The Effect Of Liraglutide Intervention On Body Weight, Serum Lipid, Expressions Of Hypothalamic Inflammatory Cytokines In High-fat Diet Induced Obese Rats

BackgroudsIn recent years, with the changes of the lifestyle and the improvements of livingstandards, overweight and obesity has spread rapidly, and become a major healthproblem worldwide. In addition to the fat accumulation, obesity also plays a crucialrole in the development of type2diabetes mellitus, impaired glucose tolerance,hypertention, atherosclerosis, hypertriglyceridemia, non-alcoholic fatty liver diseaseand other metabolic disorders. Therefore, it is of great significance to explore safe,effective, well toleratable drugs with the capacity to reduce the risk of obesity-relateddiseases.Central nervous system (CNS), especially the hypothalamus, is considered tohave a decisive role in maintaining the body’s metabolic balance homeostasis.Thehypothalamus possess a variety of complex neural networks,modulating central andperipheral energy homeostasis by neuropeptides and neurotransmitters. However,many chronic metabolic diseases, such as obesity, T2DM, hypertension andatherosclerosis, et al, usually associated with a state of chronic low-gradeinflammation. Interdisciplinary researches have found that overnutrition could induce systematic immunological changes, including the activation of hypothalamicproinflammatory IKKβ, NF-κB and other molecules. It is believed that inflammatorypathological processes persist throughout the metabolic syndrome, suggesting thatinhibition of hypothalamic inflammatory signaling pathways is crucial for thetreatment of obesity and other metabolic syndrome.Novel antidiabetic drug Liraglutide is a glucagon like peptide-1(GLP-1) receptoragonist, which promotes insulin release in a glucose-dependent manner. It hasaroused wide concern that besides the pancreatic effect, Liraglutide also haveextrapancreatic functions,for example, protecting islet β cells, suppressing appetiteand food intake, contributing to weight loss, which may benefit obese patients.Whether Liraglutide could prevent the occurrence of metabolic disorders and obesity,through inhibiting of hypothalamic pathway, needs further study.ObjectiveTo investigate effects of Liraglutide intervention on body weight, serum TC andTG, expressions of hypothalamic inflammatory cytokines NF-κB and SOCS3withinhigh-fat diet induced obese SD rats.MethodsForty-eight5-week-old male SD rats were housed with regulated temperature（22±2）℃and humidity（50±10）%on a daily cycle of12h light and darkness.Allrats were allowed adlibitum aecess to water and food during the experimental period.After a week acclimation, all rats were randomly divided into two groups, includingnormal diet (NC，n=8) group, and a high-fat diet (HF,n=40) group. At the end of8thweek, rats that fed high-fat diet with body weights more than x+1.96s of NC groupwere classified as high fat diet induced obesity (DIO) group.Then subdivided DIOgroup into two groups, including a liraglutide-treated (DIO-Lira) subgroup and asaline-treated (DIO-saline) subgroup. The body weights and concentration oftriglyceride (TG) and total cholesterol (TC) of NC and DIO group were measured atthe end of8thweek. In the following8weeks, rats in DIO-Lira group receive 100μg/kg Liraglutide (intraperitoneal injection, ip) twice a day, DIO-saline and NCgroup receive the same volume saline (ip) twice a day. At the end of the16thweek, allgroups were sacrificed. Each rat of three groups were weighted, and serum TC andTG was evaluated by Elisa，expressions of NF-κB mRNA and SOCS3protein inhypothalamus were respectively measured by RT-PCR and Western blot method.Results1. After8weeks saturated fat enriched high fat diet feeding, seventeen rats of HFgroup were classified as DIO rats, and the incidence of obesity was42.5%. The bodyweight and serum TC and TG of DIO rats was significantly increased compared toNC rats(P＜0.01).2. At the end of16thweek, body weight combine with serum TC and TG andhypothalamic NF-κB mRNA，SOCS3protein expression in DIO-saline rats wassignificantly increased compared to NC and DIO-Lira group rats(P＜0.01).Compared to NC rats, body weight, serum TC and TG and hypothalamic NF-κBmRNA，SOCS3protein expression in DIO-Lira rats were still significantly increased(P＜0.01).Conclusion1. Saturated fat enriched high fat diet feeding could induce obesity in SD rats.2. High fat diet could induce obesity and dyslipidemia through upregulatingexpression of proinflammatory factors,including NF-κB gene and SOCS3protein.3. Liraglutide treatment may ameliorate the body weight gain and dyslipidemiain high-fat diet induced obese rats, and the protective mechanism might involve theimprovement of inflammatory signaling pathways in hypothalamic.