Alemzadeh Ramin, Karlstad Michael D, Tushaus Kathryn, Buchholz Margaret
Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Metabolism. 2008 Nov;57(11):1597-607. doi: 10.1016/j.metabol.2008.06.017.
Persistent suppression of hyperinsulinemia in genetically obese (fa/fa) Zucker rats by diazoxide (DZ) reduces food intake and weight gain; improves insulin sensitivity, glycemic control, and lipid profile; and enhances beta(3)-adrenergic function and lipolysis in adipose tissue. The aim of this study was to elucidate the effects of DZ on basal metabolic rate (BMR), fat oxidation, and adrenergic function of lean and obese Zucker rats. Diazoxide (150 mg/kg/d) or vehicle (control) was administered for 4 weeks in 7-week-old obese and lean Zucker rats (n = 8-9 per subgroup). Animals underwent indirect calorimetry, body composition analysis, and determination of uncoupling proteins (UCPs) messenger RNA (mRNA) in brown and white adipose tissues (BAT and WAT) and skeletal muscle (SM), beta(3)-adrenergic receptor (AR) mRNA in BAT and WAT, beta(2)-AR in SM as well as WAT, and SM adenylate cyclase (AC) activity at the completion of study. Diazoxide treatment decreased food intake, weight gain, and body fat in obese rats (P < .01). Although DZ treatment lowered fasting plasma glucose, insulin, leptin, adiponectin, and lipids in obese rats (P < .01), it increased adiponectin-leptin ratio (P < .01). Plasma adiponectin-leptin ratio was inversely correlated with fat mass in obese and lean rats (r = -0.86, P < .0001). Diazoxide treatment resulted in higher BMR and fat oxidation rate in obese compared with control animals (P < .01), without any effect in lean animals. Furthermore, plasma adiponectin was inversely correlated with BMR (-0.56, P < .001) and lipid oxidation rate (-0.61, P < .0005) and was positively correlated with nonprotein respiratory quotient (r = 0.41, P < .01) in obese and lean rats. This was associated with increased beta(3)-AR mRNA expression in BAT and WAT (P < .01), UCP-1 and UCP-3 in BAT and AC activity in WAT (P < .02), and AC activity in SM of DZ obese rats compared with controls (P < .01), without significant change in SM beta(2)-AR mRNA expressions. Diazoxide attenuation of hyperinsulinemia decreased the rate of weight gain but enhanced insulin sensitivity, BMR, and fat oxidation in obese rats. This was associated with increased receptor- and non-receptor-mediated adrenergic function in adipose and muscle tissues in obese rats, respectively. These metabolic changes in obese Zucker rats suggest that antiobesity effects of DZ appear to be not only through its anorectic effect, modification of disturbed insulin metabolism, and inhibition of lipogenesis, but also due to augmentation of adrenergic function, energy expenditure, and fat utilization.
二氮嗪（DZ）对遗传性肥胖（fa/fa） Zucker大鼠高胰岛素血症的持续抑制作用可减少食物摄入量和体重增加；改善胰岛素敏感性、血糖控制和血脂水平；增强脂肪组织中的β(3)-肾上腺素能功能和脂肪分解。本研究的目的是阐明DZ对瘦型和肥胖型Zucker大鼠基础代谢率（BMR）、脂肪氧化和肾上腺素能功能的影响。7周龄的肥胖和瘦型Zucker大鼠（每个亚组n = 8 - 9）接受二氮嗪（150 mg/kg/d）或赋形剂（对照）治疗4周。在研究结束时，对动物进行间接测热法、身体成分分析，并测定棕色和白色脂肪组织（BAT和WAT）及骨骼肌（SM）中解偶联蛋白（UCPs）信使核糖核酸（mRNA）、BAT和WAT中β(3)-肾上腺素能受体（AR） mRNA、WAT及SM中β(2)-AR以及SM腺苷酸环化酶（AC）活性。二氮嗪治疗可降低肥胖大鼠的食物摄入量、体重增加和体脂（P <.01）。虽然DZ治疗可降低肥胖大鼠的空腹血糖、胰岛素、瘦素、脂联素和血脂水平（P <.01），但可增加脂联素 - 瘦素比值（P <.01）。肥胖和瘦型大鼠的血浆脂联素 - 瘦素比值与脂肪量呈负相关（r = -0.86，P <.0001）。与对照动物相比，二氮嗪治疗使肥胖大鼠的BMR和脂肪氧化率更高（P <.01），对瘦型动物无影响。此外，肥胖和瘦型大鼠的血浆脂联素与BMR（-0.56，P <.001）和脂质氧化率（-0.61，P <.0005）呈负相关，与非蛋白呼吸商呈正相关（r = 0.41，P <.01）。这与DZ治疗的肥胖大鼠BAT和WAT中β(3)-AR mRNA表达增加（P <.01）、BAT中UCP - 1和UCP - 3以及WAT中AC活性增加（P <.02）以及SM中AC活性增加（P <.01）相关，而SM中β(2)-AR mRNA表达无显著变化。二氮嗪对高胰岛素血症的减轻作用降低了肥胖大鼠的体重增加速率，但增强了胰岛素敏感性、BMR和脂肪氧化。这分别与肥胖大鼠脂肪组织和肌肉组织中受体介导和非受体介导的肾上腺素能功能增加有关。肥胖Zucker大鼠的这些代谢变化表明，DZ的抗肥胖作用似乎不仅通过其厌食作用、改善紊乱的胰岛素代谢和抑制脂肪生成，还由于增强了肾上腺素能功能、能量消耗和脂肪利用。
