The Study Of Chrysin On High-fat Diet-related Metabolic Diseases Based On The Mechanisms Of Mast Cell Regulating Obesity And Energy Metabolism

As the main energy storage organ,adipose tissues play an essential role in maintaining energy homeostasis.Besides the typical white adipocytes,there are scattered beige adipocytes that metabolically benefit thermogenesis in white adipose tissue.There also exist stromal vascular fraction(SVF)cells,including immune cells,preadipocytes,and endothelial cells,which crosstalk with adipocytes in control of adipose tissue and systemic energy homeostasis.In 2009,our team first reported that MC plays a critical role in developing obesity and insulin resistance induced by the high-cholesterol Western diet(WD),affecting the white adipose tissue vascularization.However,other following research teams have reported that MC has no apparent role in developing obesity and insulin resistance induced by a high-fat diet(HFD).Therefore,to clarify the effects and mechanisms of mast cells and its dietary stabilizer chrysin in diet-induced obesity(DIO)and associated energy expenditure,we carried out the following three studies.In adipose tissue,besides the adipocytes,there also exist SVF cells,including immune cells,preadipocytes,and endothelial cells,which crosstalk with adipocyte in control of adipose tissue and systemic energy homeostasis.In 2009,our team first reported that MC plays a critical role in developing obesity and insulin resistance induced by the high-cholesterol Western diet(WD),affecting the white adipose tissue vascularization.However,other following research teams have reported that MC has no apparent role in developing obesity and insulin resistance induced by HFD.Therefore,in order to clarify the effects and mechanisms of mast cells and their dietary stabilizer chrysin in DIO and associated energy expenditure,we carried out the following three studies.1)The effects of MC on diet-induced obesity and insulin resistance.We investigated the effects of MC stabilizer DSCG and ketotifen on obesity and insulin resistance in mice fed with WD,HFD,and HFD supplemented with cholesterol(HFD+Cho).In mice fed high-cholesterol diets such as WD and HFD+Cho,DSCG and ketotifen significantly improved obesity and insulin resistance;however,in HFD-fed mice,ketotifen mitigated obesity and insulin resistance considerably less than in those mice fed high-cholesterol diets,while DSCG did not affect.DSCG and ketotifen treatment prevented high cholesterol diet-induced elevation of blood histamine and adipose tissue MC degranulation.Moreover,plasma histamine concentrations were positively correlated with total or low-density lipoprotein cholesterol(LDL).Treatment with LDL significantly activated MC,and DSCG and ketotifen inhibited the LDL-induced MC activation,while LDL receptor deficiency counteracted the effects of DSCG or ketotifen on MC activation induced by LDL.These results suggest that MC plays a crucial role in high-cholesterol diet-induced obesity and insulin resistance,as food-derived cholesterol contributes to the associated MC activation.2)The mechanism of MC regulating white adipose tissue browning and energy expenditure.Since MC plays an inherently critical role in DIO development,it was necessary to uncover its effects on adipocyte browning and associated energy expenditure.Therefore,this study further investigated the changes in systemic energy metabolism and adipose tissue browning levels following MC functional inactivation.MC deficiency or drug stabilization significantly enhanced norepinephrine-induced energy expenditure and promoted subcutaneous adipose tissue(SAT)browning.Reconstitution of MC in the SAT of MC-deficient Kit^w-sh/w-sh mice reversed these changes.Mechanistic studies suggest that MC inactivation actives the proliferation and brown differentiation of SAT PDGFR?⁺adipocyte progenitor cells.Further,we identified MC as a primary source of serotonin in adipose tissue,and MC-derived serotonin inhibited browning and systemic energy expenditure.In conclusion,MC inhibited SAT browning and systemic energy metabolism by releasing serotonin in mice.3)The effect of dietary MC stabilizers chrysin on DIO and energy metabolism in mice.Chrysin is a potent natural MC stabilizer.Using it as a dietary supplement,we found that chrysin improved HFD-induced weight acquire and adipose tissue weight gain in mice and reduced insulin resistance.During this time,chrysin increased systemic energy expenditure,SAT browning and beige preadipocyte recruitments and angiogenesis,and upregulated PDGFR?expression,PDGFR?⁺adipocyte progenitor cell numbers in SAT.Further,we found that chrysin induced brown differentiation of SAT SVF cells,which was reversed by the PDGFR?-specific inhibitor imatinib.Finally,we found that dietary chrysin reduced the level of micro RNA expression that inhibited PDGFR?activation or adipocyte browning in SAT of mice.In conclusion,dietary chrysin initiates SAT browning and systemic energy expenditure by modulating PDGFR?activation and associated micro RNA expression in mice,which improves DIO and insulin resistance.In summary,this paper identifies a crucial role of MC in developing DIO and insulin resistance.The mechanism of MC inhibiting SAT browning and system energy expenditure through the release of serotonin.It was suggested that the dietary MC stabilizer,chrysin,could improve DIO and insulin resistance by regulating the activation of PDGFR?and the associated mi Rs expressions,which initiates the SAT browning program and systemic energy expenditure in mice.