目的:线粒体丙酮酸载体(MPC)占据中间代谢的关键节点,促使人们对其作为治疗肥胖和心脏代谢疾病的治疗靶标的实用性产生兴趣。脂肪组织中营养代谢失调是肥胖病理生理学的突出特征,然而,脂肪MPC的功能作用尚未被探索。我们调查了MPC是否影响雌性和雄性小鼠脂肪组织对饮食压力的适应。
方法:在3T3L1脂肪细胞和鼠脂肪外植体中评估了MPC的药理和遗传破坏对甘油三酯组装的线粒体途径(脂肪生成和甘油生成)的影响,结合代谢受损人群中脂肪MPC表达的分析。随后在缺乏脂肪细胞MPC1(Mpc1AD-/-)的雄性和雌性小鼠中研究了全身和脂肪特异性葡萄糖代谢,高脂肪西式,或高蔗糖脂质限制饮食24周,使用放射性标记示踪剂和GC/MS代谢组学的组合。
结果:用UK5099或siMPC1处理损害了丙酮酸盐的脂质和3-磷酸甘油酯的合成,并抑制了3T3L1脂肪细胞中甘油三酯的积累,而人脂肪组织中MPC的表达与全身和脂肪组织代谢功能障碍的指标呈负相关。来自Mpc1AD-/-小鼠的成熟脂肪外植体本质上不能将丙酮酸掺入甘油三酯中。在体内,MPC缺失限制了循环葡萄糖掺入脂肪甘油三酯,但只有在饲喂零脂肪饮食的雌性小鼠中,这与三羧酸循环池大小的性别特异性减少以及脂肪生成和甘油代谢途径的代偿性转录变化有关。然而,无论性别如何,Mpc1AD-/-小鼠都能保持全身肥胖和代谢健康,即使在零膳食脂肪的条件下。
结论:这些发现强调了雌性小鼠与雄性小鼠相比,线粒体驱动的甘油三酯在脂肪中组装的能力更大,并暴露了在饮食脂质限制条件下,雌性脂肪中葡萄糖分配对MPC门控代谢的依赖性。
OBJECTIVE: The mitochondrial pyruvate carrier (MPC) occupies a critical node in intermediary metabolism, prompting interest in its utility as a therapeutic target for the treatment of obesity and cardiometabolic disease. Dysregulated nutrient metabolism in
adipose tissue is a prominent feature of obesity pathophysiology, yet the functional role of
adipose MPC has not been explored. We investigated whether the MPC shapes the adaptation of
adipose tissue to dietary stress in female and male mice.
METHODS: The impact of pharmacological and genetic disruption of the MPC on mitochondrial pathways of triglyceride assembly (lipogenesis and glyceroneogenesis) was assessed in 3T3L1 adipocytes and murine adipose explants, combined with analyses of
adipose MPC expression in metabolically compromised humans. Whole-body and
adipose-specific glucose metabolism were subsequently investigated in male and female mice lacking adipocyte MPC1 (Mpc1AD-/-) and fed either standard chow, high-fat western style, or high-sucrose lipid restricted diets for 24 weeks, using a combination of radiolabeled tracers and GC/MS metabolomics.
RESULTS: Treatment with UK5099 or siMPC1 impaired the synthesis of lipids and glycerol-3-phosphate from pyruvate and blunted triglyceride accumulation in 3T3L1 adipocytes, whilst MPC expression in human adipose tissue was negatively correlated with indices of whole-body and adipose tissue metabolic dysfunction. Mature adipose explants from Mpc1AD-/- mice were intrinsically incapable of incorporating pyruvate into triglycerides. In vivo, MPC deletion restricted the incorporation of circulating glucose into adipose triglycerides, but only in female mice fed a zero fat diet, and this associated with sex-specific reductions in tricarboxylic acid cycle pool sizes and compensatory transcriptional changes in lipogenic and glycerol metabolism pathways. However, whole-body adiposity and metabolic health were preserved in Mpc1AD-/- mice regardless of sex, even under conditions of zero dietary fat.
CONCLUSIONS: These findings highlight the greater capacity for mitochondrially driven triglyceride assembly in adipose from female versus male mice and expose a reliance upon MPC-gated metabolism for glucose partitioning in female adipose under conditions of dietary lipid restriction.