Department of Molecular and Integrative Physiology, University of Michigan , Ann Arbor, Michigan.
Department of Physiology, School of Medicine of Ribeirao Preto, University of Sao Paulo , Brazil.
Am J Physiol Endocrinol Metab. 2019 Jan 1;316(1):E121-E134. doi: 10.1152/ajpendo.00287.2018. Epub 2018 Oct 30.
Hypothalamic neurons detect changes in circulating hormones such as leptin and insulin and put forward outputs to sustain energy and glucose homeostasis. Because leptin and insulin receptors colocalize in ~40-60% of neurons in the hypothalamus, we characterized the metabolic phenotype of mice with selective deletion of the insulin receptor (InsR) in LepR cells. LR mice presented no difference in body weight and insulin levels but increased fat mass. In the light phase, LR mice exhibited increased food intake, locomotor activity, carbon dioxide production, and respiratory exchange rate. These mice showed reduced fat oxidation and reduced expression of cluster of differentiation 36 and AMP-activated protein kinase-α in the liver, increased glucose oxidation in the light phase, and overall reduced basal glucose levels. To verify the impact of InsR deletion in LepR cells in obesity, we generated ob/ ob InsR, ob/ ob LR, and ob/ ob LR mice. The ob/ ob LR mice had higher body weight, fat mass, and expression of genes related to fat metabolism in the liver. No difference in food intake despite increased neuropeptide Y and agouti-related peptide expression, and no difference in energy expenditure, fat, or glucose oxidation was found in ob/ ob LR compared with LR or LR controls. Remarkably, basal glucose levels were reduced, and the expression of genes associated with glucose metabolism in the liver was higher. Insulin signaling in LepR cells is required for the proper fat and glucose oxidation. These effects are independent of leptin given that the leptin-deficient ob/ ob LR mice also presented reduced glycemia and higher adiposity. The mechanisms underlying these responses remain to be unveiled.
下丘脑神经元检测到循环激素（如瘦素和胰岛素）的变化，并提出输出以维持能量和葡萄糖稳态。由于瘦素和胰岛素受体在 ~40-60%的下丘脑神经元中共定位，我们对 LepR 细胞中选择性缺失胰岛素受体 (InsR) 的小鼠进行了代谢表型特征分析。LR 小鼠的体重和胰岛素水平没有差异，但脂肪量增加。在光照阶段，LR 小鼠的食物摄入量、运动活性、二氧化碳产生和呼吸交换率增加。这些小鼠表现出脂肪氧化减少，肝脏中 CD36 和 AMP 激活蛋白激酶-α 的表达减少，光照阶段葡萄糖氧化增加，基础葡萄糖水平总体降低。为了验证 LepR 细胞中 InsR 缺失对肥胖的影响，我们生成了 ob/ob InsR、ob/ob LR 和 ob/ob LR 小鼠。ob/ob LR 小鼠的体重、脂肪量和肝脏中与脂肪代谢相关的基因表达更高。ob/ob LR 与 LR 或 LR 对照相比，尽管神经肽 Y 和刺鼠相关肽表达增加，但进食量没有差异，能量消耗、脂肪或葡萄糖氧化也没有差异。值得注意的是，基础葡萄糖水平降低，肝脏中与葡萄糖代谢相关的基因表达更高。LepR 细胞中的胰岛素信号对于适当的脂肪和葡萄糖氧化是必需的。这些作用与瘦素无关，因为瘦素缺乏的 ob/ob LR 小鼠也表现出较低的血糖和更高的肥胖程度。这些反应的机制仍有待揭示。
