Le May Marie V, Peris-Sampedro Fiona, Stoltenborg Iris, Schéle Erik, Bake Tina, Adan Roger A H, Dickson Suzanne L
Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
Department of Translational Neuroscience, UMC Utrecht Brain Center, Utrecht University, Utrecht, Netherlands.
Front Neurosci. 2021 Feb 15;15:633018. doi: 10.3389/fnins.2021.633018. eCollection 2021.
The lateral parabrachial nucleus (lPBN), located in the pons, is a well-recognized anorexigenic center harboring, amongst others, the calcitonin gene-related peptide (CGRP)-expressing neurons that play a key role. The receptor for the orexigenic hormone ghrelin (the growth hormone secretagogue receptor, GHSR) is also abundantly expressed in the lPBN and ghrelin delivery to this site has recently been shown to increase food intake and alter food choice. Here we sought to explore whether GHSR-expressing cells in the lPBN (GHSR cells) contribute to feeding control, food choice and body weight gain in mice offered an obesogenic diet, involving studies in which GHSR cells were silenced. We also explored the neurochemical identity of GHSR cells. To silence GHSR cells, male mice were bilaterally injected intra-lPBN with a Cre-dependent viral vector expressing tetanus toxin-light chain. Unlike control wild-type littermates that significantly increased in body weight on the obesogenic diet (i.e., high-fat high-sugar free choice diet comprising chow, lard and 9% sucrose solution), the heterozygous mice with silenced GHSR cells were resistant to diet-induced weight gain with significantly lower food intake and fat weight. The lean phenotype appeared to result from a decreased food intake compared to controls and caloric efficiency was unaltered. Additionally, silencing the GHSR cells altered food choice, significantly reducing palatable food consumption. RNAscope and immunohistochemical studies of the lPBN revealed considerable co-expression of GHSR with glutamate and pituitary adenylate cyclase-activating peptide (PACAP), and much less with neurotensin, substance P and CGRP. Thus, the GHSR cells are important for diet-induced weight gain and adiposity, as well as in the regulation of food intake and food choice. Most GHSR cells were found to be glutamatergic and the majority (76%) do not belong to the well-characterized anorexigenic CGRP cell population.
外侧臂旁核（lPBN）位于脑桥，是一个公认的厌食中枢，其中含有降钙素基因相关肽（CGRP）表达神经元等，这些神经元发挥着关键作用。食欲素激素胃饥饿素的受体（生长激素促分泌素受体，GHSR）在lPBN中也大量表达，最近研究表明，向该部位递送胃饥饿素会增加食物摄入量并改变食物选择。在此，我们试图探究lPBN中表达GHSR的细胞（GHSR⁺细胞）是否在给予致肥胖饮食的小鼠的摄食控制、食物选择和体重增加中发挥作用，其中涉及对GHSR⁺细胞进行沉默的研究。我们还探究了GHSR⁺细胞的神经化学特征。为了沉默GHSR⁺细胞，对雄性小鼠双侧脑桥臂旁核内注射表达破伤风毒素轻链的Cre依赖性病毒载体。与在致肥胖饮食（即由食物、猪油和9%蔗糖溶液组成的高脂肪高糖自由选择饮食）下体重显著增加的对照野生型同窝小鼠不同，GHSR⁺细胞沉默的杂合小鼠对饮食诱导的体重增加具有抗性，食物摄入量和脂肪重量显著降低。与对照组相比，瘦型表型似乎是由于食物摄入量减少所致，而能量效率未改变。此外，沉默GHSR⁺细胞会改变食物选择，显著减少美味食物的摄入量。对脑桥臂旁核进行RNAscope和免疫组织化学研究发现，GHSR与谷氨酸和垂体腺苷酸环化酶激活肽（PACAP）大量共表达，而与神经降压素、P物质和CGRP共表达较少。因此，GHSR⁺细胞对饮食诱导的体重增加和肥胖以及食物摄入和食物选择的调节很重要。大多数GHSR⁺细胞被发现是谷氨酸能的，并且大多数（76%）不属于特征明确的厌食性CGRP细胞群体。
