabolismo , Western Blotting , Estudos Cross-Over , Técnica Clamp de Glucose , Humanos , Lipólise/efeitos dos fármacos , Masculino , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/enzimologia , Músculo Esquelético/fisiopatologia , Reação em Cadeia da Polimerase em Tempo Real , Adulto JovemRESUMO
Direct FFA storage in adipose tissue is a recently appreciated pathway for postabsorptive lipid storage. We evaluated the effect of body fat distribution on direct FFA storage in women with different obesity phenotypes. Twenty-eight women [10 upper body overweight/obese (UBO; WHR >0.85, BMI >28 kg/m(2)), 11 lower body overweight/obese (LBO; WHR <0.80, BMI >28 kg/m(2)), and 7 lean (BMI <25 kg/m(2))] received an intravenous bolus dose of [9,10-(3)H]palmitate- and [1-(14)C]triolein-labeled VLDL tracer followed by upper body subcutaneous (UBSQ) and lower body subcutaneous (LBSQ) fat biopsies. Regional fat mass was assessed by combining DEXA and CT scanning. We report greater fractional storage of FFA in UBSQ fat in UBO women compared with lean women (P < 0.01). The LBO women had greater storage per 10(6) fat cells in LBSQ adipocytes compared with UBSQ adipocytes (P = 0.04), whereas the other groups had comparable storage in UBSQ and LBSQ adipocytes. Fractional FFA storage was significantly associated with fractional VLDL-TG storage in both UBSQ (P < 0.01) and LBSQ (P = 0.03) adipose tissue. In conclusion, UBO women store a greater proportion of FFA in the UBSQ depot compared with lean women. In addition, LBO women store FFA more efficiently in LBSQ fat cells compared with UBSQ fat cells, which may play a role in development of their LBO phenotype. Finally, direct FFA storage and VLDL-TG fatty acid storage are correlated, indicating they may share a common rate-limiting pathway for fatty acid storage in adipose tissue.
Assuntos
Composição Corporal/fisiologia , Distribuição da Gordura Corporal , Ácidos Graxos não Esterificados/metabolismo , Sobrepeso/metabolismo , Absorciometria de Fóton , Adipócitos/ultraestrutura , Adulto , Índice de Massa Corporal , Feminino , Humanos , Lipoproteínas VLDL/sangue , Obesidade/metabolismo , Palmitatos/metabolismo , Gordura Subcutânea/metabolismo , Tomografia Computadorizada por Raios X , Triglicerídeos/sangue , Relação Cintura-QuadrilRESUMO
OBJECTIVE: A well known inverse relationship exists between obesity and circulating ghrelin concentrations. However, obesity is a heterogeneous disease entity and upper-body obesity (UBO) is associated with more profound metabolic disturbances than lower-body obesity (LBO). We therefore aimed to investigate the impact of body composition on circulating ghrelin levels in women spanning a wide range of body composition phenotypes. SUBJECTS AND METHODS: Ten (UBO; waist-to-hip ratio (WHR) >0.85, body mass index (BMI) >28 kg/m(2)), ten LBO (WHR <0.80, BMI >28 kg/m(2)) and ten lean women (BMI<25 kg/m(2)) were studied. Total ghrelin levels were measured under basal and hyperinsulinemic (0.6 mU/kg per min) conditions. Body fat distribution was determined by dual X-ray absorptiometry in combination with computed tomography at the L2-L3 level. RESULTS: As expected, an inverse correlation existed between basal ghrelin concentration and BMI (r=-0.40, P=0.03) and total fat mass (r=-0.39, P=0.04). Visceral fat mass was a strong predictor (r=-0.56, P=0.003) of circulating ghrelin levels, even when adjusted for BMI (P=0.02) or body composition group (P=0.04). The suppressive effect of insulin on ghrelin concentration was significantly diminished in the UBO compared with the lean controls (P=0.012) and a highly significant inverse correlation existed with visceral fat mass (r=-0.52, P=0.004). CONCLUSIONS: Visceral fat mass is a strong predictor of basal ghrelin concentrations and also attenuates the suppressive effect of insulin on ghrelin concentrations. These data provide further evidence that the UBO phenotype is associated with more profound metabolic abnormalities than obesity per se.