Exploration Of Characteristics Of Traditional Chinese Medicine Constitution In Hypertensive Disorders Of Obesity And Mechanism Of Polyamine Flux Regulates Activation Of Beige Adipocytes

Objective:Observe the distribution characteristics of TCM constitution of overweight/obesity-related hypertensive patients and conduct preliminary analysis.Cold and ?3-adrenergic receptor(AR)agonists activate beige adipocyte biogenesis in white adipose tissue(WAT).The two stimuli also induce expression of inflammatory cytokines in WAT.The low-grade inflammation may further promote WAT browning.However,the mechanisms to reconcile these two biological processes remain to be elucidated.In this study,we aim to investigate the roles of the rate-limiting polyamine catabolic enzyme spermidine/spermine N1-acetyltransferase(SAT1)in regulating beige adipocyte biogenesis and inflammation.Methods:1 Clinical TrialWe recruited all residents over the age of 30 to participate in this study in the station community of Danyang City,Zhenjiang,China.The study lasted from June 3rd,2017 to June 29th,2017 and included 1154 participants.All of them completed the "Clinical Data Information Survey Form".Descriptive statistics were made on the demographics,incidence,auxiliary examination,medication status,and constitution of Traditional Chinese medicine.The collection of complexion,tongue coating,and pulse signals combined with the physical examation instrument in our hospital analyzed the distribution characteristics of Traditional Chinese medicine constitution of hypertensive patients and hypertension-associated abdominal obesity patients,as well as the correlation between indicators of gender,age,visceral fat and them.2 Experimental StudyAdipose-specific SAT1 knockout mice(SAT1-aKO)were generated by crossing adiponectin-cre to SAT1-lox/lox mice.Metabolic phenotype was investigated.Primary pre-adipocytes were isolated from inguinal WAT(iWAT)and differentiated to adipocytes for studying beige adipocyte biogenesis.Result:1 Clinical Trial1)There are differences between the distribution of TCM constitution of hypertensive population and non-hypertensive population.2)There are differences between the distribution of TCM constitution of abdominal obesity related hypertensive population and non-abdominal obesity related hypertensive population.3)The distribution of TCM constitution of abdominal obesity related hypertensive population had the trend related to sex(P=0.07).4)The distribution of TCM constitution of abdominal obesity related obesity related hypertensive population was related to age(P<0.01).5)The distribution of TCM constitution was of abdominal obesity related hypertensive population was related to visceral fat area and subcutaneous fat area(P<0.01),but not relevant to their ratio.6)The distribution of TCM constitution was of abdominal obesity related obesity related hypertensive population was related to visceral fat area(P<0.01),but not relevant to subcutaneous fat area or their ratio.2 Experiment Study1)The expression and enzymatic activity of SAT1 were up-regulated by cold exposure and?3-AR treatment in iWAT.2)SAT1-aKO mice developed late-onset obesity on a high-fat diet with impaired cold-induced beige adipocyte biogenesis and energy expenditure.3)RNA-seq analysis of iMAT from cold-challenged SAT1-aKO mice revealed that,in addition to beige adipocyte biogenesis signatures,the immune response markers were highly enriched among reduced genes.4)In cultured adipocytes,SAT1 overexpression or pharmacological activation with N1,N11-diethylnorspermine(DENSpm)elevated oxygen consumption and increased the expression of beige adipocyte markers UCP1 and PGC-la.5)DENSpm treatment of adipocytes also increased the expression of inflammatory genes.SAT1 activation enhanced hydrogen peroxide production in adipocytes.6)Antioxidant N-acetylcysteine abrogated the elevated UCP1 expression and reversed some inflammatory genes induced by SAT1 activation.7)In differentiated adipocytes,berberine can induce activation of SAT1 and increase the expression of the UCP1 and PGC1-? genes of the beige.8)In adipocytes,down-regulation of SAT1 gene expression can reduce berberine-induced UCP1 gene expression levels.Conclusion:There was a significant difference in the distribution of TCM syndromes between hypertensive patients and non-hypertensive patients,hypertension with abdominal obesity and hypertension with non-abdominal obesity.The correlation between characteristics of physical distribution and sex,age,and visceral fat distribution in hypertension with abdominal obesity population were found.The situation provides a basis for the clinical prevention and treatment of different types of hypertension and abdominal obesity.SAT 1-mediated polyamine catabolism is sufficient and necessary for beige adipocyte biogenesis.This is mediated by the direct effects of SAT1-induced ROS production in adipocytes.SAT 1-induced inflammation and immune cell infiltration may also contribute to the beige adipocyte biogenesis indirectly.Thus,the current study identifies SAT 1-mediate polyamine catabolism as a novel mechanistic node for beige adipocyte biogenesis during cold and ?3-AR stimulation and berberine may regulate the biosynthesis of beige adipocytes through the SAT 1 node.