Burkey B F, Dong M, Gagen K, Eckhardt M, Dragonas N, Chen W, Grosenstein P, Argentieri G, de Souza C J
Department of Metabolic and Cardiovascular Diseases, Novartis Biomedical Research Institute, Summit, NJ 07901-1398, USA.
Metabolism. 2000 Oct;49(10):1301-8. doi: 10.1053/meta.2000.9524.
Recent advances in the treatment of non-insulin-dependent diabetes mellitus (NIDDM) include the use of thiazolidinediones (TZDs), agents that enhance insulin action, in part, through an activation of adipose tissue peroxisome proliferator-activated receptor gamma. Current evidence also indicates that these agents upregulate uncoupling protein 1 (UCP1) gene expression in brown adipocytes and increase interscapular brown adipose tissue (IBAT) mass in rodents, suggestive of a thermogenic component to their mechanism of action. In the present study, the TZD pioglitazone (PIO) and the beta3-adrenoceptor agonist CL 316,243 (CL), were used to determine whether the antidiabetic effects of PIO, like those of CL, may, in part, be mediated by an increase in either IBAT thermogenesis or whole-body energy expenditure. Treatment of obese, insulin resistant fa/fa Zucker rats with PIO for 10 days resulted in a 2- to 3-fold increase in IBAT mass, due largely to an increase in adipocyte size and number, and increased fatty acid biosynthesis. However, unlike the effects of CL, the PIO-induced IBAT changes were not associated with an increase in UCP1 expression or whole-body energy expenditure. In contrast to CL, PIO substantially increased body weight gains over the 10-day treatment period by increasing feeding efficiency. These data suggest that, unlike CL, the actions of PIO in the obese Zucker rat does not include increased energy expenditure, but rather strengthens its role as an adipogenic and lipogenic agent, which promotes energy storage.
非胰岛素依赖型糖尿病（NIDDM）治疗的最新进展包括使用噻唑烷二酮类药物（TZDs），这类药物可部分通过激活脂肪组织过氧化物酶体增殖物激活受体γ来增强胰岛素作用。目前的证据还表明，这些药物可上调棕色脂肪细胞中解偶联蛋白1（UCP1）的基因表达，并增加啮齿动物肩胛间棕色脂肪组织（IBAT）的质量，提示其作用机制中存在产热成分。在本研究中，使用噻唑烷二酮类药物吡格列酮（PIO）和β3-肾上腺素能受体激动剂CL 316,243（CL）来确定PIO的抗糖尿病作用是否像CL一样，部分可能是由IBAT产热增加或全身能量消耗增加介导的。用PIO治疗肥胖、胰岛素抵抗的fa/fa Zucker大鼠10天，导致IBAT质量增加2至3倍，这主要归因于脂肪细胞大小和数量的增加以及脂肪酸生物合成的增加。然而，与CL的作用不同，PIO诱导的IBAT变化与UCP1表达增加或全身能量消耗增加无关。与CL相反，PIO在10天的治疗期内通过提高摄食效率显著增加了体重增加。这些数据表明，与CL不同，PIO在肥胖Zucker大鼠中的作用不包括增加能量消耗，而是增强了其作为脂肪生成和脂质生成剂的作用，促进能量储存。
