Department of Physiology and Pharmacology, Molecular & Cellular Exercise Physiology, Karolinska Institutet, Biomedicum, Stockholm, Sweden.
J Intern Med. 2018 Nov;284(5):519-533. doi: 10.1111/joim.12830. Epub 2018 Sep 25.
Obesity ultimately results from an imbalance between energy intake and expenditure. However, in addition to their bioenergetic value, nutrients and their metabolites can function as important signalling molecules in energy homeostasis. Indeed, macronutrients and their metabolites can be direct regulators of metabolism through their actions on different organs. In turn, target organs can decide to use, store or transform the incoming nutrients depending on their physiological context and in coordination with other cell types. Tryptophan-kynurenine metabolites are an example of a family of compounds that can serve as systemic integrators of energy metabolism by signalling to different cell types. These include adipocytes, immune cells and muscle fibres, in addition to the well-known effects of kynurenine metabolites on the central nervous system. In the context of energy metabolism, several of the effects elicited by kynurenic acid are mediated by the G-protein-coupled receptor, GPR35. As GPR35 is expressed in tissues such as the adipose tissue, immune cells and the gastrointestinal tract, this receptor could be a potential therapeutic target for the treatment of obesity, diabetes and other metabolic diseases. In addition, metabolic disorders often coincide with states of chronic inflammation, which further highlights GPR35 as an integration node in conditions where inflammation skews metabolism. Defining the molecular interplay between different tissues in the regulation of energy homeostasis can help us understand interindividual variability in the response to nutrient intake and develop safe and efficient therapies to fight obesity and metabolic disease.
肥胖最终是由于能量摄入和消耗之间的失衡所致。然而，除了它们的生物能量值外，营养素及其代谢物还可以作为能量平衡的重要信号分子发挥作用。事实上，宏量营养素及其代谢物可以通过其对不同器官的作用直接调节代谢。反过来，靶器官可以根据其生理环境并与其他细胞类型协调，决定使用、储存或转化摄入的营养素。色氨酸-犬尿氨酸代谢物就是可以作为能量代谢系统整合者的化合物家族的一个例子，通过向不同细胞类型发出信号来实现这一点。这些细胞类型包括脂肪细胞、免疫细胞和肌肉纤维，除了犬尿氨酸代谢物对中枢神经系统的众所周知的影响之外。在能量代谢的背景下，犬尿酸引起的几种作用是通过 G 蛋白偶联受体 GPR35 介导的。由于 GPR35 在脂肪组织、免疫细胞和胃肠道等组织中表达，因此该受体可能是治疗肥胖症、糖尿病和其他代谢疾病的潜在治疗靶点。此外，代谢紊乱通常与慢性炎症状态同时发生，这进一步凸显了 GPR35 作为炎症影响代谢的情况下的整合节点。定义不同组织在调节能量平衡中的分子相互作用可以帮助我们了解个体对营养素摄入的反应的个体差异，并开发安全有效的治疗方法来对抗肥胖症和代谢疾病。
