Barazzoni Rocco, Zanetti Michela, Cattin Maria Rosa, Visintin Luca, Vinci Pierandrea, Cattin Luigi, Stebel Marco, Guarnieri Gianfranco
Clinica Medica, Dipartimento di Scienze Cliniche, Morfologiche, e Tecnologiche, University of Trieste, Trieste, Italy.
Obesity (Silver Spring). 2007 Nov;15(11):2614-23. doi: 10.1038/oby.2007.313.
Ghrelin administration can induce fat weight gain and hyperglycemia (potentially through ghrelin-induced hepatic glucose production), but plasma ghrelin is positively associated with whole-body insulin sensitivity (mainly reflecting muscle insulin action) being increased in lean individuals or after diet-induced weight loss and reduced in obesity or after diet-induced weight gain. To investigate potential mechanisms, we measured in vivo effects of sustained ghrelin administration at a non-orexigenic dose on skeletal muscle and liver insulin signaling at the AKT level and adipokine expression changes.
Young-adult male rats received 4-day, twice daily subcutaneous ghrelin (200 mug/injection) or saline. We measured skeletal muscle (mixed, gastrocnemius; oxidative, soleus) and liver protein levels of activated [phosphorylated (P)] and total (T) AKT and glycogen synthase kinase (GSK; reflecting AKT-dependent GSK inactivation) and epididymal adipose tissue adipokine mRNA.
Ghrelin increased body weight (+1.4%) and blood glucose (both p < 0.05 vs. saline) but not food intake, plasma insulin, or free fatty acids. Ghrelin, however, enhanced P/T/AKT and P/T/GSK ratios and glucose transporter-4 mRNA in soleus (p < 0.05), but not in gastrocnemius, muscle. In contrast, ghrelin reduced hepatic P/T-AKT and P/T-GSK. No alterations occurred in adiponectin, leptin, or resistin transcripts or plasma adiponectin.
Despite moderate weight gain and in the absence of insulin-free fatty acid changes, sustained ghrelin administration enhanced oxidative muscle AKT activation. Reduced liver AKT signaling could potentially contribute to concomitant blood glucose increments. These findings support ghrelin as a novel tissue-specific modulator of lean tissue AKT signaling with insulin-sensitizing effects in skeletal muscle but not in liver in vivo.
给予胃饥饿素可导致脂肪量增加和高血糖（可能是通过胃饥饿素诱导的肝脏葡萄糖生成），但血浆胃饥饿素与全身胰岛素敏感性呈正相关（主要反映肌肉胰岛素作用），在瘦人或饮食诱导体重减轻后全身胰岛素敏感性增加，而在肥胖或饮食诱导体重增加后则降低。为了研究潜在机制，我们在非促食欲剂量下持续给予胃饥饿素，测量其对骨骼肌和肝脏胰岛素信号通路中AKT水平及脂肪因子表达变化的体内效应。
年轻成年雄性大鼠每日皮下注射胃饥饿素（200μg/次）或生理盐水，共4天，每日2次。我们测量了骨骼肌（混合肌，腓肠肌；氧化型肌，比目鱼肌）和肝脏中活化的[磷酸化（P）]和总（T）AKT以及糖原合酶激酶（GSK；反映AKT依赖性GSK失活）的蛋白水平，以及附睾脂肪组织中脂肪因子的mRNA水平。
胃饥饿素使体重增加（+1.4%），血糖升高（与生理盐水相比，两者p<0.05），但食物摄入量、血浆胰岛素或游离脂肪酸无变化。然而，胃饥饿素提高了比目鱼肌中P/T/AKT和P/T/GSK比值以及葡萄糖转运蛋白4 mRNA水平（p<0.05），但腓肠肌中未出现此情况。相反，胃饥饿素降低了肝脏中的P/T-AKT和P/T-GSK。脂联素、瘦素或抵抗素转录本以及血浆脂联素均未发生改变。
尽管体重有适度增加且胰岛素和游离脂肪酸无变化，但持续给予胃饥饿素可增强氧化型肌肉中AKT的活化。肝脏AKT信号通路的降低可能是导致血糖随之升高的潜在原因。这些发现支持胃饥饿素是一种新型的瘦组织AKT信号通路的组织特异性调节剂，在体内对骨骼肌具有胰岛素增敏作用，而对肝脏则无此作用。
