Mack Christine, Wilson Julie, Athanacio Jennifer, Reynolds James, Laugero Kevin, Guss Stacy, Vu Calvin, Roth Jonathan, Parkes David
Amylin Pharmaceuticals, Inc., 9360 Towne Centre Dr., San Diego, CA 92121, USA.
Am J Physiol Regul Integr Comp Physiol. 2007 Nov;293(5):R1855-63. doi: 10.1152/ajpregu.00297.2007. Epub 2007 Sep 12.
The ability of amylin to reduce acute food intake in rodents is well established. Longer-term administration in rats (up to 24 days) shows a concomitant reduction in body weight, suggesting energy intake plays a significant role in mediating amylin-induced weight loss. The current set of experiments further explores the long-term effects of amylin (4-11 wk) on food preference, energy expenditure, and body weight and composition. Furthermore, we describe the acute effect of amylin on locomotor activity and kaolin consumption to test for possible nonhomeostatic mechanisms that could affect food intake. Four-week subcutaneous amylin infusion of high-fat fed rats (3-300 microg.kg(-1).day(-1)) dose dependently reduced food intake and body weight gain (ED(50) for body weight gain = 16.5 microg.kg(-1).day(-1)). The effect of amylin on body weight gain was durable for up to 11 wks and was associated with a specific loss of fat mass and increased metabolic rate. The body weight of rats withdrawn from amylin (100 microg.kg(-1).day(-1)) after 4 wks of infusion returned to control levels 2 wks after treatment cessation, but did not rebound above control levels. When self-selecting calories from a low- or high-fat diet during 11 wks of infusion, amylin-treated rats (300 microg.kg(-1).day(-1)) consistently chose a larger percentage of calories from the low-fat diet vs. controls. Amylin acutely had no effect on locomotor activity or kaolin consumption at doses that decreased food intake. These results demonstrate pharmacological actions of amylin in long-term body weight regulation in part through appetitive-related mechanisms and possibly via changes in food preference and energy expenditure.
胰岛淀粉样多肽降低啮齿动物急性食物摄入量的能力已得到充分证实。在大鼠中进行长达24天的长期给药显示体重随之下降，这表明能量摄入在介导胰岛淀粉样多肽引起的体重减轻中起重要作用。当前这组实验进一步探究了胰岛淀粉样多肽（4 - 11周）对食物偏好、能量消耗以及体重和身体组成的长期影响。此外，我们描述了胰岛淀粉样多肽对运动活动和高岭土消耗的急性影响，以测试可能影响食物摄入的非稳态机制。对高脂喂养的大鼠进行为期四周的皮下注射胰岛淀粉样多肽（3 - 300微克·千克⁻¹·天⁻¹），剂量依赖性地降低了食物摄入量和体重增加（体重增加的半数有效剂量 = 16.5微克·千克⁻¹·天⁻¹）。胰岛淀粉样多肽对体重增加的影响可持续长达11周，并与脂肪量的特定减少和代谢率增加相关。在输注4周后停止给予胰岛淀粉样多肽（100微克·千克⁻¹·天⁻¹）的大鼠，其体重在停止治疗2周后恢复到对照水平，但未反弹至对照水平以上。在输注11周期间从低脂或高脂饮食中自行选择热量时，接受胰岛淀粉样多肽治疗的大鼠（300微克·千克⁻¹·天⁻¹）与对照组相比，始终从低脂饮食中选择更大比例的热量。在降低食物摄入量的剂量下，胰岛淀粉样多肽对运动活动或高岭土消耗无急性影响。这些结果表明，胰岛淀粉样多肽在长期体重调节中具有药理学作用，部分是通过与食欲相关的机制，可能还通过食物偏好和能量消耗的变化来实现。
