Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, NYU School of Medicine, 435 East 30(th) Street, New York, NY 10016, USA.
Program in Molecular Medicine, Department of Medicine, University of Massachusetts Medical School, 368 Plantation Street, Albert Sherman Center, Worcester, MA 01605, USA.
Cell Rep. 2019 Jul 16;28(3):773-791.e7. doi: 10.1016/j.celrep.2019.06.061.
Exquisite regulation of energy homeostasis protects from nutrient deprivation but causes metabolic dysfunction upon nutrient excess. In human and murine adipose tissue, the accumulation of ligands of the receptor for advanced glycation end products (RAGE) accompanies obesity, implicating this receptor in energy metabolism. Here, we demonstrate that mice bearing global- or adipocyte-specific deletion of Ager, the gene encoding RAGE, display superior metabolic recovery after fasting, a cold challenge, or high-fat feeding. The RAGE-dependent mechanisms were traced to suppression of protein kinase A (PKA)-mediated phosphorylation of its key targets, hormone-sensitive lipase and p38 mitogen-activated protein kinase, upon β-adrenergic receptor stimulation-processes that dampen the expression and activity of uncoupling protein 1 (UCP1) and thermogenic programs. This work identifies the innate role of RAGE as a key node in the immunometabolic networks that control responses to nutrient supply and cold challenges, and it unveils opportunities to harness energy expenditure in environmental and metabolic stress.
精细调控能量稳态可防止营养缺乏，但在营养过剩时会导致代谢功能障碍。在人和鼠的脂肪组织中，晚期糖基化终产物受体（RAGE）配体的积累伴随着肥胖，表明该受体参与能量代谢。在这里，我们证明，在禁食、冷应激或高脂肪喂养后，全身性或脂肪细胞特异性缺失编码 RAGE 的基因 Ager 的小鼠表现出更好的代谢恢复。RAGE 依赖的机制可以追溯到β-肾上腺素能受体刺激时蛋白激酶 A（PKA）介导的其关键靶标，激素敏感脂肪酶和 p38 丝裂原活化蛋白激酶的磷酸化受到抑制，这一过程抑制了解偶联蛋白 1（UCP1）和产热程序的表达和活性。这项工作确定了 RAGE 的固有作用，即作为控制对营养供应和冷应激反应的免疫代谢网络中的关键节点，并且为在环境和代谢应激下利用能量消耗提供了机会。
