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Voluntary feeding induces obesity in broiler breeder hens - collateral effects on cardio- and skelato-muscular functions
|關鍵字:||Broiler breeder hens|
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本研究將白肉種雞分為限飼組與任飼組，餵飼7天或是21天後犧牲採樣。葡萄糖清除率實驗顯示任飼雞隻葡萄糖清除有暫時性遲緩的現象，但最終仍會回復與限飼雞隻相同正常濃度，推論此暫時性的高血糖會經由其他組織代償性清除。以AMPK（AMP-activated protein kinase）的活化檢視組織內的能量狀態，結果顯示胸肌AMPK活性在任飼7與21天後都顯著較低，此顯示胸肌其能量處於充足狀態。不論是7或21天任飼對胸肌三酸甘油脂（TG）堆積皆沒有影響，但carnitine palmitoyltransferase I（CPT1）與diglyceride acyltransferase（DGAT）基因表達提高，此表示任飼導致胸肌過多acyl-CoA可能被導入β-oxidation。任飼雞隻胸肌神經鞘磷（sphingomyeline）含量提高但神經醯胺（ceramide）含量正常，且促發炎因子IL-1β（interleukin-1β）含量高於限飼組僅發生在7天處理組，此顯示任飼雞隻胸肌可能脂肪中毒（lipotoxicity）機制並非透過ceramide與IL-1β達成。而任飼導致胸肌的Akt活化降低，且甚至在主要抗氧化物榖胱甘肽（glutathione）與其氧化態（glutathione disulfide）之比值(GSH/GSSG)亦降低，而超氧歧化酶（superoxide dismutase，SOD）活性顯著高於限飼雞隻，由此推斷過多的游離脂肪酸造成胸肌細胞毒性與後續可能胰島素抗性係由於β-oxidation增強與過多reactive oxygen species（ROS）釋出所引起。與胸肌類似，腿肌AMPK活化在任飼7天後顯著較低，任飼對腿肌TG堆積明顯提高，且提高DGAT但抑制acetyl-CoA carboxylase（ACC）基因表達，而對CPT1沒影響，此表示任飼導致腿肌過多acyl-CoA係因外源性攝入所引起，同時DGAT可能扮演著保護腿肌細胞角色，免於過多acyl-CoA被導入ceramide新生合成途徑或β-oxidation。任飼雞隻腿肌神經鞘磷sphingomyelinc與ceramide含量正常，但21天處理IL-1β含量顯著高於限飼組，此顯示任飼雞隻腿肌脂肪中毒機制可能透過IL-1β達成。而任飼亦導致腿肌Akt活化降低，其SOD活性卻顯著低於限飼雞隻，由此推斷過多的游離脂肪酸造成腿胸肌細胞毒性與胰島素抗性可能是透過IL-1β干擾Akt訊號途徑而達成。任飼對心臟AMPK與Akt活化及IL-1β含量沒有影響，任飼亦提高心臟ceramide與TG含量，也一致性的提高serine palmitoyl transferase（SPT）、sphingomyelinase（SMase），ACC、CPT1與DGAT基因表現，但對sphingomyelin含量沒有影響，這些結果顯示心臟過多acyl-CoA可能被導入ceramide生成途徑與β-oxidation，進而造成細胞毒性。而任飼雞隻心臟SOD活性與inducible nitric oxide synthase（iNOS）基因表達顯著提高，而榖胱甘肽氧化還原比例降低，同時其心臟相對重量、心室肥大程度以及組織切片免疫細胞滲入情形顯著較限飼組高，這些結果顯示過多的游離脂肪酸造成心臟過高氧化壓力與ceramide堆積，而此脂肪中毒的逐步發展可能造成心臟功能失調與肥大的病變。
After decades of genetic selection for rapid growth and high feed conversion rate, the modern broilers developed a tendency to overeat and several undesirable defects, including obesity, fatty liver, ascites, and sudden death. In mammals, the mechanisms linking obesity to metabolic syndrome and mellitus diabetes are well studied. Due to the intrinsic differences in physiology of avian species such as natural hyperinsulinemia and insulin insensitivity of peripheral tissues, however, the mechanisms linking obesity to tissue steatosis are poorly studied. In the study, a series of approaches were undertaken to explore the mechanisms linking obesity to cardio- and skelato-muscular dysfunctions. Broiler breeder hens receiving ad libitum or restricted feeding for 7 or 21 days were sacrificed for analyses. Results showed that overfeeding resulted in a temporarily sluggish plasma glucose clearance rate, suggesting transient insulin resistance but followed by compensatory uptake of blood glucose by some certain tissues/organs. In breast muscle, analyses of AMP-activated protein kinase (AMPK), a sensor of cellular energy status suggested that overfeeding suppressed AMPK activation and thereby indicated fuel saturation in the breast muscle of overfed hens. Breast triglyceride content was not affected by ad libitum feeding but carnitine palmitoyl transferase I(CPT1)and diglyceride acyltransferase(DGAT)transcript abundance were promoted, suggesting that accumulated acyl-CoA may be channeled into β-oxidation. Ad libitum feeding also promoted breast sphingomyelin content, but exerted no effects on ceramide content. Increased IL-1β(interleukin-1β)production only temporarily occurred after ad libitum feeding for 7 days. These results suggest that susceptible lipotoxicity is not mediated by ceramide and IL-1β in the breast muscle. Overfeeding also suppressed breast Akt activation and superoxide dismutase (SOD) activity, despite that glutathione/glutathione disulfide rario (GSH/GSSG) was concomitantly decreased, suggesting that excessive fatty acid-induced cytoxicity and susceptible insulin insensitivity are mediated by enhanced β-oxidation and subsequent electron leakage and reactive oxygen species (ROS) production. Similar to the responses of breast muscle, overfeeding promoted AMPK activation, triglyceride content and DGAT expression in leg muscle, but decreased acetyl-CoA carboxylase (ACC)transcript abundance and exerted no effects on CPT1 expression. These results suggest that accumulated fatty acyl-CoA of leg muscle is derived from exogenous origins and DGAT may function as a cytoprotective mechanism to direct the cellular fatty acids away from ceramide de novo synthesis and β-oxidation. Leg muscle sphingomyelin and ceramide content were not affected, but IL-1β production was significantly increased by ad libitum feeding, suggesting that susceptible lipotoxicity in the leg muscle may be operated through proinflammatory IL-1β production. Overfeeding suppressed leg muscle Akt activation and SOD activity, but had no effects on glutathione redox ratios. Therefore, the cause of excessive fatty acid-induced cytoxicity and susceptible insulin insensitivity in the leg muscle may be attributed to perturbations of Akt signaling by IL-1β. Activation of AMPK and Akt and IL-1β production in the heart were not different between overfed and restricted hens. Ad libitum feeding significantly promoted heart ceramide and TG content consistent with upregulation of serine palmitoyl transferase(SPT), sphingomyelinase(SMase), ACC, CPT1 and DAG transcript abundance, but exerted no effects on sphingomyelin content. These results suggest that excessive acyl-CoA is channeled into ceramide synthesis and β-oxidation leading to lipotoxicity in the heart of overfed hens. Ad libitum feeding also significantly promoted heart SOD activity and inducible nitric oxide synthase(iNOS)transcription, and glutathione redox ratios were significantly decreased. Furthermore, overfeeding also resulted in a higher fractional heart weight, ventricle hypertrophy, and infiltration of immune cells into the cardiomuscular matrices. These results indicate that increased cellular fatty acid availability causes oxidative pressure and ceramide accumulation in the heart, which in turn may render the progression of lipotoxicity leading to cardiomyocyte dysfunction and steatotic hypertrophy. Taken together, ad libitum feeding induces lipotoxic development and susceptible insulin resistance in the skeletal muscle of broiler hens. However, refusal of excessive fuels in the skeletal muscle may shuttle the fuels to other vulnerary organs such as heart leading to higher insults of oxidative stress and ceramide accumulation, which thereby impair heart functionality and induce steatotic hypertrophy.
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