Peripheral cannabinoid 1 receptor blockade activates brown adipose tissue and diminishes dyslipidemia and obesity
Peripheral cannabinoid 1 receptor blockade activates brown adipose tissue and diminishes dyslipidemia and obesity
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DOI：
10.1096/fj.13-247643
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发表时间：
2014-12-01
期刊：
影响因子：
4.8
通讯作者：
Rensen, Patrick C. N.
中科院分区：
文献类型：
--
作者：
Boon, Mariette R.;Kooijman, Sander;Rensen, Patrick C. N.
内源性大麻素系统通过调节食欲、脂解和能量消耗在能量代谢中起重要作用。大麻素1受体（CB 1 R）的慢性阻断导致实验性和人类肥胖中体重减轻和血脂异常减少的长期维持。CB 1 R阻断逆转肥胖症血脂异常的分子机制尚未阐明。在这项研究中，我们发现，CB 1 R阻断剂利莫那班全身CB 1 R阻断增强全身能量消耗和激活棕色脂肪组织（BAT），增加参与BAT产热的基因表达和减少BAT中的脂滴大小。这伴随着BAT选择性增加甘油三酯（TG）摄取和降低血浆TG水平。有趣的是，在热中性条件下，对BAT激活的影响仍然存在，并且可以通过使用严格的外周CB 1 R拮抗剂AM 6545来重现，表明BAT的直接外周激活。事实上，CB 1 R阻断直接激活了T37 i棕色脂肪细胞，导致增强的非偶联呼吸，最有可能是通过增强cAMP/PKA信号转导，通过肾上腺素能受体途径。我们的数据表明，选择性靶向BAT中的外周CB 1 R在减轻血脂异常和肥胖方面具有治疗潜力。
The endocannabinoid system is an important player in energy metabolism by regulating appetite, lipolysis, and energy expenditure. Chronic blockade of the cannabinoid 1 receptor (CB1R) leads to long-term maintenance of weight loss and reduction of dyslipidemia in experimental and human obesity. The molecular mechanism by which CB1R blockade reverses dyslipidemia in obesity has not yet been clarified. In this study, we showed that CB1R blockade with the systemic CB1R blocker rimonabant enhanced whole-body energy expenditure and activated brown adipose tissue (BAT), indicated by increased expression of genes involved in BAT thermogenesis and decreased lipid droplet size in BAT. This was accompanied by selectively increased triglyceride (TG) uptake by BAT and lower plasma TG levels. Interestingly, the effects on BAT activation were still present at thermoneutrality and could be recapitulated by using the strictly peripheral CB1R antagonist AM6545, indicatingdirect peripheral activation of BAT. Indeed, CB1R blockade directly activated T37i brown adipocytes, resulting in enhanced uncoupled respiration, most likely via enhancing cAMP/PKA signaling via the adrenergic receptor pathway. Our data indicate that selective targeting of the peripheral CB1R in BAT has therapeutic potential in attenuating dyslipidemia and obesity.