Myers Jacob W, Park Woo Yong, Eddie Alexander M, Shinde Abhijit B, Prasad Praveena, Murphy Alexandria C, Leonard Michael Z, Pinette Julia A, Rampy Jessica J, Montufar Claudia, Shaikh Zayedali, Hickman Tara T, Reynolds Garrett N, Winn Nathan C, Lantier Louise, Peck Sun H, Coate Katie C, Stein Roland W, Carrasco Nancy, Calipari Erin S, McReynolds Melanie R, Zaganjor Elma
Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, USA.
Department of Biochemistry and Molecular Biology, Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA.
bioRxiv. 2024 Nov 1:2024.10.28.620705. doi: 10.1101/2024.10.28.620705.
Obesity is a major health concern, largely because it contributes to type 2 diabetes mellitus (T2DM), cardiovascular disease, and various malignancies. Increase in circulating amino acids and lipids, in part due to adipose dysfunction, have been shown to drive obesity-mediated diseases. Similarly, elevated purines and uric acid, a degradation product of purine metabolism, are found in the bloodstream and in adipose tissue. These metabolic changes are correlated with metabolic syndrome, but little is known about the physiological effects of targeting purine biosynthesis.
To determine the effects of purine biosynthesis on organismal health we treated mice with mizoribine, an inhibitor of inosine monophosphate dehydrogenase 1 and 2 (IMPDH1/2), key enzymes in this pathway. Mice were fed either a low-fat (LFD; 13.5% kcal from fat) or a high-fat (HFD; 60% kcal from fat) diet for 30 days during drug or vehicle treatment. We ascertained the effects of mizoribine on weight gain, body composition, food intake and absorption, energy expenditure, and overall metabolic health.
Mizoribine treatment prevented mice on a HFD from gaining weight, but had no effect on mice on a LFD. Body composition analysis demonstrated that mizoribine significantly reduced fat mass but did not affect lean mass. Although mizoribine had no effect on lipid absorption, food intake was reduced. Furthermore, mizoribine treatment induced adaptive thermogenesis in skeletal muscle by upregulating sarcolipin, a regulator of muscle thermogenesis. While mizoribine-treated mice exhibited less adipose tissue than controls, we did not observe lipotoxicity. Rather, mizoribine-treated mice displayed improved glucose tolerance and reduced ectopic lipid accumulation.
Inhibiting purine biosynthesis prevents mice on a HFD from gaining weight, and improves their metabolic health, to a significant degree. We also demonstrated that the purine biosynthesis pathway plays a previously unknown role in skeletal muscle thermogenesis. A deeper mechanistic understanding of how purine biosynthesis promotes thermogenesis and decreases food intake may pave the way to new anti-obesity therapies. Crucially, given that many purine inhibitors have been FDA-approved for use in treating various conditions, our results indicate that they may benefit overweight or obese patients.
肥胖是一个主要的健康问题，很大程度上是因为它会导致2型糖尿病（T2DM）、心血管疾病和各种恶性肿瘤。循环氨基酸和脂质的增加，部分归因于脂肪功能障碍，已被证明会引发肥胖介导的疾病。同样，在血液和脂肪组织中也发现嘌呤和尿酸（嘌呤代谢的降解产物）水平升高。这些代谢变化与代谢综合征相关，但关于靶向嘌呤生物合成的生理效应知之甚少。
为了确定嘌呤生物合成对机体健康的影响，我们用霉酚酸酯处理小鼠，霉酚酸酯是肌苷单磷酸脱氢酶1和2（IMPDH1/2）的抑制剂，这是该途径中的关键酶。在药物或载体处理期间，给小鼠喂食低脂（LFD；13.5%千卡来自脂肪）或高脂（HFD；60%千卡来自脂肪）饮食30天。我们确定了霉酚酸酯对体重增加、身体组成、食物摄入和吸收、能量消耗以及整体代谢健康的影响。
霉酚酸酯处理可防止高脂饮食的小鼠体重增加，但对低脂饮食的小鼠没有影响。身体组成分析表明，霉酚酸酯显著降低了脂肪量，但不影响瘦体重。虽然霉酚酸酯对脂质吸收没有影响，但食物摄入量减少。此外，霉酚酸酯处理通过上调肌脂蛋白（一种肌肉产热调节剂）诱导骨骼肌适应性产热。虽然经霉酚酸酯处理的小鼠脂肪组织比对照组少，但我们没有观察到脂毒性。相反，经霉酚酸酯处理的小鼠表现出改善的葡萄糖耐量和减少的异位脂质积累。
抑制嘌呤生物合成可防止高脂饮食的小鼠体重增加，并在很大程度上改善它们的代谢健康。我们还证明嘌呤生物合成途径在骨骼肌产热中发挥了以前未知的作用。对嘌呤生物合成如何促进产热和减少食物摄入的更深入机制理解可能为新的抗肥胖疗法铺平道路。至关重要的是，鉴于许多嘌呤抑制剂已获美国食品药品监督管理局批准用于治疗各种病症，我们的结果表明它们可能使超重或肥胖患者受益。
