To investigate the effects of glycyl-glutamine (Gly-Gln) on the growth performance and body composition in Yue-Huang broilers, two hundreds and seventy 9-d-old birds were randomly allocated to 3 groups of 90 birds each, incorporating 3 cages per group. All the birds were offered a commercial starter feed supplemented with 0, 0.01 or 0.05 mg Gly-Gln per kg for next 5 weeks, then given a commercial grower feed for another 5 weeks. The results showed that Gly-Gln could not only significantly increase the body weight of Yue-Huang broilers but also enhanced breast muscle and leg muscle yields, while it declined abdominal fat percentage in a dose-dependent manner. The concentration of triglyceride and total cholesterol (T-CHO) in serum and that of T-CHO in pectoralis major muscle were reduced with the up-regulated mRNA expression of peroxisome proliferatoractivated receptors α (PPAR-α) and down-regulated transcript levels of acetyl-CoA carboxylase (ACC) and sterol regulatory element binding protein-2 (SREBP-2).
While resistance exercise effectively improves overall health in diabetic patients, the underlying biological mechanism by which resistance exercise improves metabolic function and glucose homeostasis remain mostly unknown. Previously, we identified a myometabolite-mediated metabolic pathway that is essential for the beneficial effects of resistance exercise on metabolic function. We found that resistance exercise-induced α-ketoglutaric acid (AKG) stimulates muscle hypertrophy and fat loss through 2-oxoglutarate receptor 1 (OXGR1)-dependent adrenal activation. Here, we provided evidence for the beneficial effects of AKG on glucose homeostasis in a diet-induced obesity (DIO) mouse model, which are independent of OXGR1. We showed that circulating AKG levels are negatively correlated with the fraction of blood glycated hemoglobin (HbA1c) in both humans and mice and significantly decreased in DIO mice. Consistently, pharmacological elevation of AKG effectively decreased body weight, blood glucose, and hepatic gluconeogenesis without changing insulin sensitivity and glucose tolerance in DIO mice. Notably, OXGR1KO blocked the inhibitory effects of AKG on body weight but failed to affect AKG’s suppression on blood glucose and hepatic gluconeogenesis, indicating distinct mechanisms for AKG’s regulation on energy balance and glucose homeostasis. In supporting this view, we showed that serpina1e, a member of protease inhibitor serpins superfamily, mediates the direct inhibitory effects of AKG on gluconeogenesis in both in vitro hepatocytes and liver slice. By using a liver-specific serpina1e deletion mouse model, we further demonstrated that liver serpina1e is required for the inhibitory effects of AKG on hepatic gluconeogenesis and hyperglycemia in DIO mice. Finally, we provided in vitro evidence to support a model in which AKG decreases hepatic gluconeogenesis by targeting trimethylation of lysine 27 on histone 3 (H3K27me3) in seprina1e promoter region. Our studies established an important role of AKG in glucose homeostasis, and identified the AKG-serpina1e pathway as potential therapeutic targets to attenuate hyperglycemia.
Background: Fatty liver hemorrhagic syndrome (FLHS) is a chronic hepatic disease which occurs when there is a disorder in lipid metabolism. This disease is often observed in caged laying hens and characterized by a decrease in egg production and dramatic increase of mortality. Salidroside (SDS) is an herbal drug which has shown numerous pharmacological activities, such as protective effects on mitochondrial function, attenuates cell apoptosis and inflammation, and promotes strong antioxidant defense system. We aimed to determine the therapeutic effects of SDS on FLHS in laying hens and investigate the underlying mechanisms through which SDS operates these functions. We constructed oleic acid (OA)-induced fatty liver model in vitro and high-fat diet-induced FLHS of laying hens in vivo.Results: Results indicated that SDS inhibited OA-induced lipid accumulation in chicken primary hepatocytes, increased hepatocyte activity, elevated the mRNA expression of proliferation related genes PCNA, CDK2, and cyclinD1 and increased the protein levels of PCNA and CDK2, as well as decreased the cleavage levels of Caspase-9, Caspase-8, and Caspase-3 and apoptosis in hepatocytes. Moreover, SDS promoted the phosphorylation levels of PDK1, AKT, and Gsk3-β, while inhabited the PI3K inhibitor. Additionally, we found that high-fat diet-induced FLHS of laying hens in vivo resulted in heavier body weight, liver weight, and abdominal fat weight, and severer steatosis in histology, compared with the control group (Con). However, SDS maintained lighter body weight, liver weight, and abdominal fat weight and alleviate hepatic steatosis in Model+SDS group. In addition, high-fat diet-induced FLHS (Model) of laying hens had higher total cholesterol (TC), triglyceride (TG), alanine transaminase (ALT), and aspartate aminotransferase (AST) levels in serum than Con group, while SDS maintained low TC, TG, ALT, and AST levels and high Superoxide dismutase (SOD) activity in Model+SDS group. Moreover, SDS decreased the mRNA expression abundances of PPARγ, SCD, and FAS in liver, whereas increased those of PPARα and MTTP, and decreased the mRNA expression of TNF-α, IL-1β, IL-6, and IL-8 in Model+SDS group.Conclusions: Generally, SDS attenuated OA-induced ROS generation, inhibited lipid accumulation and hepatocyte apoptosis, and promoted hepatocyte proliferation by targeting the pathway PI3K/AKT/Gsk3-β in OA-induced fatty liver model in vitro, and alleviated high-fat diet-induced hepatic steatosis, oxidative stress, and inflammatory response in laying hens in vivo.
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