Study On The Function And Mechanism Of New Endogenous Peptide Hormone Metabolitin

Obesity,nonalcoholic fatty liver disease(NAFLD)and type 2 diabetes mellitus(T2DM)are major metabolic disorders in both developed and developing countries in recent decades,due to excess energy intake and other obesogenic factors.Obesity increases risks of NAFLD,T2 DM,cardiovascular disease and some cancers.More than 90% of obese patients and 70% of T2 DM patients have NAFLD.NAFLD affects 30-40% of the adult population,and about 2.4-12.8% of NAFLD patients with cirrhosis progress to NAFLD-associated hepatocellular carcinoma.Studies have associated these diseases with the worldwide spreading of the Western lifestyle.The abundant fatty acids absorbed in intestines can cause obesity,be accumulated in liver,skeletal muscle and fat tissue,lead to insulin resistance(IR)and contribute to the T2 DM development.Meanwhile,hyperinsulinemia or hyperglycemia accelerate the deterioration of the NAFLD,thus create a ‘vicious circle'.Intestinal absorption may play a critical role in the disease progress,the mechanism underlying deterioration of metabolic disorder remains unknown and still lacks specific medication.Osteocalcin(OCN)is well-known as a bone matrix protein and bone-formation biomarker which mainly originates from osteoblast.In the last decade,it was demonstrated that the uncarboxylated OCN(ucOCN)can regulate glucose metabolism,energy expenditure,increase ?-cell proliferation,insulin expression and secretion,and improve insulin sensitivity in peripheral tissues in mice.Recently,studies have highlighted the decreased serum OCN negatively correlated with the liver functional enzyme and inflammatory markers.And,a few studies have investigated OCN effects on NAFLD development and progression in mice model.These studies have made OCN a potential target for metabolism disorders treatment and received considerable attention,but so far there is no more progress for OCN in this regard.Based on bioinformatic prediction and biological experiments,we have predicted and confirmed a novel circulating peptide hormone derived from osteocalcin in the mouse.The new peptide hormone is nominated as Metabolitin,a contraction of metabolism,from Greek “metabole”,meaning ‘change',the conversion of food or fuel to energy to run cellular processes,metabolite;and –in,word-forming element in chemistry,usually indicating a hormone,neural substance,antibiotic,or vitamin.In sera of mouse,we have detected MTL by high resolution Mass-Spectrometry analysis.We have also confirmed its interacting receptor and bioeffects in the murine obesity-NAFLD-T2 DM model in which MTL can significantly improve hepatosteatosis and insulin resistance.More interestingly,possibly due to its intrinsic structure,enterally absorbed MTL shows similar biological effects and potency as i.p.injected MTL.When MTL interacts with GPRC6 A expressed in intestine,the expression of neurotensin is inhibited,which in turn activates the adenosine 5'-monophosphate-activated protein(AMPK)pathway,then ultimately inhibits lipid absorption in the small intestine.Less absorption of fatty acids in the intestine and suppressed de novo lipid synthesis in the liver through the ACC pathway,together,MTL treatment improved NAFLD and insulin resistance in the mice.