Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706, Spain.
Department of Neuroscience & Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA.
Mol Metab. 2022 May;59:101465. doi: 10.1016/j.molmet.2022.101465. Epub 2022 Feb 23.
Bone morphogenetic protein 8B (BMP8B) plays a major role in the regulation of energy homeostasis by modulating brown adipose tissue (BAT) thermogenesis and white adipose tissue (WAT) browning. Here, we investigated whether BMP8B's role in metabolism is affected by obesity and the possible molecular mechanisms underlying that action.
Central treatments with BMP8B were performed in rats fed a standard (SD) and high-fat diet (HFD), as well as in genetically modified mice. Energy balance studies, infrared thermographic analysis of BAT and molecular analysis of the hypothalamus, BAT and WAT were carried out.
We show for the first time that HFD-induced obesity elicits resistance to the central actions of BMP8B on energy balance. This obesity-induced BMP8B resistance is explained by i) lack of effects on AMP-activated protein kinase (AMPK) signaling, ii) decreased BMP receptors signaling and iii) reduced expression of Bardet-Biedl Syndrome 1 (BBS1) protein, a key component of the protein complex BBSome in the ventromedial nucleus of the hypothalamus (VMH). The possible mechanistic involvement of BBS1 in this process is demonstrated by lack of a central response to BMP8B in mice carrying a single missense disease-causing mutation in the Bbs1 gene.
Overall, our data uncover a new mechanism of central resistance to hormonal action that may be of relevance in the pathophysiology of obesity.
骨形态发生蛋白 8B（BMP8B）通过调节棕色脂肪组织（BAT）产热和白色脂肪组织（WAT）褐变，在调节能量平衡方面发挥重要作用。在此，我们研究了肥胖是否会影响 BMP8B 在代谢中的作用，以及这种作用的潜在分子机制。
对喂食标准（SD）和高脂肪饮食（HFD）的大鼠以及基因修饰的小鼠进行中枢 BMP8B 处理。进行能量平衡研究、BAT 的红外热成像分析以及下丘脑、BAT 和 WAT 的分子分析。
我们首次表明，HFD 诱导的肥胖会引起对 BMP8B 对能量平衡的中枢作用的抗性。这种肥胖诱导的 BMP8B 抗性可以解释为：i）对 AMP 激活的蛋白激酶（AMPK）信号通路没有影响，ii）BMP 受体信号降低，iii）Bardet-Biedl 综合征 1（BBS1）蛋白表达减少，BBS1 蛋白是下丘脑腹内侧核（VMH）中 BBSome 蛋白复合物的关键组成部分。BBS1 在该过程中的可能机制参与通过在携带 Bbs1 基因单一错义疾病相关突变的小鼠中缺乏对 BMP8B 的中枢反应来证明。
总体而言，我们的数据揭示了一种对激素作用的中枢抗性的新机制，这在肥胖的病理生理学中可能具有相关性。
