Essner Rachel A, Smith Alison G, Jamnik Adam A, Ryba Anna R, Trutner Zoe D, Carter Matthew E
Department of Biology, Program in Neuroscience, Williams College, Williamstown, Massachusetts 01267.
Department of Biology, Program in Neuroscience, Williams College, Williamstown, Massachusetts 01267
J Neurosci. 2017 Sep 6;37(36):8678-8687. doi: 10.1523/JNEUROSCI.0798-17.2017. Epub 2017 Aug 7.
To maintain energy homeostasis, orexigenic (appetite-inducing) and anorexigenic (appetite suppressing) brain systems functionally interact to regulate food intake. Within the hypothalamus, neurons that express agouti-related protein (AgRP) sense orexigenic factors and orchestrate an increase in food-seeking behavior. In contrast, calcitonin gene-related peptide (CGRP)-expressing neurons in the parabrachial nucleus (PBN) suppress feeding. PBN CGRP neurons become active in response to anorexigenic hormones released following a meal, including amylin, secreted by the pancreas, and cholecystokinin (CCK), secreted by the small intestine. Additionally, exogenous compounds, such as lithium chloride (LiCl), a salt that creates gastric discomfort, and lipopolysaccharide (LPS), a bacterial cell wall component that induces inflammation, exert appetite-suppressing effects and activate PBN CGRP neurons. The effects of increasing the homeostatic drive to eat on feeding behavior during appetite suppressing conditions are unknown. Here, we show in mice that food deprivation or optogenetic activation of AgRP neurons induces feeding to overcome the appetite suppressing effects of amylin, CCK, and LiCl, but not LPS. AgRP neuron photostimulation can also increase feeding during chemogenetic-mediated stimulation of PBN CGRP neurons. AgRP neuron stimulation reduces Fos expression in PBN CGRP neurons across all conditions. Finally, stimulation of projections from AgRP neurons to the PBN increases feeding following administration of amylin, CCK, and LiCl, but not LPS. These results demonstrate that AgRP neurons are sufficient to increase feeding during noninflammatory-based appetite suppression and to decrease activity in anorexigenic PBN CGRP neurons, thereby increasing food intake during homeostatic need. The motivation to eat depends on the relative balance of activity in distinct brain regions that induce or suppress appetite. An abnormal amount of activity in neurons that induce appetite can cause obesity, whereas an abnormal amount of activity in neurons that suppress appetite can cause malnutrition and a severe reduction in body weight. The purpose of this study was to determine whether a population of neurons known to induce appetite ("AgRP neurons") could induce food intake to overcome appetite-suppression following administration of various appetite-suppressing compounds. We found that stimulating AgRP neurons could overcome various forms of appetite suppression and decrease neural activity in a separate population of appetite-suppressing neurons, providing new insights into how the brain regulates food intake.
为维持能量平衡，促食欲（诱导食欲）和抑食欲（抑制食欲）的脑系统在功能上相互作用以调节食物摄入。在下丘脑中，表达刺鼠相关蛋白（AgRP）的神经元感知促食欲因子并协调觅食行为的增加。相比之下，臂旁核（PBN）中表达降钙素基因相关肽（CGRP）的神经元会抑制进食。进食后，PBN CGRP神经元会因释放的抑食欲激素而变得活跃，这些激素包括胰腺分泌的胰淀素和小肠分泌的胆囊收缩素（CCK）。此外，外源性化合物，如会引起胃部不适的盐——氯化锂（LiCl），以及诱导炎症的细菌细胞壁成分——脂多糖（LPS），会发挥抑制食欲的作用并激活PBN CGRP神经元。在抑制食欲的条件下，增加进食的稳态驱动力对进食行为的影响尚不清楚。在此，我们在小鼠中发现，食物剥夺或AgRP神经元的光遗传学激活会诱导进食，以克服胰淀素、CCK和LiCl的抑食欲作用，但不能克服LPS的抑食欲作用。在化学遗传学介导的PBN CGRP神经元刺激过程中，AgRP神经元的光刺激也能增加进食。在所有条件下，AgRP神经元刺激都会降低PBN CGRP神经元中的Fos表达。最后，刺激从AgRP神经元到PBN的投射，在给予胰淀素、CCK和LiCl后会增加进食，但给予LPS后不会。这些结果表明，在基于非炎症的食欲抑制过程中，AgRP神经元足以增加进食，并降低抑食欲的PBN CGRP神经元的活性，从而在稳态需求时增加食物摄入量。进食动机取决于诱导或抑制食欲的不同脑区活动的相对平衡。诱导食欲的神经元活动异常会导致肥胖，而抑制食欲的神经元活动异常会导致营养不良和体重严重下降。本研究的目的是确定一群已知能诱导食欲的神经元（“AgRP神经元”）在给予各种抑制食欲的化合物后是否能诱导食物摄入以克服食欲抑制。我们发现，刺激AgRP神经元可以克服各种形式的食欲抑制，并降低另一群抑制食欲的神经元的神经活动，这为大脑如何调节食物摄入提供了新的见解。
