Metformin effectively restores the HPA axis function in diet-induced obese rats.
Metformin effectively restores the HPA axis function in diet-induced obese rats.
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二甲双胍可有效恢复饮食诱导的肥胖大鼠的 HPA 轴功能。
DOI：
10.1038/s41366-020-00688-z
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
MohanKumar PS
中科院分区：
文献类型：
--
作者：
Shin AC;Balasubramanian P;Suryadevara P;Zyskowski J;Herdt TH;MohanKumar SMJ;MohanKumar PS
肥胖患者的下丘脑-垂体-肾上腺(HPA)轴受到干扰。我们先前报道了肥胖倾向(DIO)大鼠脑干存在瘦素抵抗以及中枢去甲肾上腺素能张力和HPA轴之间的脱偶联。二甲双胍被证明可以降低体重和肥胖，但其潜在机制尚不清楚。我们推测这与HPA轴功能的恢复有关。成年雄性DIO大鼠按常规饮食或HF饮食饲养7周。从第4周开始，给动物饮用低剂量(60 mg/kg)或高剂量(300 mg/kg)的二甲双胍。除了体重和进食，我们还检查了HPA轴的不同手臂，以测试二甲双胍是否可以恢复其功能和偶联。为了了解可能的机制，还评估了脑干中的瘦素信号和循环中的游离脂肪酸水平。二甲双胍治疗可降低体重增加、脂肪质量、卡路里摄入量和血清瘦素水平。促肾上腺皮质激素释放激素测定的正中隆起HPA轴活性和血清皮质酮均呈剂量依赖性降低，室旁核去甲肾上腺素(NE)也呈剂量依赖性降低。重要的是，二甲双胍使NE-HPA轴去偶联完全正常化。虽然脑干pSTAT-3和SOCS-3，瘦素信号的关键标记物，在组间没有差异，但循环中饱和和不饱和脂肪酸在喂食HF和二甲双胍治疗的动物中减少。这些发现表明，口服二甲双胍可以成功纠正DIO大鼠HPA轴功能障碍，这与循环中游离脂肪酸的降低有关，从而揭示了二甲双胍治疗肥胖的新作用。
The hypothalamo-pituitary-adrenal (HPA) axis is perturbed in obesity. We previously reported presence of leptin resistance in the brainstem and uncoupling between central noradrenergic tone and the HPA axis in obesity-prone (DIO) rats. Metformin is shown to lower body weight and adiposity, but the underlying mechanism is unclear. We hypothesized that this is associated with restored HPA axis function. Adult male DIO rats were placed on either a regular chow or HF diet for 7 weeks. Starting week 4, the animals were given either a low dose (60mg/kg) or high dose (300mg/kg) of metformin in drinking water. In addition to body weight and feeding, we examined different arms of the HPA axis to test if metformin can reinstate its function and coupling. To understand potential mechanisms, leptin signaling in the brainstem and circulating free fatty acid levels were also assessed. Metformin treatment lowered weight gain, fat mass, caloric intake, and serum leptin levels. HPA axis activity as determined by corticotropin-releasing hormone in the median eminence and serum corticosterone was decreased by metformin in a dose-dependent manner, and so was norepinephrine (NE) in the paraventricular nucleus. Importantly, metformin completely normalized the NE-HPA axis uncoupling. While brainstem pSTAT-3 and SOCS-3, key markers of leptin signaling, were not different between groups, circulating saturated and unsaturated free fatty acids were reduced in HF-fed, metformin-treated animals. These findings suggest that oral metformin can successfully correct HPA axis dysfunction that is associated with lowered circulating free fatty acids in DIO rats, thereby uncovering a novel effect of metformin in the treatment of obesity.
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