Study On The Efficacy Of Ophioposide D In The Treatment Of Obesity And Related Diseases In Mice Induced By High-fat Diet

Obesity is a typical chronic disease characterized by abnormally excess fat accumulation in adipose tissue and other organs such as heart,liver and skeletal muscle.Obesity is accompanied by metabolic complications,such as hyperglycemia,hyperlipidemia,insulin resistance,fatty liver,etc.,and is one of the main contributors to cardiovascular diseases.Nowadays,obesity has become a serious global epidemic,which poses a huge threat to human health.The prevalence of obesity is increasing not only in adults,but also in children and adolescents.Therefore,prevention and treatment of obesity and its complications is one of the major challenges for the modern society and the medical profession.Although the fundamental cause of obesity is a positive imbalance between energy intake and energy expenditure,the etiology of the disease is multifactorial,involving complex interactions among environmental,psychological,genetic and behavioral factors.Obesity involves a variety of tissue and organ dysfunction.First of all,adipose tissue expansion plays an essential role in the pathogenesis of obesity.With the development of obesity,adipocytes increase their volume(hypertrophy)and number(hyperplasty)in the subcutaneous and visceral white adipose tissue(WAT),and the infiltrated macrophages also increase.In particular,central obesity which caused by visceral fat accumulation is more harmful and has a closer correlation to metabolic syndrome than the peripheral obesity caused by subcutaneous fat accumulation.With amplification of adipose tissue,it produces large amounts of cytokines,including free fatty acids(FFA),pro-inflammatory factors(i.e.TNF-?,IL-6,IL-1? and MCP-1),hormones(i.e.leptin and resistin)and reactive oxygen species(ROS),which promote the occurrence of chronic low-grade inflammation and insulin resistance,and then induce type 2 diabetes.Secondly,excessive FFA secretion will lead to increased triglycerides(TG)content in the liver,and promotes the formation of fatty liver.Under the condition of hyperglycemia and hyperinsulinemia induced,by insulin resistance,transcription factors involved in lipid synthesis such as SREBP-lc,ChREBP and PPARy are activated,then promote the expression of downstream lipogenic genes(i.e.FAS,ACC,SCD),which induce TG accumulation in liver and further lead to fatty liver.Finally,FFA can reduce the secretion of high density lipoprotein(HDL)synthesis and increased low density lipoprotein(LDL)synthesis.Moreover,increased TG content in the liver will promote the form and secretion of very low density lipoprotein(VLDL)into the circulation to peripheral tissues for utilization or storage.However,in obesity,lipoprotein lipase(LPL)activity in peripheral tissues was inhibited,leading to TG-rich VLDL accumulate in the blood.At the same time,blood levels of LDL-C increases and HDL-C declines.All of these processes result in hyperlipidemia,which will further increase the risk of cardiovascular diseases such as atherosclerosis.Medicinal plants have been used as a traditional treatment for several hundred years.Ophiopogon japonicus is an important traditional Chinese herbal medicine,which is widely used for treatment of various cancers,inflammatory diseases,hepatitis,diarrhea and other syndromes in some East Asian countries including China,South Korea and Japan.It contains a lot of steroidal saponins,in which ophiopogonin D(OpD)is the major pharmacologically active component isolated from the root of Ophiopogon japonicus.Previous studies have found that OpD has a variety of pharmacological effects,including anti-inflammation and anti-oxidation,anti-thrombosis,and so on.In recent years,researchers have made further investigations on its functions,and found its new properties including anti-osteoporosis,preventing tumor metastasis and protecting heart.However,it is not yet known whether OpD also has metabolic benefits,such as improving glucose and lipid metabolism.We constructed a high-fat diet(HFD)-induced obese mouse model,and studied the effects of intragastric administration of OpD on HFD-induced obesity and its related metabolic abnormalities.Our results showed that treatment with OpD for 8 weeks reduced the weight gain of obese mice and inhibited the lipid accumulation in liver and WAT.RT-qPCR and Western Blot experiments confirmed obvious inhibitory effects of OpD on HFD-induced mRNA and protein expression of lipogenic gene such as SREBP-lc,PPARy and FAS in liver,which may be a mechanism by which OpD alleviated mouse fatty liver.GTT,ITT and PTT results suggested that OpD dose-dependently improved glucose intolerance,insulin resistance and inhibited glucose production in animals.In addition,OpD also improved HFD-induced hyperlipidemia and chronic inflammation to some extent,evidenced by the facts that OpD dose-dependently decreased the levels of serum lipids such as TG,TC and LDL-C and inflammatory cytokines such as TNF-a and MCP-1.In summary,our study found that OpD had a significant anti-obesity effect on diet-induced obesity.It antagonized inflammation and improved glucose and lipid metabolism,thus achieving a systemic improvement in metabolic dysfuction.Our results suggest that OpD is a promising monomer to treat obesity and provide a theoretical basis for the comprehensive utilization of Ophiopogon japonicus extract.Our study also raises possibilities for further development of natural compunds in the prevention or treatment of obesity and its related diseases.