| Background:The study of our group found that the ability of glucose tolerance impaired in the oral glucose tolerance test (OGTT) of chronic mild stress (CMS) rats and their serum insulin significantly reduced. It prompted CMS rats developed insulin resistance. At the same time, we also observed that the free fatty acids (FFA) was increased in serum of CMS rats. A lot of evidence means that peripheral tissue insulin resistance is caused the elevation of FFA in serum. Objective:To explore the causes and mechanisms of the elevation of FFA in CMS rats serum, as well as the therapeutic effects of icariin (Ica) with antidepressants effect, curcumin (Cur), pioglitazone (Pio) with anti-diabetic effect for reducing the level of FFA in the circulation and their possible mechanisms.Method:Weight of250-280g male Wistar rats were adapt to the environment. intake of sucrose/water training for one week. Rats were divided into normal control group (7) and model group (28) with CMS randomly. Normal control group rats were kept under normal conditions. The model group were under the condition of a series of modest, non-repeat-stimulating factor:dirty cage (200mLwater at the end of the cage), no food (14h or18h/time), to change the light cycle (alternating light and dark/2h), noise (6300HZ for10h or12h/time). The intake of sucrose/water (1%) must be measured for all rats weekly from beginning to the end of the experiment. The model group (28) were divided into model group with no treatment(7), model group with Icariin (60mg/kg)(7), model group with Curcumin (20mg/kg)(7), model group with Pioglitazone (4mg/kg)(7), treating for4weeks. Detection indicators:Measured the level of FFA, insulin, corticotropin-releasing hormone (CRF), corticosterone; Measured the ability of glucose tolerance with OGTT; Determinated the mRNA expression of two kinds of the key enzymes in lipid solution:the adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL), peroxisome proliferator-activated receptor gamma (PPARy), Toll-like receptor-4(TLR4), inhibitor the of nuclear factor kappa B (NF-κB), tumor necrosis factor alpha (TNF-alpha), leukocyte interleukin-6(IL-6) of white adipose tissue with polymerase chain reaction Polymerase Chain Reaction (PCR) method. Determinated the protein expression of inhibator of nuclear factor kappa B kinasep (IKKβ), and the level of phosphorylation of IRS-1tyrosine/serine (Tyr/Ser), IKKβserine (Ser).Results:Compared with normal control group, as model CMS rats, the intake of sucrose/water was significantly reduced; the OGTT results showed that the ability of glucose tolerance were impaired; and their serum insulin insignificantly reduced; the level of FFA, CRF, Corticosterone were significantly increased;in the white adipose tissue, the mRNA expression of TLR4, TNF-a, IL-6, NF-kappa B, ATGL, HSL were significantly the rised, but the mRNA expression of PPARy was significantly lower; the protein expression of IKKβ and the level of IKKβserine phosphorylation were both rised; the level of IRS-1Ser phosphorylation was rised significantly, but the level of IRS-1Tyr phosphorylation was reduced. After4weeks administration of therapeutic intervention, compared with model group, the intake of sucrose/water of icariin treatment group and curcumin treatment group rats increased significantly, but the pioglitazone treatment group did not change significantly; the OGTT results show that the ability of glucose tolerance of three treatment group rats were improved, insulin increased insignificantly in serum of curcumin treatment group and pioglitazone treatment group rats, but the insulin increased significantly in serum of icariin treatment group rats; the level of FFA, CRF, Corticosterone in serum of icariin treatment group and curcumin treatment group rats were lower, but pioglitazone have not the effect; the mRNA expression of TLR4, TNF-α, IL-6, NF-kappa B, ATGL, HSL were significantly reduced in white adipose tissue of three treatment group rats, the mRNA expression of ATGL decreased significantly in white adipose tissue of the three treatment group rats except pioglitazone treatment group rats; the mRNA expression of ATGL can not decreased significantly in white adipose tissue of pioglitazone treatment group rats, the mRNA expression of PPARy was significantly lower in white adipose tissue of curcumin treatment group and pioglitazone treatment group rats, but insignificantly in white adipose tissue of icariin treatment group rats; in the the white adipose tissue, the protein expression of IKKβ were all decreased in all treatment groups, the level of phosphorylation of IKKβSer were decreased significantly in white adipose tissue of icariin treatment group and curcumin treatment group rats, but insignificantly in white adipose tissue of pioglitazone treatment group, the level of phosphorylation of IRS-1Ser was reduced significantly in all treatment group rats, the phosphorylation of IRS-1Tyr was increased significantly in icariin treatment group and curcumin treatment group rats, but not significantly in pioglitazone treatment group.Conclusion:The activation of IKKβ/NF-κB inflammatory signaling channel can be caused by TNF-a, IL-6mRNA expression. The activation of IKKβ/NF-κB will inhibit the phosphorylation of IRS-1Try to interfere with insulin signaling channel, resulting in the increasing of mRNA expression of ATGLand HSL. So the lipolysis of white adipose tissue was promoted, causing the elevation of FFA in serum. Icariin, curcumin can inhibit the activity of IKKβ and reduce the generation of FFA in white adipose tissue of CMS rats, reducing the level of FFA in serum. Pioglitazone can promote the mRNA expression of PPARy in white adipose tissue, but can not inhibit the activity of IKKβ. It also can not reduce the level of FFA in circulation of CMS rats. |
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