Sowton Alice P, Holzner Lorenz M W, Krause Fynn N, Baxter Ruby, Mocciaro Gabriele, Krzyzanska Dominika K, Minnion Magdalena, O'Brien Katie A, Harrop Matthew C, Darwin Paula M, Thackray Benjamin D, Vacca Michele, Feelisch Martin, Griffin Julian L, Murray Andrew J
Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom.
Department of Biochemistry and Systems Biology Centre, University of Cambridge, Cambridge, United Kingdom.
Am J Physiol Endocrinol Metab. 2025 Jan 1;328(1):E69-E91. doi: 10.1152/ajpendo.00256.2024. Epub 2024 Dec 9.
Inorganic nitrate (NO) has been proposed to be of therapeutic use as a dietary supplement in obesity and related conditions including the metabolic syndrome (MetS), type II diabetes, and metabolic dysfunction-associated steatotic liver disease (MASLD). Administration of NO to endothelial nitric oxide synthase-deficient mice reversed aspects of MetS; however, the impact of NO supplementation in diet-induced obesity is not well understood. Here we investigated the whole body metabolic phenotype and cardiac and hepatic metabolism in mice fed a high-fat, high-sucrose (HFHS) diet for up to 12 mo of age, supplemented with 1 mM NaNO (or NaCl) in their drinking water. HFHS feeding was associated with a progressive obesogenic and diabetogenic phenotype, which was not ameliorated by NO. Furthermore, HFHS-fed mice supplemented with NO showed elevated levels of cardiac fibrosis and accelerated progression of MASLD including development of hepatocellular carcinoma in comparison with NaCl-supplemented mice. NO did not enhance mitochondrial β-oxidation capacity in any tissue assayed and did not suppress hepatic lipid accumulation, suggesting it does not prevent lipotoxicity. We conclude that NO is ineffective in preventing the metabolic consequences of an obesogenic diet and may instead be detrimental to metabolic health against the background of HFHS feeding. This is the first report of an unfavorable effect of long-term nitrate supplementation in the context of the metabolic challenges of overfeeding, warranting urgent further investigation into the mechanism of this interaction. Inorganic nitrate has been suggested to be of therapeutic benefit in obesity-related conditions, as it increases nitric oxide bioavailability, enhances mitochondrial β-oxidation, and reverses metabolic syndrome in mice. However, we here show that over 12 months nitrate was ineffective in preventing metabolic consequences in high fat, high sucrose-fed mice and worsened aspects of metabolic health, impairing cholesterol handling, increasing cardiac fibrosis, and exacerbating steatotic liver disease progression, with acceleration to hepatocellular carcinoma.
无机硝酸盐（NO）已被提议作为一种膳食补充剂用于肥胖及相关病症的治疗，这些病症包括代谢综合征（MetS）、II型糖尿病和代谢功能障碍相关脂肪性肝病（MASLD）。给内皮型一氧化氮合酶缺陷小鼠施用NO可逆转MetS的某些方面；然而，补充NO对饮食诱导肥胖的影响尚不清楚。在此，我们研究了在长达12个月龄的时间里喂食高脂高糖（HFHS）饮食，并在饮用水中补充1 mM硝酸钠（或氯化钠）的小鼠的全身代谢表型以及心脏和肝脏代谢。喂食HFHS与逐渐出现致肥胖和致糖尿病表型相关，而NO并不能改善这些表型。此外，与补充氯化钠的小鼠相比，补充NO的HFHS喂养小鼠心脏纤维化水平升高，MASLD进展加速，包括肝细胞癌的发生。在任何检测的组织中，NO均未增强线粒体β-氧化能力，也未抑制肝脏脂质积累，这表明它不能预防脂毒性。我们得出结论，NO在预防致肥胖饮食的代谢后果方面无效，相反，在HFHS喂养的背景下，它可能对代谢健康有害。这是关于长期补充硝酸盐在过量喂养的代谢挑战背景下产生不利影响的首份报告，有必要对这种相互作用的机制进行紧急深入研究。有人提出无机硝酸盐对肥胖相关病症有治疗益处，因为它可提高一氧化氮生物利用度、增强线粒体β-氧化并逆转小鼠的代谢综合征。然而，我们在此表明，在12个月的时间里，硝酸盐在预防高脂高糖喂养小鼠的代谢后果方面无效，且会恶化代谢健康状况，损害胆固醇处理能力，增加心脏纤维化，并加剧脂肪性肝病进展，加速发展为肝细胞癌。
