Glutamine and glutamate are interconverted by several enzymes and alterations in this metabolic cycle are linked to cardiometabolic traits. Herein, we show that obesity-associated insulin resistance is characterized by decreased plasma and white adipose tissue glutamine-to-glutamate ratios. We couple these stoichiometric changes to perturbed fat cell glutaminase and glutamine synthase messenger RNA and protein abundance, which together promote glutaminolysis. In human white adipocytes, reductions in glutaminase activity promote aerobic glycolysis and mitochondrial oxidative capacity via increases in hypoxia-inducible factor 1α abundance, lactate levels and p38 mitogen-activated protein kinase signalling. Systemic glutaminase inhibition in male and female mice, or genetically in adipocytes of male mice, triggers the activation of thermogenic gene programs in inguinal adipocytes. Consequently, the knockout mice display higher energy expenditure and improved glucose tolerance compared to control littermates, even under high-fat diet conditions. Altogether, our findings highlight white adipocyte glutamine turnover as an important determinant of energy expenditure and metabolic health.

谷氨酰胺和谷氨酸通过多种酶相互转化，并且该代谢周期的改变与心脏代谢特征相关。在此，我们表明肥胖相关的胰岛素抵抗的特征是血浆和白色脂肪组织谷氨酰胺与谷氨酸比率降低。我们将这些化学计量变化与受干扰的脂肪细胞谷氨酰胺酶和谷氨酰胺合酶信使 RNA 和蛋白质丰度结合起来，共同促进谷氨酰胺分解。在人白色脂肪细胞中，谷氨酰胺酶活性的降低通过增加缺氧诱导因子 1α 丰度、乳酸水平和 p38 丝裂原激活蛋白激酶信号传导来促进有氧糖酵解和线粒体氧化能力。雄性和雌性小鼠的全身谷氨酰胺酶抑制，或雄性小鼠脂肪细胞的遗传抑制，触发腹股沟脂肪细胞中生热基因程序的激活。因此，即使在高脂肪饮食条件下，与对照同窝小鼠相比，基因敲除小鼠也表现出更高的能量消耗和改善的葡萄糖耐量。总而言之，我们的研究结果强调白色脂肪细胞谷氨酰胺周转是能量消耗和代谢健康的重要决定因素。