Mechanisms by which adiponectin reverses high fat diet-induced insulin resistance in mice.
Mechanisms by which adiponectin reverses high fat diet-induced insulin resistance in mice.
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DOI：
10.1073/pnas.1922169117
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发表时间：
2020-12-22
影响因子：
11.1
通讯作者：
Shulman GI
中科院分区：
文献类型：
--
作者：
Li X;Zhang D;Vatner DF;Goedeke L;Hirabara SM;Zhang Y;Perry RJ;Shulman GI
据估计，到2050年，三分之一的美国人将患有2型糖尿病，因此改善胰岛素抵抗的干预措施非常有意义。脂联素已成为一种很有前途的胰岛素增敏脂肪因子；然而，脂联素改善胰岛素敏感性的机制尚不清楚。在这里，我们证明了球状脂联素(GAcrp30)和全长脂联素(Acrp30)通过减少肝脏和肌肉中的异位脂类，可能是通过刺激eWAT中的LPL活性和增加肌肉中eNOS/AMPK的激活和脂肪氧化来逆转高脂饮食小鼠的胰岛素抵抗。这些作用进而导致质膜二酰甘油含量降低，导致肝脏PKCε活性降低，肌肉PKCε/PKCθ活性降低，从而改善这些组织中的胰岛素信号转导。脂联素已成为治疗2型糖尿病的潜在药物，但脂联素逆转胰岛素抵抗的分子机制尚不清楚。两周的球形脂联素(GAcrp30)治疗降低了空腹血糖、甘油三酯(TAG)和胰岛素浓度，逆转了全身胰岛素抵抗，这可能归因于改善了胰岛素介导的内源性葡萄糖生成抑制，以及增加了肌肉和脂肪组织中胰岛素刺激的葡萄糖摄取。肝脏和肌肉敏感度的这些改善与∼使肝脏和肌肉TAG和质膜相关的二酰甘油(DAG)含量减少50%有关，并且与总神经酰胺含量的减少无关。肝脏和骨骼肌中PMDAG含量的减少与肝脏中PKCε易位的减少以及骨骼肌中PKCθ和PKCε易位的减少有关，从而导致胰岛素刺激的胰岛素受体酪氨酸1162磷酸化、IRS-1/IRS-2相关的PI3-K活性和Akt-丝氨酸磷酸化的增加。GAcrp30和全长脂联素(Acrp30)处理均增加肌肉eNOS/AMPK活性和肌肉脂肪酸氧化。注射gAcrp30和Acrp30也增加了附睾白脂肪组织(EWAT)对Tag的摄取，这可能是由于增加了脂蛋白脂酶(LPL)的活性。这些结果表明，脂联素及其相关分子通过减少脂肪在肝脏和肌肉中的异位储存，降低质膜sn-1，2-DAG诱导的nPKC活性，增加胰岛素信号转导，从而逆转脂质诱导的肝脏和肌肉胰岛素抵抗。脂联素通过促进eWAT中TAG的储存，可能是通过刺激LPL以及刺激肌肉中的AMPK，从而增加肌肉脂肪的氧化，从而介导这些效应。
As it is estimated that one in three Americans will suffer from type 2 diabetes by 2050, interventions to ameliorate insulin resistance are of great interest. Adiponectin has emerged as a promising insulin-sensitizing adipokine; however, the mechanisms by which adiponectin administration improves insulin sensitivity are unclear. Here, we show that globular adiponectin (gAcrp30) and full-length adiponectin (Acrp30) reverse insulin resistance in HFD-fed mice through reductions in ectopic lipid in liver and muscle likely by stimulation of LPL activity in eWAT and increased eNOS/AMPK activation and fat oxidation in muscle. These effects, in turn, lead to decreased plasma membrane diacylglycerol content, resulting in decreased PKCε activation in liver and decreased PKCε/PKCθ activity in muscle and improved insulin signaling in these tissues. Adiponectin has emerged as a potential therapy for type 2 diabetes mellitus, but the molecular mechanism by which adiponectin reverses insulin resistance remains unclear. Two weeks of globular adiponectin (gAcrp30) treatment reduced fasting plasma glucose, triglyceride (TAG), and insulin concentrations and reversed whole-body insulin resistance, which could be attributed to both improved insulin-mediated suppression of endogenous glucose production and increased insulin-stimulated glucose uptake in muscle and adipose tissues. These improvements in liver and muscle sensitivity were associated with ∼50% reductions in liver and muscle TAG and plasma membrane (PM)-associated diacylglycerol (DAG) content and occurred independent of reductions in total ceramide content. Reductions of PM DAG content in liver and skeletal muscle were associated with reduced PKCε translocation in liver and reduced PKCθ and PKCε translocation in skeletal muscle resulting in increased insulin-stimulated insulin receptor tyrosine1162 phosphorylation, IRS-1/IRS-2–associated PI3-kinase activity, and Akt-serine phosphorylation. Both gAcrp30 and full-length adiponectin (Acrp30) treatment increased eNOS/AMPK activation in muscle and muscle fatty acid oxidation. gAcrp30 and Acrp30 infusions also increased TAG uptake in epididymal white adipose tissue (eWAT), which could be attributed to increased lipoprotein lipase (LPL) activity. These data suggest that adiponectin and adiponectin-related molecules reverse lipid-induced liver and muscle insulin resistance by reducing ectopic lipid storage in these organs, resulting in decreased plasma membrane sn-1,2-DAG–induced nPKC activity and increased insulin signaling. Adiponectin mediates these effects by both promoting the storage of TAG in eWAT likely through stimulation of LPL as well as by stimulation of AMPK in muscle resulting in increased muscle fat oxidation.
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