Natriuretic peptides/cGMP/cGMP-dependent protein kinase cascades promote muscle mitochondrial biogenesis and prevent obesity.
Natriuretic peptides/cGMP/cGMP-dependent protein kinase cascades promote muscle mitochondrial biogenesis and prevent obesity.
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作者：
Miyashita K;Itoh H;Tsujimoto H;Tamura N;Fukunaga Y;Sone M;Yamahara K;Taura D;Inuzuka M;Sonoyama T;Nakao K
利钠肽（NPs）是一类通过鸟苷酸环化酶（GC）、环鸟苷酸（cGMP）和cGMP依赖性蛋白激酶（cGK）调节血管紧张度的血管激素。最近的临床研究表明，血浆NP水平较低的代谢综合征的主题。本研究旨在阐明NP/cGK级联在能量代谢中的作用。我们使用了三种类型的基因工程小鼠：脑NP（BNP）转基因（BNP-Tg）、cGK-Tg和鸟苷酸环化酶-A（GCA）杂合敲除（GCA+/−）小鼠，并分析了体内NP/cGK级联慢性激活的代谢后果。我们还研究了NPs在培养的心肌细胞中的作用。高脂饮食喂养的BNP-Tg小鼠可以防止饮食诱导的肥胖和胰岛素抵抗，而cGK-Tg小鼠即使在标准饮食下体重也有所减轻;令人惊讶的是，骨骼肌中密集地堆积着巨大的线粒体。通过上调过氧化物酶体增殖物激活受体（PPAR）-γ共激活因子（PGC）-1α和PPARδ，两只小鼠均显示肌肉线粒体含量和脂肪氧化增加。功能性NP受体GCA和鸟苷酸环化酶B通过喂食高脂饮食下调，而GCA+/−小鼠在喂食高脂饮食时表现出体重增加和葡萄糖耐受不良。NPs直接增加培养心肌细胞PGC-1α和PPARδ的表达及线粒体含量。这些发现共同表明，NP/cGK级联可以促进肌肉线粒体生物合成和脂肪氧化，以防止肥胖和葡萄糖耐受不良。血管激素NP将有助于协调氧供应和消耗的调节。
Natriuretic peptides (NPs) have been characterized as vascular hormones that regulate vascular tone via guanylyl cyclase (GC), cyclic GMP (cGMP), and cGMP-dependent protein kinase (cGK). Recent clinical studies have shown that plasma NP levels were lower in subjects with the metabolic syndrome. The present study was conducted to elucidate the roles for NP/cGK cascades in energy metabolism. We used three types of genetically engineered mice: brain NP (BNP) transgenic (BNP-Tg), cGK-Tg, and guanylyl cyclase-A (GCA) heterozygous knockout (GCA+/−) mice and analyzed the metabolic consequences of chronic activation of NP/cGK cascades in vivo. We also examined the effect of NPs in cultured myocytes. BNP-Tg mice fed on high-fat diet were protected against diet-induced obesity and insulin resistance, and cGK-Tg mice had reduced body weight even on standard diet; surprisingly, giant mitochondria were densely packed in the skeletal muscle. Both mice showed an increase in muscle mitochondrial content and fat oxidation through upregulation of peroxisome proliferator–activated receptor (PPAR)-γ coactivator (PGC)-1α and PPARδ. The functional NP receptors, GCA and guanylyl cyclase-B, were downregulated by feeding a high-fat diet, while GCA+/− mice showed increases in body weight and glucose intolerance when fed a high-fat diet. NPs directly increased the expression of PGC-1α and PPARδ and mitochondrial content in cultured myocytes. The findings together suggest that NP/cGK cascades can promote muscle mitochondrial biogenesis and fat oxidation, as to prevent obesity and glucose intolerance. The vascular hormone, NP, would contribute to coordinated regulation of oxygen supply and consumption.