名家说“肽” | GLP-1体重影响机制一探究竟！

*仅供医学专业人士阅读参考

了解GLP-1影响体重的相关机制。

自胰高糖素样肽-1（GLP-1）被发现以来，已然成为一种“多面手”激素——其接二连三的代谢功能被人们发现，远远超出了作为肠促胰素的经典定义。GLP-1众多有益的作用使其受体激动剂逐渐成为更多新兴的治疗领域如脂肪肝、肥胖和神经退行性疾病等的冉冉之“星”药物，而GLP-1的减重作用甚至已经在中国以外的其他一部分国家作为适应症被写在药品说明书当中。时值利拉鲁肽在我国上市10周年，司美格鲁肽新上市之际，我们邀请一众专家，讲述一系列关于GLP-1的故事。本期特邀南京鼓楼医院朱大龙教授带您了解GLP-1影响体重的相关机制。

PART1：GLP-1对食物摄入量和体重的影响

GLP-1类似物最为大众熟悉的胰腺外效应之一是通过抑制中枢调控摄食来减重（图1）。这种GLP-1R激动剂的中枢抑制食物摄入作用已经在小鼠^[1-5]、大鼠^[6，7]、鸟类^[8，9]、猪^[10，11]，非人类灵长类动物^[12，13]和人类^[14，15]等多个物种中被确认。同时在人类的健康个体和2型糖尿病（T2DM）患者中均有体现^[16-18]。

图1. GLP-1的代谢作用示意图

▎GLP-1类似物外周给药对摄食的影响

GLP-1类似物外周给药可通过抑制摄食量来降低体重^[1-4，19]。根据分子构象（天然GLP-1或长效GLP-1类似物）和给药途径的不同，GLP-1及其类似物会通过不同的信号通路直接或间接地向中枢神经系统（CNS）传递减少摄食的信号。

在啮齿类动物，外周给予GLP-1R激动剂须通过中枢GLP-1R才能发挥食欲抑制效应^[20，21]，因为在中枢特异性GLP-1R缺失的小鼠中进食不受抑制。另一项研究表明，静脉注射利拉鲁肽抑制大鼠进食是通过直接激活下丘脑弓状核（ARC）的阿黑皮素（Pomc）/（可卡因和苯丙胺调节转录子）Cart神经元（饱食信号）发挥作用^[20]。在大鼠中，中枢（i.c.v）给予exendin（9-39）可减弱腹腔注射利拉鲁肽和exendin-4的食欲抑制效应^[21]，臂旁外侧核（IPBN）与鹅膏蕈氨酸的双侧神经化学损伤亦可削弱外周给予exendin-4的食欲抑制效应^[22]。当皮下注射（s.c.）或腹腔注射（i.p.）exendin-4和利拉鲁肽时，可诱导PVN、AP和孤束核（NTS）的急性神经元激活（通过cFos的激活测定）^[20，23]。有趣的是，去膈下迷走神经传入也可减弱i.p低剂量利拉鲁肽和exendin-4的短期食欲抑制效应^[21，24]，但它们对食物摄入的长期影响并不完全依赖迷走神经传入^[24]。所有这些发现都与GLP-1R激动剂主要通过直接作用于不同大脑区域来抑制进食和减轻体重的说法相吻合，这也反映了长效GLP-1类似物具有进入血脑屏障（BBB）不完整区域（如正中隆起）的能力。

关于肠道来源天然GLP-1在生理剂量是否能发挥抑制摄食作用尚不清楚。当肝门静脉注入GLP-1（7-36酰胺）增加了NTS、AP和杏仁核中央核团cFos的表达，但对下丘脑ARC或PVN没有影响^[25]，即天然GLP-1在大脑中诱导的激活模式与长效GLP-1受体激动剂诱导的激活模式不同。虽然外周给予天然GLP-1似乎通过简单扩散穿过BBB，但其半衰期小于2分钟，导致在生理条件下激活CNS GLP-1R的原因仍存在分歧。

静脉注射高生理剂量的GLP-1可刺激大鼠迷走神经传入，exendin（9-39）可阻断^[26]。这种激活参与了外源性GLP-1的促胰岛素和对胃排空的抑制作用^[26]，但静脉注射天然GLP-1无此作用。但i.p.给予所谓“生理”剂量的GLP-1（7-36酰胺）后，抑制摄食作用则可通过完整的腹部迷走神经传入通路^[27]，这表明外周GLP-1给药至少可以通过两条部分分离的途径抑制进食。迷走神经传入神经元中病毒介导GLP-1R敲除的大鼠食欲不受抑制，胃排空加速，并减少膳食胰岛素分泌^[43]。在人类迷走神经干切断后，静脉输注GLP-1对食物摄入的影响也消失^[29]，这些数据表明迷走神经传入通路参与了GLP-1对食欲的影响。另一方面在大鼠中，AP的损伤或向第四脑室注射exendin（9-39）可阻断肝门静脉GLP-1输注对摄食的抑制^[30]，提示高浓度GLP-1作用于后脑以减少摄食量。在一项大鼠研究中，颈静脉注入GLP-1比肝门静脉注入GLP-1可以更有效地抑制食物摄入^[31]。这些发现提示在分析GLP-1R激动剂对摄食抑制时，给药途径是一个重要考虑因素。

▎中枢给予GLP-1R类似物对摄食的影响

1996年，Steve Bloom的研究小组^[7]和Mads Tang-Christensen等人^[32]同时描述了中枢给予GLP-1的急性食欲抑制效应，并被其他人证实^[6，33]。在小鼠和大鼠中，脑室内（i.c.v.）给予GLP-1R激动剂引起的剂量依赖性短期摄食抑制，可被exendin（9-39）抑制^[7，33]，而在GLP-1R敲除小鼠中无此效应^[23]。中枢给予GLP-1R类似物可抑制食物摄入，伴随着PVN、杏仁核、NTS、AP、臂旁外侧核和ARC中cFos神经元活性的增加^[7，33]。这与整个CNS中GLP-1R的表达一致^[34，35]。进一步在NTS中检测到对GLP-1抗血清有免疫反应的细胞体，GLP-1免疫反应神经纤维广泛分布于整个大脑，密度最高的是下丘脑、丘脑和隔膜区，而密度最低的是皮层和后脑^[36，33]。NTS中腺病毒（AAV）介导的GLP-1R敲除导致更频繁地摄食和更大食量^[37]，这支持了NTS介导GLP-1对摄食方面的作用^[37]。向第三脑室内灌注exendin（9-39）可缓慢阻断GLP-1R从而增加摄食和脂肪摄入^[38]。直接在脑实质内给予低剂量、脑室阈下剂量的GLP-1R激动剂到大脑中表达GLP-1R的核团，如NTS、IPBN、腹侧被盖区（VTA）、PVH、PVT、伏隔核（NAcc）、腹侧海马和侧隔，可减少摄食量。无独有偶，将exendin（9-39）输注到这些部位会增加摄食量^[39，40]。

后脑GLP-1R激活增强了NTS中PKA和MAPK的磷酸化，同时降低了AMPK的活性。给予cAMP抑制剂（Rp-cAMP）或MAP激酶抑制剂（UO126）抑制PKA/MAPK活性，可减弱exendin-4给药至第4脑室对摄食量的抑制^[41]。所以，后脑GLP-1R激活通过PKA/MAPK诱导AMPK抑制实现摄食抑制^[42]。白喉毒素诱导的NTS中GLP-1产生神经元的消融对随意进食和葡萄糖代谢均无影响。然而，通过向大鼠第4脑室注入exendin-4可激活后脑GLP-1R，通过减少进食频率或者增加饱腹感^[41]来减少食物摄入量。第4脑室注射exendin（9-39）或AP病变也可阻断注入肝门静脉（HPV）^[30]的GLP-1发挥抑制食物摄入的作用，这表明循环中高水平的GLP-1部分通过作用于后脑中的GLP-1R而非通过大脑自身产生GLP-1神经元来发挥抑制进食的作用。

▎GLP-1抑制食物摄取的分子机制

调节GLP-1抑制摄食和减轻体重的分子基础很复杂。毫无疑问，脑GLP-1R信号对于外源性长效GLP-1R激动剂的食欲抑制效应至关重要，因为利拉鲁肽对CNS特异性GLP-1R敲除小鼠无进食抑制作用^[44]，而脑室内给予exendin（9-39）足以减弱外周注射利拉鲁肽和exendin-4给药的食欲抑制效应^[21]，这提示GLP-1R可能是GLP-1发生药理反应的必需条件。根据给药途径，外周给予GLP-1类似物要么直接作用于下丘脑和后脑（这两个区域都有不完全的血脑屏障），要么通过迷走神经传入信号到后脑，然后投射到大脑的其他关键进食区域。后脑GLP-1R的激活增强了PKA和MAPK的磷酸化，同时降低了NTS中AMPK的活性。输注Rp-cAMP或UO126抑制PKA/MAPK活性，可减弱第4脑室exendin-4给药后的摄食抑制^[41]。这表明，后脑GLP-1R激活通过PKA/MAPK诱导抑制AMPK从而抑制摄食。

当中枢给予GLP-1也发现AMPK的活性（磷酸化）降低^[45，46]，用exendin-4处理小鼠下丘脑GT1-7细胞可刺激糖酵解，降低AMPK的磷酸化^[47]。在第3脑室^[47]或第4脑室^[41]给予5-氨基咪唑-4-甲酰胺-1-β-D-和呋喃糖苷（AICAR）药理性激活AMPK可减弱注射到同一脑室的exendin-4的食欲抑制作用。同样脑室内注射糖酵解抑制剂2-脱氧葡萄糖（2-DG）增加AMPK的活性，并减弱脑室内注射exendin-4对摄食的抑制^[47]。总之，中枢GLP-1受体激活的食欲抑制效应部分是由刺激中枢糖酵解和伴随的AMPK活性沉默介导的。

GLP-1的食欲抑制效应通过GLP-1R信号传导到大脑的几个区域，包括下丘脑诸核团如NTS、VMH、下丘脑外侧区（LH）、背内侧核（DMH）、PVN、ARC、LHA等和后脑。例如在NTS中微量注射exendin-4可减少对美味高脂饮食的摄入并抑制食物奖赏行为^[48]，通过给第四脑室注射exendin（9-39）抑制后脑GLP-1R可增加摄食^[49]。外周给予GLP-1（7-36酰胺）可增强VMH中的神经元活性^[50，51]，直接将GLP-1给药至大鼠下丘脑外侧区(LH)、VMH或背内侧核（DMH）中可急性减少摄食^[52]。将GLP-1（7-36酰胺）直接注入大鼠PVN也有类似的发现^[53，54]。直接注射利拉鲁肽到大鼠ARC、LHA或PVN中可减少摄食，而直接注入VMH可不影响摄食而直接降低体重，但可增加棕色脂肪和腹股沟白色脂肪组织中解耦连蛋白1（Ucp1）的表达^[5]。

▎GLP-1对内脏疾病的影响

除了饱腹感以外，摄食抑制的其他因素包括胃不适，如胃轻瘫，通常与内脏疾病和内脏压力有关。与内脏疾病相关的食欲受抑可由氯化锂（LiCl）——已知的促进人类恶心和呕吐的物质^[55]化学诱导引起，可对啮齿类动物则引起味觉回避条件反射和异食癖，但并不呕吐^[56]。异食癖是指诱发人类恶心和呕吐的高岭土消耗的量，也被认为是引起大鼠内脏不适的替代测量值。味觉回避条件反射描述了对新味道或食物的摄入减少，通常与引发负面后果的治疗有关，如外周疼痛的影响、乳糖吸收不良或LiCl的影响^[57]。在大鼠，外周和中枢给予LiCI均诱导IPBN、AP和NTS中的cFos神经元活动^{[66，58，59]}，LiCl和中枢GLP-1R激动都减少运动活动^[7，60]，减缓胃肠蠕动和胃排空^[61]降低体温^[61，62]，诱发胃肠道副作用包括恶心、呕吐、厌食^[55，63]。

总的来说，在某些物种中，GLP-1和LiCI可能有类似的中枢信号机制，并提示中枢GLP-1s的厌食效应可能受到厌恶通路和胃不适的影响。靶向激动剂传递到CNS GLP1-R表达位点：PVT、NTS、VTA、NAcc或PBN可减少食物摄入，但不导致内脏疾病^{[48，64，65]}。此外Jelsing等人报道，在没有减少胃排空效应的情况下观察到利拉鲁肽抑制食物摄入^[66]。Bloomendaal等^[18]和Kulve等^[67]也支持GLP-1受体激动后的食物摄入量减少受人脑食欲和奖赏相关区域的活动介导的这一假设，这一解释也得到了啮齿动物研究的支持^{[48，64，65]}。

▎GLP-1对奖赏行为的影响

GLP-1还通过影响奖赏、动机、成瘾有关的目标大脑区域如VTA、NAcc、侧隔^{[39，65，68]}和PVT影响非饥饿相关的（欣快感）进食。在NTS中这些边缘区域表达GLP-1R^[69]，并接受PPG神经元的投射^[65，68]。外周给予exendin-4^[24]或直接将GLP-1注入NAcc中心区^[68]可增加该区域的cFos表达，而直接激活NAcc GLP-1R可减少摄食，并被exendin（9-39）抑制^[68]。NAcc GLP-1R的摄食抑制与味觉减退无关^[68]，也不会诱导异食癖^[39，65]。在渐进比例（PR）操作条件试验中，将exendin-4注入NAcc的外壳可以降低蔗糖奖励行为^[39]。与此同时，GLP-1R激动剂降低啮齿动物的各种奖赏行为：包括在操作条件测试中杠杆压力以获得食物奖励的动机^[70]、酒精摄入^[71，72]、寻求酒精行为^[71]，安非他命诱导的条件性位置偏好（Amp-CPP）^[72]、享乐喂食^[72]。在CNS特异性GLP-1R缺失的小鼠中，GLP-1R类似物对奖赏行为的抑制作用减弱^[72]。一些证据表明，NAcc的 GLP-1R激活通过降低食物的适口性来减少食物摄入。饱食的大鼠在普通鼠粮和高脂肪食物（HFD）之间进行选择时，exendin-4会优先减少食用更美味的HFD^[65]。在大鼠NAcc内注射exendin（9-39）会增加蔗糖餐的食量，并在第一餐时加速舔舐的频率（即适口性增加的指标）^[73]。综上所述，GLP-1R激动作用可通过中脑边缘系统的信号调节食物摄入降低了体内饮食平衡和享乐性进食，在中脑边缘系统中，GLP-1R激活影响奖赏行为和适口性。

▎GLP-1通过BBB的转运

外周给予GLP-1可以穿过脑内不完整BBB的区域，如穹窿下区和AP进入脑组织。使用稳定的放射性标记（Ser8）GLP-1的研究显示，当未标记Ser8的GLP-1剂量增加时或在exendin（9-39）预处理抑制脑GLP-1内流时，静脉（i.v.）输注给予（Ser8）GLP-1时，GLP-1无自我抑制地被快速摄取入大脑。外周给予小分子肽GLP-1R类似物，包括利拉鲁肽、利司那肽、exendin-4等，均已证实可穿过BBB^[74，75]，高效液相色谱法（HPLC）分析证实外周给药的exendin-4大多数能完整到达大脑^[75，76]。虽然这些研究表明，GLP-1进入脑组织可能是独立于GLP-1R的被动扩散进入BBB的过程^[74-76]，但也有研究发现利拉鲁肽进入大脑依赖于GLP-1R^[20，77]。

PART2：GLP-1对饮水的影响

GLP-1抑制水摄入最早由Mads Tang-Christensen于1996年报道^[32]，后来被其他人证实^[78，80]。GLP-1对水的抑制作用独立于摄食^[79]，可被exendin（9-39）阻断^[32]。在大鼠中，GLP-1（7-36酰胺）对饮水的抑制呈剂量依赖性，并在中枢（i.c.v）或外周（i.p）给药后30分钟内发生^[32]。在一项对健康志愿者的研究中，静脉输注高渗盐水（5% NaCl）和GLP-1后，可减少36%的饮水量^[78]。用味精（MSG）诱导ARC和室周感觉器官受损的大鼠，外周给予GLP-1未能抑制血管紧张素（ANG）Ⅱ诱导的饮水行为，这表明外周给药GLP-1必须通过CNS机制影响饮水行为^[80]。

GLP-1通过减少饮水以及刺激尿和钠的排泄来影响肾功能（图1）。GLP-1R激动剂的利钠利尿作用于1996年首次被发现^[32]，随后在啮齿动物^[81，82]和健康、肥胖及T2DM患者^[83，84]中得到证实。GLP-1的急性利钠作用已在人类中得到确切证实^[85]，但利拉鲁肽或DPP-4抑制剂西格列汀对T2DM患者进行12周治疗时，肾功能指标包括肾小球滤过率、肾血浆流量、白蛋白/肌酐比值、钠、钾和尿素排泄并无影响^[86]。这表明，GLP-1对肾功能的影响可能是短暂的。但另一针对T2DM患者的研究中，利拉鲁肽的利钠作用在治疗3周后持续存在^[87]。

在大鼠中，GLP-1诱导的利钠和利尿伴随着肾血流量和肾小球滤过率增加^[81，82]，可能是GLP-1增加了肾入球小动脉的扩张而介导。肾脏去神经会导致GLP-1不能增加肾小球滤过率，降低GLP-1的利钠和利尿作用^[81]，这也表明GLP-1的利钠利尿作用可能是由于抑制近端小管的钠重吸收，并强调GLP-1需要完整的肾神经支配来增加肾小球滤过。在啮齿动物和人的研究中表明GLP-1R在肾血管系统中表达^[88]。GLP-1、exendin-4和DPP-4抑制剂西格列汀降低大鼠^{[81，82，89]}和人^[84]近端小管钠的重吸收。在肾近端小管，GLP-1减少Na⁺/H⁺交换体亚型3（NHE3）介导的碳酸氢盐重吸收^[82]。同样，exendin-4降低了NHE3介导的猪肾LLC-PK1细胞钠依赖性pH恢复^[90]。GLP-1R激动剂抑制NHE3活性似乎是通过cAMP激活PKA，再将NHE3的Ser552和Ser605残基磷酸化^{[82，90，91]}发挥作用的。在啮齿动物^[81，82]和人类^[84，85]中，GLP-1R激动剂可增加肾脏锂离子（近端肾小管钠离子重吸收的标志）清除率。这表明，GLP-1的利尿、利钠作用包括改变肾脏血流动力学和PKA依赖的下调肾近端小管的NHE3活性引起钠重吸收下降。GLP-1也可能通过其心血管作用影响肾功能。野生型小鼠中利拉鲁肽可刺激心房心肌细胞分泌利钠肽（ANP），但对ANP缺乏小鼠的尿钠排泄和血管舒张没有影响^[92]。

PART3：GLP-1对能量代谢的影响

与野生型对照组相比，饮食诱导肥胖的GLP-1R敲除小鼠在标准环境室温下表现出能量代谢减少。因为热中性（即标准室温条件）可使非寒战产热对全身能量代谢的贡献最小化，而且非寒战产热需要功能性棕色脂肪组织（BAT）^[93]，这暗示了内源性GLP-1R信号通过调节BAT活性参与了能量代谢的控制，至少在饮食诱导的肥胖小鼠中是这样。这种作用需要大脑中的GLP-1R信号，包括在参与BAT控制的核团中表达^[69]，因此大脑GLP-1R表达在BAT活动的控制中起关键作用^[94]。当大鼠DMH神经元上的GLP-1R位点特异性破坏可导致体重显著增加，同时能量代谢和BAT产热减少^[95]。DMH是参与控制BAT产热的神经网络的一部分^[94]，并接受后脑前胰高糖素原表达神经元的神经支配^[96]。据此推理：这些神经元定位是通过调节BAT产热来控制啮齿动物能量代谢的神经回路的潜在贡献者。然而白喉毒素介导的这些神经元的消融^[97]不会导致食物摄入量或体重的长期变化，这表明对能量代谢的影响很小。相反，这些神经元的急性化学激活没有增加反而暂时减少了能量代谢^[98]。

所以，除了脑源性GLP-1的生理调节外，大脑内源性GLP-1R信号可能在BAT产热的稳态控制中发挥构成性作用。但是，这并不排除外源GLP-1给药可能通过作用于脑GLP-1R来调节能量代谢的可能性。事实上，一份早期的研究报告称，中枢给予低剂量GLP-1（7-37酰胺），在黑暗周期的最初几小时，大鼠的能量代谢会增加^[99]。

对小鼠快速中枢（i.c.v）GLP-1给药增加了BAT的温度，并增加了神经支配腹股沟BAT的交感纤维的活动^[100]。同时，GLP-1R激动剂利拉鲁肽和exendin-4的中枢给药通过包括中基下丘脑AMPK信号转导在内的机制增加了能量代谢和BAT产热^[5]。所以，这些研究表明大脑GLP-1R信号的药理学激活增加了小鼠的能量代谢。

外周GLP-1R激动剂给药可产生不同的能量代谢结果。一项对大鼠的研究发现，静脉输注GLP-1相较中枢GLP-1给药，能量代谢量更大^[101]。这意味着静脉输注GLP-1通过激活后脑GLP-1受体刺激能量代谢。另一项研究报告称，对大鼠腹腔注射（i.p）exentin-4后，发生与肩胛骨间皮肤温度下降相关的能量代谢急剧下降。而当迷走神经传入神经元GLP-1R敲除时，这种作用减弱^[102]。这些数据与GLP-1腹腔给药产生的食欲抑制效应依赖迷走传入的报道一致^[25，27]，因此提示腹腔GLP-1给药对能量代谢的作用机制类似。但在小鼠^[1，3，19]和人类^[103，104]的几项研究在不同GLP-1R激动剂慢性或急性外周给药后未能检测到能量代谢的变化。

总之，至少啮齿动物的证据支持脑GLP-1R信号通过调控BAT活动控制能量代谢。而外周给予GLP-1类似物在小鼠和人类中对能量代谢的作用缺乏可能有如下可能：首先，血脑屏障可能会限制GLP-1R进入能量代谢的大脑区域。第二，不同GLP-1类似物，试验对象的喂食状态和给药途径是分析GLP-1对能量代谢影响的重要考虑因素。第三，啮齿动物可能对通过交感神经系统激活能量代谢的途径特别敏感。

PART4：GLP-1对胃排空的影响

除了对β细胞直接和迷走介导的促胰岛素作用外，GLP-1还通过抑制胃排空、减慢葡萄糖被吸收到循环中的速度来改善餐后葡萄糖（图1）^[105，106]。GLP-1R激动剂对小鼠^[107]、大鼠^[108，109]、狗^[110]、猪^[111，112]和人类^{[105，106，111，113]}胃肠蠕动和胃酸分泌均有抑制作用。在大鼠中，外周或中枢GLP-1给药后，通过后脑GLP-1R信号介导^[114]抑制胃排空^[109]。迷走传入GLP-1受体敲除可加速胃排空^[115]，迷走传入去神经^[109]或外周exendin（9-39）给药^[108，109]均可阻断中枢或外周GLP-1给药对胃排空的作用。GLP-1不能抑制迷走神经切除的人体胃酸分泌，^[116]也不能抑制离体灌注猪胃窦中迷走神经诱导的胃肠运动^[112]。所以，GLP-1介导的胃肠运动抑制包括迷走神经传入，并依赖于外周和大脑GLP-1R^[109]。通过酚妥拉明和普萘洛尔联合给药抑制肾上腺素能信号，可消除GLP-1对胃蠕动的抑制作用，提示GLP-1通过肾上腺素能信号抑制胃排空^[108]。对健康的志愿者静脉注射GLP-1使第一餐后胃排空速度比第二餐后更慢，表明GLP-1对胃排空的抑制作用会迅速脱敏^[113]。在超重人群中，3mg利拉鲁肽在治疗5周后可强烈抑制胃排空，但在治疗16周后该作用显著下降，但与安慰剂治疗相比仍有效果^[117]。在大鼠中，治疗14周后利拉鲁肽诱导的胃排空抑制明显减轻^[66]。

GLP-1通过其减缓胃排空的能力也能降低1型糖尿病患者的血糖，这表明GLP-1调节血糖的作用并非仅仅来自于对β细胞或胰岛素作用^[118，119]。在迷走传入神经元中敲除GLP-1R后，大鼠餐后门静脉血糖水平升高，胰岛素水平下降，提示GLP-1也通过激活迷走神经传入GLP-1R来调节血糖^[115]。这些数据均支持迷走神经传入GLP-1受体对代谢稳态的重要性。

专家寄语

朱大龙

南京鼓楼医院

GLP-1RA近年来在内分泌代谢领域是非常热门的话题，其本身也是一类非常有效的抗糖尿病药物。甚至这类药物积累的有效降糖、心脏获益、肾脏获益的循证证据驱动了指南改变。GLP-1对于体重的作用主要源于对摄食行为、能量代谢方面的影响。此次就GLP-1通过中枢特定区域的受体依赖途径和外周迷走神经传入受体依赖途径，发挥摄食抑制作用、对食物喜好的改变甚至出现食物厌恶情绪、对边缘系统奖赏行为的抑制、能量代谢和消耗方面的作用等一系列作用环节做了详细而细致的梳理。众所周知，以往一些传统降糖药强效降糖同时引起的体重增加让我们一度对T2DM患者的治疗产生困扰。而GLP-1强效降糖和减轻体重的疗效，为我们内分泌医生的临床工作增添了有利的武器，我们有义务为患者充分解释清楚这类药物的减重获益；同时作为科研工作者，我们对于这类药物引领人类代谢何去何从还将进行不断地探索，特别是对体重、腹部脂肪、肝脏脂肪、异位脏器脂肪沉积、肾脏、心脏等的获益进行研究，最终使广大患者受益。

参考文献：

[1] Finan, B., Ma, T., Ottaway, N., Muller, T.D., Habegger, K.M., Heppner, K.M., et al. 2013.Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, andhumans. Sci Transl Med 5:209ra151.

[2] Finan, B., Yang, B., Ottaway, N., Smiley, D.L., Ma, T., Clemmensen, C., et al. 2015. Arationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents.Nat Med 21:27-36.

[3] Finan, B., Yang, B., Ottaway, N., Stemmer, K., Muller, T.D., Yi, C.X., et al. 2012. Targeted estrogen delivery reverses the metabolic syndrome. Nat Med 18:1847-1856.

[4] Henderson, S.J., Konkar, A., Hornigold, D.C., Trevaskis, J.L., Jackson, R., Fritsch Fredin, M., et al. 2016. Robust anti-obesity and metabolic effects of a dual GLP-1/glucagon receptor peptide agonist in rodents and non-human primates. Diabetes Obes Metab 18:1176-1190.

[5] Beiroa, D., Imbernon, M., Gallego, R., Senra, A., Herranz, D., Villarroya, F., et al. 2014. GLP-1 agonism stimulates brown adipose tissue thermogenesis and browning through hypothalamic AMPK. Diabetes 63:3346-3358.

[6] Donahey, J.C., van Dijk, G., Woods, S.C., Seeley, R.J. 1998. Intraventricular GLP-1 reduces short- but not long-term food intake or body weight in lean and obese rats. Brain Res 779:75-83.

[7] Turton, M.D., O'Shea, D., Gunn, I., Beak, S.A., Edwards, C.M., Meeran, K., et al. 1996. A role for glucagon-like peptide-1 in the central regulation of feeding. Nature 379:69-72.

[8] Furuse, M., Matsumoto, M., Okumura, J., Sugahara, K., Hasegawa, S. 1997. Intracerebroventricular injection of mammalian and chicken glucagon-like peptide-1 inhibits food intake of the neonatal chick. Brain Res 755:167-169.

[9] Shousha, S., Nakahara, K., Nasu, T., Sakamoto, T., Murakami, N. 2007. Effect of glucagon-like peptide-1 and -2 on regulation of food intake, body temperature and locomotor activity in the Japanese quail. Neurosci Lett 415:102-107.

[10] Raun, K., von Voss, P., Knudsen, L.B. 2007. Liraglutide, a once-daily human glucagonlike peptide-1 analog, minimizes food intake in severely obese minipigs. Obesity (Silver Spring) 15:1710-1716.

[11] Renner, S., Blutke, A., Dobenecker, B., Dhom, G., Muller, T.D., Finan, B., et al. 2018. Metabolic syndrome and extensive adipose tissue inflammation in morbidly obese Gottingen minipigs. Mol Metab.

[12] Elvert, R., Bossart, M., Herling, A.W., Weiss, T., Zhang, B., Kannt, A., et al. 2018. Team Players or Opponents: Coadministration of Selective Glucagon and GLP-1 Receptor Agonists in Obese Diabetic Monkeys. Endocrinology 159:3105-3119.

[13] Scott, K.A., Moran, T.H. 2007. The GLP-1 agonist exendin-4 reduces food intake in nonhuman primates through changes in meal size. Am J Physiol Regul Integr Comp Physiol 293:R983-987.

[14] Gutzwiller, J.P., Goke, B., Drewe, J., Hildebrand, P., Ketterer, S., Handschin, D., et al. 1999. Glucagon-like peptide-1: a potent regulator of food intake in humans. Gut 44:81-86.

[15] Verdich, C., Flint, A., Gutzwiller, J.P., Naslund, E., Beglinger, C., Hellstrom, P.M., et al. 2001. A meta-analysis of the effect of glucagon-like peptide-1 (7-36) amide on ad libitum energy intake in humans. J Clin Endocrinol Metab 86:4382-4389.

[16] Schlogl, H., Kabisch, S., Horstmann, A., Lohmann, G., Muller, K., Lepsien, J., et al. 2013. Exenatide-induced reduction in energy intake is associated with increase in hypothalamic connectivity. Diabetes Care 36:1933-1940.

[17] Ten Kulve, J.S., Veltman, D.J., van Bloemendaal, L., Barkhof, F., Drent, M.L., Diamant, M., et al. 2016. Liraglutide Reduces CNS Activation in Response to Visual Food Cues Only After Short-term Treatment in Patients With Type 2 Diabetes. Diabetes Care 39:214-221.

[18] van Bloemendaal, L., RG, I.J., Ten Kulve, J.S., Barkhof, F., Konrad, R.J., Drent, M.L., et al. 2014. GLP-1 receptor activation modulates appetite- and reward-related brain areas in humans. Diabetes 63:4186-4196.

[19] Clemmensen, C., Finan, B., Fischer, K., Tom, R.Z., Legutko, B., Sehrer, L., et al. 2015. Dual melanocortin-4 receptor and GLP-1 receptor agonism amplifies metabolic benefits in diet-induced obese mice. EMBO Mol Med 7:288-298.

[20] Secher, A., Jelsing, J., Baquero, A.F., Hecksher-Sorensen, J., Cowley, M.A., Dalboge, L.S., et al. 2014. The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss. J Clin Invest 124:4473-4488.

[21] Kanoski, S.E., Fortin, S.M., Arnold, M., Grill, H.J., Hayes, M.R. 2011. Peripheral and central GLP-1 receptor populations mediate the anorectic effects of peripherally administered GLP-1 receptor agonists, liraglutide and exendin-4. Endocrinology 152:3103- 3112.

[22] Swick, J.C., Alhadeff, A.L., Grill, H.J., Urrea, P., Lee, S.M., Roh, H., et al. 2015. Parabrachial Nucleus Contributions to Glucagon-Like Peptide-1 Receptor Agonist-Induced Hypophagia. Neuropsychopharmacology 40:2001-2014.

[23] Baggio, L.L., Huang, Q., Brown, T.J., Drucker, D.J. 2004. Oxyntomodulin and glucagonlike peptide-1 differentially regulate murine food intake and energy expenditure. Gastroenterology 127:546-558.

[24] Labouesse, M.A., Stadlbauer, U., Weber, E., Arnold, M., Langhans, W., Pacheco-Lopez, G. 2012. Vagal afferents mediate early satiation and prevent flavour avoidance learning in response to intraperitoneally infused exendin-4. J Neuroendocrinol 24:1505-1516.

[25] Baumgartner, I., Pacheco-Lopez, G., Ruttimann, E.B., Arnold, M., Asarian, L., Langhans, W., et al. 2010. Hepatic-portal vein infusions of glucagon-like peptide-1 reduce meal size and increase c-Fos expression in the nucleus tractus solitarii, area postrema and central nucleus of the amygdala in rats. J Neuroendocrinol 22:557-563.

[26] Bucinskaite, V., Tolessa, T., Pedersen, J., Rydqvist, B., Zerihun, L., Holst, J.J., et al. 2009. Receptor-mediated activation of gastric vagal afferents by glucagon-like peptide-1 in the rat. Neurogastroenterol Motil 21:978-e978.

[27] Ruttimann, E.B., Arnold, M., Hillebrand, J.J., Geary, N., Langhans, W. 2009. Intrameal hepatic portal and intraperitoneal infusions of glucagon-like peptide-1 reduce spontaneous meal size in the rat via different mechanisms. Endocrinology 150:1174-1181.

[28] Krieger, J.P., Arnold, M., Pettersen, K.G., Lossel, P., Langhans, W., Lee, S.J. 2016. Knockdown of GLP-1 Receptors in Vagal Afferents Affects Normal Food Intake and Glycemia. Diabetes 65:34-43.

[29] Plamboeck, A., Veedfald, S., Deacon, C.F., Hartmann, B., Wettergren, A., Svendsen, L.B., et al. 2013. The effect of exogenous GLP-1 on food intake is lost in male truncally vagotomized subjects with pyloroplasty. Am J Physiol Gastrointest Liver Physiol 304:G1117-1127.

[30] Punjabi, M., Arnold, M., Ruttimann, E., Graber, M., Geary, N., Pacheco-Lopez, G., et al. 2014. Circulating glucagon-like peptide-1 (GLP-1) inhibits eating in male rats by acting in the hindbrain and without inducing avoidance. Endocrinology 155:1690-1699.

[31] Kim, D.H., D'Alessio, D.A., Woods, S.C., Seeley, R.J. 2009. The effects of GLP-1 infusion in the hepatic portal region on food intake. Regul Pept 155:110-114.

[32] Tang-Christensen, M., Larsen, P.J., Goke, R., Fink-Jensen, A., Jessop, D.S., Moller, M., et al. 1996. Central administration of GLP-1-(7-36) amide inhibits food and water intake in rats. Am J Physiol 271:R848-856.

[33] Larsen, P.J., Tang-Christensen, M., Jessop, D.S. 1997. Central administration of

glucagon-like peptide-1 activates hypothalamic neuroendocrine neurons in the rat.

Endocrinology 138:4445-4455.

[34] Richards, P., Parker, H.E., Adriaenssens, A.E., Hodgson, J.M., Cork, S.C., Trapp, S., et al. 2014. Identification and characterization of GLP-1 receptor-expressing cells using a new transgenic mouse model. Diabetes 63:1224-1233.

[35] Cork, S.C., Richards, J.E., Holt, M.K., Gribble, F.M., Reimann, F., Trapp, S. 2015. Distribution and characterisation of Glucagon-like peptide-1 receptor expressing cells in the mouse brain. Mol Metab 4:718-731.

[36] Jin, S.L., Han, V.K., Simmons, J.G., Towle, A.C., Lauder, J.M., Lund, P.K. 1988. Distribution of glucagonlike peptide I (GLP-I), glucagon, and glicentin in the rat brain: an immunocytochemical study. J Comp Neurol 271:519-532.

[37] Alhadeff, A.L., Mergler, B.D., Zimmer, D.J., Turner, C.A., Reiner, D.J., Schmidt, H.D., et al. 2017. Endogenous Glucagon-like Peptide-1 Receptor Signaling in the Nucleus Tractus Solitarius is Required for Food Intake Control. Neuropsychopharmacology 42:1471-1479.

[38] Barrera, J.G., Jones, K.R., Herman, J.P., D'Alessio, D.A., Woods, S.C., Seeley, R.J. 2011. Hyperphagia and increased fat accumulation in two models of chronic CNS glucagon-like peptide-1 loss of function. J Neurosci 31:3904-3913.

[39] Dickson, S.L., Shirazi, R.H., Hansson, C., Bergquist, F., Nissbrandt, H., Skibicka, K.P. 2012. The glucagon-like peptide 1 (GLP-1) analogue, exendin-4, decreases the rewarding value of food: a new role for mesolimbic GLP-1 receptors. J Neurosci 32:4812-4820.

[40] Terrill, S.J., Holt, M.K., Maske, C.B., Abrams, N., Reimann, F., Trapp, S., et al. 2019. Endogenous GLP-1 in lateral septum promotes satiety and suppresses motivation for food in mice. Physiol Behav 206:191-199.

[41] Hayes, M.R., Leichner, T.M., Zhao, S., Lee, G.S., Chowansky, A., Zimmer, D., et al. 2011. Intracellular signals mediating the food intake-suppressive effects of hindbrain glucagonlike peptide-1 receptor activation. Cell Metab 13:320-330.

[42] Barrington, P., Chien, J.Y., Tibaldi, F., Showalter, H.D., Schneck, K., Ellis, B. 2011. LY2189265, a long-acting glucagon-like peptide-1 analogue, showed a dose-dependent effect on insulin secretion in healthy subjects. Diabetes Obes Metab 13:434-438.

[43] Roberge, J.N., Brubaker, P.L. 1991. Secretion of proglucagon-derived peptides in response to intestinal luminal nutrients. Endocrinology 128:3169-3174.

[44] Sisley, S., Gutierrez-Aguilar, R., Scott, M., D'Alessio, D.A., Sandoval, D.A., Seeley, R.J. 2014. Neuronal GLP1R mediates liraglutide's anorectic but not glucose-lowering effect. J Clin Invest 124:2456-2463.

[45] Burmeister, M.A., Ferre, T., Ayala, J.E., King, E.M., Holt, R.M., Ayala, J.E. 2012. Acute activation of central GLP-1 receptors enhances hepatic insulin action and insulin secretion in high-fat-fed, insulin resistant mice. Am J Physiol Endocrinol Metab 302:E334-343.

[46] Seo, S., Ju, S., Chung, H., Lee, D., Park, S. 2008. Acute effects of glucagon-like peptide-1 on hypothalamic neuropeptide and AMP activated kinase expression in fasted rats. Endocr J 55:867-874.

[47] Burmeister, M.A., Ayala, J., Drucker, D.J., Ayala, J.E. 2013. Central glucagon-like peptide 1 receptor-induced anorexia requires glucose metabolism-mediated suppression of AMPK and is impaired by central fructose. Am J Physiol Endocrinol Metab 304:E677-685.

[48] Alhadeff, A.L., Grill, H.J. 2014. Hindbrain nucleus tractus solitarius glucagon-like peptide-1 receptor signaling reduces appetitive and motivational aspects of feeding. Am J Physiol Regul Integr Comp Physiol 307:R465-470.

[49] Hayes, M.R., Bradley, L., Grill, H.J. 2009. Endogenous hindbrain glucagon-like peptide- 1 receptor activation contributes to the control of food intake by mediating gastric satiation signaling. Endocrinology 150:2654-2659.

[50] Chaudhri, O.B., Parkinson, J.R., Kuo, Y.T., Druce, M.R., Herlihy, A.H., Bell, J.D., et al. 2006. Differential hypothalamic neuronal activation following peripheral injection of GLP-1 and oxyntomodulin in mice detected by manganese-enhanced magnetic resonance imaging. Biochem Biophys Res Commun 350:298-306.

[51] Parkinson, J.R., Chaudhri, O.B., Kuo, Y.T., Field, B.C., Herlihy, A.H., Dhillo, W.S., et al. 2009. Differential patterns of neuronal activation in the brainstem and hypothalamus following peripheral injection of GLP-1, oxyntomodulin and lithium chloride in mice detected by manganese-enhanced magnetic resonance imaging (MEMRI). Neuroimage 44:1022-1031.

[52] Schick, R.R., Zimmermann, J.P., vorm Walde, T., Schusdziarra, V. 2003. Peptides that regulate food intake: glucagon-like peptide 1-(7-36) amide acts at lateral and medial hypothalamic sites to suppress feeding in rats. Am J Physiol Regul Integr Comp Physiol 284:R1427-1435.

[53] McMahon, L.R., Wellman, P.J. 1997. Decreased intake of a liquid diet in nonfooddeprived rats following intra-PVN injections of GLP-1 (7-36) amide. Pharmacol Biochem Behav 58:673-677.

[54] McMahon, L.R., Wellman, P.J. 1998. PVN infusion of GLP-1-(7-36) amide suppresses feeding but does not induce aversion or alter locomotion in rats. Am J Physiol 274:R23-29.

[55] Thiele, T.E., Roitman, M.F., Bernstein, I.L. 1996. c-Fos induction in rat brainstem in response to ethanol- and lithium chloride-induced conditioned taste aversions. Alcohol Clin Exp Res 20:1023-1028.

[56] Mitchell, D., Wells, C., Hoch, N., Lind, K., Woods, S.C., Mitchell, L.K. 1976. Poison

induced pica in rats. Physiol Behav 17:691-697.

[57] Pelchat, M.L., Grill, H.J., Rozin, P., Jacobs, J. 1983. Quality of acquired responses to tastes by Rattus norvegicus depends on type of associated discomfort. J Comp Psychol 97:140-153.

[58] Swank, M.W., Bernstein, I.L. 1994. c-Fos induction in response to a conditioned stimulus after single trial taste aversion learning. Brain Res 636:202-208.

[59] Thiele, T.E., Seeley, R.J., D'Alessio, D., Eng, J., Bernstein, I.L., Woods, S.C., et al. 1998. Central infusion of glucagon-like peptide-1-(7-36) amide (GLP-1) receptor antagonist attenuates lithium chloride-induced c-Fos induction in rat brainstem. Brain Res 801:164-170.

[60] Meachum, C.L., Bernstein, I.L. 1992. Behavioral conditioned responses to contextual and odor stimuli paired with LiCl administration. Physiol Behav 52:895-899.

[61] Bernstein, I.L., Chavez, M., Allen, D., Taylor, E.M. 1992. Area postrema mediation of physiological and behavioral effects of lithium chloride in the rat. Brain Res 575:132-137.

[62] O'Shea, D., Gunn, I., Chen, X., Bloom, S., Herbert, J. 1996. A role for central glucagonlike peptide-1 in temperature regulation. Neuroreport 7:830-832.

[63] Bettge, K., Kahle, M., Abd El Aziz, M.S., Meier, J.J., Nauck, M.A. 2017. Occurrence of nausea, vomiting and diarrhoea reported as adverse events in clinical trials studying glucagon-like peptide-1 receptor agonists: A systematic analysis of published clinical trials. Diabetes Obes Metab 19:336-347.

[64] Alhadeff, A.L., Baird, J.P., Swick, J.C., Hayes, M.R., Grill, H.J. 2014. Glucagon-like Peptide-1 receptor signaling in the lateral parabrachial nucleus contributes to the control of food intake and motivation to feed. Neuropsychopharmacology 39:2233-2243.

[65] Alhadeff, A.L., Rupprecht, L.E., Hayes, M.R. 2012. GLP-1 neurons in the nucleus of the solitary tract project directly to the ventral tegmental area and nucleus accumbens to control for food intake. Endocrinology 153:647-658.

[66] Jelsing, J., Vrang, N., Hansen, G., Raun, K., Tang-Christensen, M., Knudsen, L.B. 2012. Liraglutide: short-lived effect on gastric emptying -- long lasting effects on body weight. Diabetes Obes Metab 14:531-538.

[67] ten Kulve, J.S., Veltman, D.J., van Bloemendaal, L., Barkhof, F., Deacon, C.F., Holst, J.J., et al. 2015. Endogenous GLP-1 mediates postprandial reductions in activation in central reward and satiety areas in patients with type 2 diabetes. Diabetologia 58:2688-2698.

[68] Dossat, A.M., Lilly, N., Kay, K., Williams, D.L. 2011. Glucagon-like peptide 1 receptors in nucleus accumbens affect food intake. J Neurosci 31:14453-14457.

[69] Merchenthaler, I., Lane, M., Shughrue, P. 1999. Distribution of pre-pro-glucagon and glucagon-like peptide-1 receptor messenger RNAs in the rat central nervous system. J Comp Neurol 403:261-280.

[70] Decarie-Spain, L., Fisette, A., Zhu, Z., Yang, B., DiMarchi, R.D., Tschop, M.H., et al. 2019. GLP-1/dexamethasone inhibits food reward without inducing mood and memory deficits in mice. Neuropharmacology 151:55-63.

[71] Egecioglu, E., Steensland, P., Fredriksson, I., Feltmann, K., Engel, J.A., Jerlhag, E. 2013. The glucagon-like peptide 1 analogue Exendin-4 attenuates alcohol mediated behaviors in rodents. Psychoneuroendocrinology 38:1259-1270.

[72] Sirohi, S., Schurdak, J.D., Seeley, R.J., Benoit, S.C., Davis, J.F. 2016. Central & peripheral glucagon-like peptide-1 receptor signaling differentially regulate addictive behaviors. Physiol Behav 161:140-144.

[73] Dossat, A.M., Diaz, R., Gallo, L., Panagos, A., Kay, K., Williams, D.L. 2013. Nucleus

accumbens GLP-1 receptors influence meal size and palatability. Am J Physiol Endocrinol Metab 304:E1314-1320.

[74] Hunter, K., Holscher, C. 2012. Drugs developed to treat diabetes, liraglutide and lixisenatide, cross the blood brain barrier and enhance neurogenesis. BMC Neurosci 13:33.

[75] Kastin, A.J., Akerstrom, V. 2003. Entry of exendin-4 into brain is rapid but may be limited at high doses. Int J Obes Relat Metab Disord 27:313-318.

[76] Kastin, A.J., Akerstrom, V., Pan, W. 2002. Interactions of glucagon-like peptide-1 (GLP-1) with the blood-brain barrier. J Mol Neurosci 18:7-14.

[77] Salinas, C.B.G., Lu, T.T., Gabery, S., Marstal, K., Alanentalo, T., Mercer, A.J., et al. 2018. Integrated Brain Atlas for Unbiased Mapping of Nervous System Effects Following Liraglutide Treatment. Sci Rep 8:10310.

[78] Gutzwiller, J.P., Hruz, P., Huber, A.R., Hamel, C., Zehnder, C., Drewe, J., et al. 2006. Glucagon-like peptide-1 is involved in sodium and water homeostasis in humans. Digestion 73:142-150.

[79] McKay, N.J., Kanoski, S.E., Hayes, M.R., Daniels, D. 2011. Glucagon-like peptide-1 receptor agonists suppress water intake independent of effects on food intake. Am J Physiol Regul Integr Comp Physiol 301:R1755-1764.

[80] Tang-Christensen, M., Vrang, N., Larsen, P.J. 1998. Glucagon-like peptide 1(7-36) amide's central inhibition of feeding and peripheral inhibition of drinking are abolished by neonatal monosodium glutamate treatment. Diabetes 47:530-537.

[81] Moreno, C., Mistry, M., Roman, R.J. 2002. Renal effects of glucagon-like peptide in rats. Eur J Pharmacol 434:163-167.

[82] Crajoinas, R.O., Oricchio, F.T., Pessoa, T.D., Pacheco, B.P., Lessa, L.M., Malnic, G., et al. 2011. Mechanisms mediating the diuretic and natriuretic actions of the incretin hormone glucagon-like peptide-1. Am J Physiol Renal Physiol 301:F355-363.

[83] Gutzwiller, J.P., Tschopp, S., Bock, A., Zehnder, C.E., Huber, A.R., Kreyenbuehl, M., et al. 2004. Glucagon-like peptide 1 induces natriuresis in healthy subjects and in insulinresistant obese men. J Clin Endocrinol Metab 89:3055-3061.

[84] Skov, J., Dejgaard, A., Frokiaer, J., Holst, J.J., Jonassen, T., Rittig, S., et al. 2013. Glucagon-like peptide-1 (GLP-1): effect on kidney hemodynamics and renin-angiotensinaldosterone system in healthy men. J Clin Endocrinol Metab 98:E664-671.

[85] Skov, J., Pedersen, M., Holst, J.J., Madsen, B., Goetze, J.P., Rittig, S., et al. 2016. Shortterm effects of liraglutide on kidney function and vasoactive hormones in type 2 diabetes: a randomized clinical trial. Diabetes Obes Metab 18:581-589.

[86] Tonneijck, L., Smits, M.M., Muskiet, M.H., Hoekstra, T., Kramer, M.H., Danser, A.H., et al. 2016. Renal Effects of DPP-4 Inhibitor Sitagliptin or GLP-1 Receptor Agonist Liraglutide in Overweight Patients With Type 2 Diabetes: A 12-Week, Randomized, Double-Blind, Placebo-Controlled Trial. Diabetes Care 39:2042-2050.

[87] Lovshin, J.A., Barnie, A., DeAlmeida, A., Logan, A., Zinman, B., Drucker, D.J. 2015. Liraglutide promotes natriuresis but does not increase circulating levels of atrial natriuretic peptide in hypertensive subjects with type 2 diabetes. Diabetes Care 38:132- 139.

[88] Schlatter, P., Beglinger, C., Drewe, J., Gutmann, H. 2007. Glucagon-like peptide 1 receptor expression in primary porcine proximal tubular cells. Regul Pept 141:120-128.

[89] Pacheco, B.P., Crajoinas, R.O., Couto, G.K., Davel, A.P., Lessa, L.M., Rossoni, L.V., et al. 2011. Dipeptidyl peptidase IV inhibition attenuates blood pressure rising in young spontaneously hypertensive rats. J Hypertens 29:520-528.

[90] Carraro-Lacroix, L.R., Malnic, G., Girardi, A.C. 2009. Regulation of Na+/H+ exchanger NHE3 by glucagon-like peptide 1 receptor agonist exendin-4 in renal proximal tubule cells. Am J Physiol Renal Physiol 297:F1647-1655.

[91] Farah, L.X., Valentini, V., Pessoa, T.D., Malnic, G., McDonough, A.A., Girardi, A.C. 2016. The physiological role of glucagon-like peptide-1 in the regulation of renal function. Am J Physiol Renal Physiol 310:F123-127.

[92] Kim, M., Platt, M.J., Shibasaki, T., Quaggin, S.E., Backx, P.H., Seino, S., et al. 2013. GLP-1 receptor activation and Epac2 link atrial natriuretic peptide secretion to control of blood pressure. Nat Med 19:567-575.

[93] Cannon, B., Nedergaard, J. 2011. Nonshivering thermogenesis and its adequate measurement in metabolic studies. J Exp Biol 214:242-253.

[94] Morrison, S.F., Madden, C.J., Tupone, D. 2014. Central neural regulation of brown adipose tissue thermogenesis and energy expenditure. Cell Metab 19:741-756.

[95] Lee, S.J., Sanchez-Watts, G., Krieger, J.P., Pignalosa, A., Norell, P.N., Cortella, A., et al. 2018. Loss of dorsomedial hypothalamic GLP-1 signaling reduces BAT thermogenesis and increases adiposity. Mol Metab 11:33-46.

[96] Shi, X., Chacko, S., Li, F., Li, D., Burrin, D., Chan, L., et al. 2017. Acute activation of GLP- 1-expressing neurons promotes glucose homeostasis and insulin sensitivity. Mol Metab 6:1350-1359.

[97] Holt, M.K., Richards, J.E., Cook, D.R., Brierley, D.I., Williams, D.L., Reimann, F., et al. 2019. Preproglucagon Neurons in the Nucleus of the Solitary Tract Are the Main Source of Brain GLP-1, Mediate Stress-Induced Hypophagia, and Limit Unusually Large Intakes of Food. Diabetes 68:21-33.

[98] Gaykema, R.P., Newmyer, B.A., Ottolini, M., Raje, V., Warthen, D.M., Lambeth, P.S., et al. 2017. Activation of murine pre-proglucagon-producing neurons reduces food intake and body weight. J Clin Invest 127:1031-1045.

[99] Hwa, J.J., Ghibaudi, L., Williams, P., Witten, M.B., Tedesco, R., Strader, C.D. 1998. Differential effects of intracerebroventricular glucagon-like peptide-1 on feeding and energy expenditure regulation. Peptides 19:869-875.

[100] Lockie, S.H., Heppner, K.M., Chaudhary, N., Chabenne, J.R., Morgan, D.A., Veyrat-Durebex, C., et al. 2012. Direct control of brown adipose tissue thermogenesis by central nervous system glucagon-like peptide-1 receptor signaling. Diabetes 61:2753-2762.

[101] Osaka, T., Endo, M., Yamakawa, M., Inoue, S. 2005. Energy expenditure by intravenous administration of glucagon-like peptide-1 mediated by the lower brainstem and sympathoadrenal system. Peptides 26:1623-1631.

[102] Krieger, J.P., Santos da Conceicao, E.P., Sanchez-Watts, G., Arnold, M., Pettersen, K.G., Mohammed, M., et al. 2018. Glucagon-like peptide-1 regulates brown adipose tissue thermogenesis via the gut-brain axis in rats. Am J Physiol Regul Integr Comp Physiol 315:R708-R720.

[103] Cegla, J., Troke, R.C., Jones, B., Tharakan, G., Kenkre, J., McCullough, K.A., et al. 2014.Coinfusion of low-dose GLP-1 and glucagon in man results in a reduction in food intake. Diabetes 63:3711-3720.

[104] Bergmann, N.C., Lund, A., Gasbjerg, L.S., Meessen, E.C.E., Andersen, M.M., Bergmann, S., et al. 2019. Effects of combined GIP and GLP-1 infusion on energy intake, appetite and energy expenditure in overweight/obese individuals: a randomised, crossover study. Diabetologia 62:665-675.

[105] Willms, B., Werner, J., Holst, J.J., Orskov, C., Creutzfeldt, W., Nauck, M.A. 1996. Gastric emptying, glucose responses, and insulin secretion after a liquid test meal: effects of exogenous glucagon-like peptide-1 (GLP-1)-(7-36) amide in type 2 (noninsulin-dependent) diabetic patients. J Clin Endocrinol Metab 81:327-332.

[106] Linnebjerg, H., Park, S., Kothare, P.A., Trautmann, M.E., Mace, K., Fineman, M., et al. 2008. Effect of exenatide on gastric emptying and relationship to postprandial glycemia in type 2 diabetes. Regul Pept 151:123-129.

[107] Tatarkiewicz, K., Sablan, E.J., Polizzi, C.J., Villescaz, C., Parkes, D.G. 2014. Long-term metabolic benefits of exenatide in mice are mediated solely via the known glucagon-like peptide 1 receptor. Am J Physiol Regul Integr Comp Physiol 306:R490-498.

[108] Giralt, M., Vergara, P. 1998. Sympathetic pathways mediate GLP-1 actions in the gastrointestinal tract of the rat. Regul Pept 74:19-25.

[109] Imeryuz, N., Yegen, B.C., Bozkurt, A., Coskun, T., Villanueva-Penacarrillo, M.L., Ulusoy, N.B. 1997. Glucagon-like peptide-1 inhibits gastric emptying via vagal afferent-mediated central mechanisms. Am J Physiol 273:G920-927.

[110] Anvari, M., Paterson, C.A., Daniel, E.E., McDonald, T.J. 1998. Effects of GLP-1 on gastric emptying, antropyloric motility, and transpyloric flow in response to a nonnutrient liquid. Dig Dis Sci 43:1133-1140.

[111] Nagell, C.F., Wettergren, A., Orskov, C., Holst, J.J. 2006. Inhibitory effect of GLP-1 on gastric motility persists after vagal deafferentation in pigs. Scand J Gastroenterol 41:667-672.

[112] Wettergren, A., Wojdemann, M., Holst, J.J. 1998. Glucagon-like peptide-1 inhibits gastropancreatic function by inhibiting central parasympathetic outflow. Am J Physiol 275:G984-992.

[113] Nauck, M.A., Kemmeries, G., Holst, J.J., Meier, J.J. 2011. Rapid tachyphylaxis of the glucagon-like peptide 1-induced deceleration of gastric emptying in humans. Diabetes 60:1561-1565.

[114] Hayes, M.R., Skibicka, K.P., Grill, H.J. 2008. Caudal brainstem processing is sufficient for behavioral, sympathetic, and parasympathetic responses driven by peripheral and hindbrain glucagon-like-peptide-1 receptor stimulation. Endocrinology 149:4059-4068.

[115] Krieger, J.P., Arnold, M., Pettersen, K.G., Lossel, P., Langhans, W., Lee, S.J. 2016. Knockdown of GLP-1 Receptors in Vagal Afferents Affects Normal Food Intake and Glycemia. Diabetes 65:34-43.

[116] Wettergren, A., Wojdemann, M., Meisner, S., Stadil, F., Holst, J.J. 1997. The inhibitory effect of glucagon-like peptide-1 (GLP-1) 7-36 amide on gastric acid secretion in humans depends on an intact vagal innervation. Gut 40:597-601.

[117] Halawi, H., Khemani, D., Eckert, D., O'Neill, J., Kadouh, H., Grothe, K., et al. 2017. Effects of liraglutide on weight, satiation, and gastric functions in obesity: a randomised, placebo-controlled pilot trial. Lancet Gastroenterol Hepatol 2:890-899.

[118] Creutzfeldt, W.O., Kleine, N., Willms, B., Orskov, C., Holst, J.J., Nauck, M.A. 1996. Glucagonostatic actions and reduction of fasting hyperglycemia by exogenous glucagon-like peptide I(7-36) amide in type I diabetic patients. Diabetes Care 19:580-586.

[119] Gutniak, M., Orskov, C., Holst, J.J., Ahren, B., Efendic, S. 1992. Antidiabetogenic effect of glucagon-like peptide-1 (7-36)amide in normal subjects and patients with diabetes mellitus. N Engl J Med 326:1316-1322.

“此文仅用于向医疗卫生专业人士提供科学信息，不代表平台立场”

投稿/转载/商务合作，请联系：[e-mail]