Adi Nikhil, Adi Jennipher, Lassance-Soares Roberta Marques, Kurlansky Paul, Yu Hong, Webster Keith A
Department of Molecular and Cellular Pharmacology, Miller School of Medicine, University of Miami, Miami, FL.
Vascular Biology Institute, Miller School of Medicine, University of Miami, Miami, FL.
J Diabetes Metab. 2016 Jun;7(6). doi: 10.4172/2155-6156.1000676. Epub 2016 Jun 16.
NONcNZO10 (NZ10) mice are predisposed to obesity and develop type 2 diabetes (T2D) and hepatic steatosis even when maintained on a control diet (CD) of 6% fat. Studies were designed to determine whether this extreme susceptibility phenotype could be alleviated by diet and if so the molecular targets of diet.
NZ10 and SWR/J (SWR) control mice were fed a CD or a test diet of high protein and fish oil (HPO) for 19 weeks and then analyzed for steatosis, blood chemistry, hepatic gene and micro-RNA expression.
HPO diet prevented steatosis, significantly increased serum adiponectin and reduced serum cholesterol and triglycerides only in NZ10 mice. The HPO diet repressed hepatic expression of fatty acid metabolic regulators including PPAR-γ, sterol regulatory element-binding protein-c1, peroxisome proliferator-activated receptor gamma co-activator-1, fatty acid synthase, fatty acid binding protein-4, and apolipoprotein A4 genes only in NZ10 mice. Also repressed by a HPO diet were adiponectinR2 receptor, leptin-R, PPAR-α, pyruvate dehydrogenase kinase isoforms 2 and 4, AKT2 and GSK3β. Micro-RNA (miR) arrays identified miRs that were diet and/or genetics regulated. QRTPCR confirmed increased expression of miR-205 and suppression of a series of miRs including miRs-411, 155, 335 and 21 in the NZ10-HPO group, each of which are implicated in the progression of diabetes and/or steatosis. Evidence is presented that miR-205 co-regulates with PPARγ and may regulate fibrosis and EMT during the progression of steatosis in the livers of NZ10-CD mice. The dietary responses of miR-205 are tissue-specific with opposite effects in adipose and liver.
The results confirm that a HPO diet overrides the genetic susceptibility of NZ10 mice and this correlates with the suppression of key genes and perhaps micro-RNAs involved in hyperglycemia, dyslipidemia and inflammation including master PPAR regulators, adiponectin and leptin receptors.
NONcNZO10（NZ10）小鼠易患肥胖症，即使维持在6%脂肪的对照饮食（CD）条件下，也会发展为2型糖尿病（T2D）和肝脂肪变性。本研究旨在确定这种极端易感性表型是否可以通过饮食得到缓解，如果可以，饮食的分子靶点是什么。
给NZ10和SWR/J（SWR）对照小鼠喂食CD或高蛋白和鱼油（HPO）的试验饮食19周，然后分析脂肪变性、血液生化、肝脏基因和微小RNA表达情况。
HPO饮食仅在NZ10小鼠中预防了脂肪变性，显著增加了血清脂联素，并降低了血清胆固醇和甘油三酯。HPO饮食仅在NZ10小鼠中抑制了包括PPAR-γ、固醇调节元件结合蛋白-c1、过氧化物酶体增殖物激活受体γ共激活因子-1、脂肪酸合酶、脂肪酸结合蛋白-4和载脂蛋白A4基因在内的脂肪酸代谢调节因子的肝脏表达。脂联素R2受体、瘦素-R、PPAR-α、丙酮酸脱氢酶激酶同工型2和4、AKT2和GSK3β也被HPO饮食抑制。微小RNA（miR）阵列鉴定出受饮食和/或基因调控的miR。定量逆转录聚合酶链反应（QRTPCR）证实，在NZ10-HPO组中，miR-205表达增加，而包括miR-411、155、335和21在内的一系列miR受到抑制，这些miR均与糖尿病和/或脂肪变性的进展有关。有证据表明，miR-205与PPARγ共同调节，可能在NZ10-CD小鼠肝脏脂肪变性进展过程中调节纤维化和上皮-间质转化（EMT）。miR-205的饮食反应具有组织特异性，在脂肪和肝脏中具有相反的作用。
结果证实，HPO饮食克服了NZ10小鼠的遗传易感性，这与抑制参与高血糖、血脂异常和炎症的关键基因以及可能的微小RNA有关，包括主要的PPAR调节因子、脂联素和瘦素受体。
