肥胖代表着重大的健康挑战,与II型糖尿病等疾病有着错综复杂的联系,代谢综合征,和肝脏脂肪变性.几种现有的肥胖治疗方法表现出有限的疗效,不良副作用或长期维持治疗效果的能力有限。最近,调节辅酶Q(CoQ)代谢已成为治疗代谢综合征的有希望的靶标。这种潜在的干预可能涉及通过使用其生物合成前体的类似物来调节内源性CoQ生物合成,例如β-间苯二酸(β-RA)。这里,我们显示口服补充β-RA,纳入饮食诱导的肥胖(DIO)小鼠的饮食中,导致体重大幅下降。通过使白色脂肪组织(WAT)中线粒体CoQ代谢正常化,部分阐明了β-RA的抗肥胖作用。此外,我们确定了肝脏脂质代谢的HFN4α/LXR依赖性转录组激活,这有助于β-RA的抗肥胖作用。因此,β-RA减轻WAT肥大,预防肝脏脂肪变性,抵消WAT和肝脏的代谢异常,并通过降低胰岛素/胰高血糖素比率和胃抑制肽(GIP)的血浆水平来增强葡萄糖稳态。此外,β-RA的药代动力学评估支持其翻译潜力。因此,β-RA作为一种有效的,安全,以及用于治疗和/或预防肥胖症的可翻译的治疗选择,代谢功能障碍相关脂肪变性肝病(MASLD)。
Obesity represents a significant health challenge, intricately linked to conditions such as type II diabetes, metabolic syndrome, and hepatic steatosis. Several existing obesity treatments exhibit limited efficacy, undesirable side effects or a limited capability to maintain therapeutics effects in the long-term. Recently, modulation Coenzyme Q (CoQ) metabolism has emerged as a promising target for treatment of metabolic syndrome. This potential intervention could involve the modulation of endogenous CoQ biosynthesis by the use of analogs of the precursor of its biosynthesis, such as β-resorcylic acid (β-RA). Here, we show that oral supplementation with β-RA, incorporated into the diet of diet-induced obese (DIO) mice, leads to substantial weight loss. The anti-obesity effects of β-RA are partially elucidated through the normalization of mitochondrial CoQ metabolism in white adipose tissue (WAT). Additionally, we identify an HFN4α/LXR-dependent transcriptomic activation of the hepatic lipid metabolism that contributes to the anti-obesity effects of β-RA. Consequently, β-RA mitigates WAT hypertrophy, prevents hepatic steatosis, counteracts metabolic abnormalities in WAT and liver, and enhances glucose homeostasis by reducing the insulin/glucagon ratio and plasma levels of gastric inhibitory peptide (GIP). Moreover, pharmacokinetic evaluation of β-RA supports its translational potential. Thus, β-RA emerges as an efficient, safe, and translatable therapeutic option for the treatment and/or prevention of obesity, metabolic dysfunction-associated steatotic liver disease (MASLD).