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【Endocrinology】ACEI对能量平衡及葡萄糖稳态的影响
Despite the presence of a rigorous homeostatic system that regulates energy balance with great precision, the incidence of obesity and obesity-related disorders continues to grow (1, 2, 3). Consequently, determining effective strategies to treat obesity and its comorbidities is a critical problem facing medical science. The renin-angiotensin system (RAS) has emerged as an important target system in this regard (4, 5, 6, 7, 8). The RAS is best known for the regulation of hydromineral balance and cardiovascular function and most physiological actions of the RAS are exerted by angiotensin-II (A-II), which is formed from angiotensinogen via cleavage first by renin and then by angiotensin-converting enzyme (ACE). A-II binds to angiotensin type 1 or type 2 receptors in diverse target tissues including adrenal cortex, kidney, vascular smooth muscle, adipose tissue, and brain. Its actions include the release of aldosterone, sodium reabsorption, vasoconstriction, adipocyte hypertrophy, activation of the hypothalamus-pituitary-adrenal axis, and increased drinking (9, 10). All of the critical components of the RAS also exist in adipose tissue and brain and A-II generated by these particular tissue-specific RASs has critical roles in adipocyte growth and as a neurotransmitter, respectively (11, 12).
Hyperactivity of systemic and adipose tissue-specific RASs is associated with obesity, and the RAS is implicated in the control of glucose homeostasis, providing a potential causal link among obesity, diabetes, and hypertension (13, 14, 15). Consistent with this, drugs that reduce A-II synthesis (ACE inhibitors) or action (angiotensin receptor blockers) alleviate many symptoms associated with obesity (16, 17, 18, 19), and genetic interference with any critical component of the RAS prevents excessive weight gain in rodent models of obesity (4, 6, 20, 21, 22). However, clinical studies directly examining effects of RAS inhibition on energy balance have produced mixed results (23, 24, 25). There are reports of decreased body weight and adiposity as well as reports no effect of pharmacological RAS interference on energy balance in humans. Nonetheless, even in humans the correlation between RAS activity and adiposity is well documented, whereas the mechanism underlying the contribution of the RAS to obesity and glucose intolerance are unknown (26, 27, 28, 29).
Whereas systemic RAS interference consistently decreases weight gain in rodents, changes of food intake are contradictory (17, 19, 30). These discrepancies may be attributed to the use of compounds that comparably reduce systemic RAS activity but differentially penetrate the blood-brain barrier to influence central angiotensin receptors. Systemic administration of ACE inhibitors that do not access the brain actually results in elevated central A-II due to increased circulating substrate [angiotensin I (A-I)] and enhanced conversion of A-I to A-II locally within the brain (31, 32, 33). This is of importance because central A-II inhibition increases food intake, whereas central A-II administration decreases food intake (34, 35).
To evaluate the role of the renin-angiotensin-system in energy and glucose homeostasis, we examined body weight and composition, food intake, and glucose tolerance in rats given the angiotensin-converting enzyme inhibitor, captopril (40 mg/kg · d). Rats given captopril weighed less than controls when fed a high-fat diet (369.3 ± 8.0 vs. 441.7 ± 8.5 g after 35 d; P < 0.001) or low-fat chow (320.1 ± 4.9 vs. 339.8 ± 5.1 g after 21 d; P < 0.0001). This difference was attributable to reductions in adipose mass gained on high-fat (23.8 ± 2.0 vs. 65.12 ± 8.4 g after 35 d; P < 0.0001) and low-fat diets (12.2 ± 0.7 vs. 17.3 ± 1.3 g after 21 d; P < 0.001). Rats given captopril ate significantly less [3110.3 ± 57.8 vs. 3592.4 ± 88.8 kcal (cumulative 35 d high fat diet intake); P < 0.001] despite increased in neuropeptide-Y mRNA expression in the arcuate nucleus of the hypothalamus and had improved glucose tolerance compared with free-fed controls. Comparisons with pair-fed controls indicated that decreases in diet-induced weight gain and adiposity and improved glucose tolerance were due, primarily, to decreased food intake. To determine whether captopril caused animals to defend a lower body weight, animals in both groups were fasted for 24 h and subsequently restricted to 20% of their intake for 2 d. When free food was returned, captopril and control rats returned to their respective body weights and elicited comparable hyperphagic responses. These results suggest that angiotensin-converting enzyme inhibition protects against the development of diet-induced obesity and glucose intolerance. 本人已认领该文编译，48小时后若未提交译文，请其他战友自由认领。
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作者:admin@医学,生命科学 2010-11-18 17:11
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