Nagaraj ShreeRanga, Raghavan Angad V, Rao Sudha N, Manjappara Uma V
Department of Protein Chemistry and Technology, CSIR-Central Food Technological Research Institute, Mysore 570020, India.
Genotypic Technology Pvt. Ltd., No. 259, Apoorva, 4th Cross, 80Ft Road, RMV II Stage, Bangalore 560094, India.
Int J Biochem Cell Biol. 2014 Aug;53:414-22. doi: 10.1016/j.biocel.2014.06.006. Epub 2014 Jun 14.
Obestatin, its N-terminal fragment and the N-terminal fragment analog Nt8U were previously shown to reduce food intake, gain in body weight and triglyceride levels in albino mice. To establish their mode of action, mRNA profiling of the epididymal adipose tissue of mice treated with these peptides were performed. The differential expressions were markedly indicative of their involvement in lipid metabolism. Obestatin showed a significant upregulation of the genes patatin-like phospholipase domain containing 3, diacylglycerol O-acyltransferase 2, monoglyceride lipase, aldo-keto reductase family 1, member 7 which are involved in glycerolipid metabolism. It also upregulated peroxisome proliferator-activated receptor gamma, retinoid X receptor gamma, cluster of differentiation 36, adiponectin, C1Q and collagen domain containing, angiopoietin-like 4, lipoprotein lipase, stearoyl-coenzyme A and desaturase 3 involved in the peroxisome proliferator-activated receptor signaling pathway. Nt8U upregulated genes implicated in the same two pathways but with lesser significance and also upregulated APOL2. The N-terminal fragment though differentially regulated a small subset of the genes differentially regulated by obestatin and Nt8U, no conclusive evidence was obtained as to assign a specific pathway for its mode of action. We hypothesize that reduced food intake brought about by obestatin and Nt8U triggers lipid catabolism. The free fatty acids and lysophosphatidic acid thus produced in turn activates peroxisome proliferator-activated receptor gamma and the genes involved in peroxisome proliferator-activated receptor signaling. All of them together lead to reduction in gain in bodyweight, stored fat and circulating lipids. These results also correlate well with the observed efficacy of the peptides.
肥胖抑制素、其N端片段以及N端片段类似物Nt8U先前已被证明可降低白化小鼠的食物摄入量、体重增加和甘油三酯水平。为了确定它们的作用模式，对用这些肽处理的小鼠附睾脂肪组织进行了mRNA谱分析。差异表达明显表明它们参与脂质代谢。肥胖抑制素显示出参与甘油olipid代谢的含patatin样磷脂酶结构域3、二酰基甘油O-酰基转移酶2、单酰基甘油脂肪酶、醛糖酮还原酶家族1成员7等基因的显著上调。它还上调了参与过氧化物酶体增殖物激活受体信号通路的过氧化物酶体增殖物激活受体γ、视黄醇X受体γ、分化簇36、脂联素、含C1Q和胶原结构域、血管生成素样4、脂蛋白脂肪酶、硬脂酰辅酶A去饱和酶3。Nt8U上调了涉及相同两条途径但意义较小的基因，还上调了APOL2。N端片段虽然差异调节了肥胖抑制素和Nt8U差异调节的一小部分基因，但没有获得确凿证据来确定其作用模式的特定途径。我们假设肥胖抑制素和Nt8U引起的食物摄入量减少会触发脂质分解代谢。由此产生的游离脂肪酸和溶血磷脂酸反过来激活过氧化物酶体增殖物激活受体γ和参与过氧化物酶体增殖物激活受体信号传导的基因。所有这些共同导致体重增加、储存脂肪和循环脂质的减少。这些结果也与观察到的肽的功效密切相关。
