A Functional And Mechanistic Study Of The Regulation Of Brown And Beige Adipose Tissue By REGγ Through The PKA-CREB Signaling Axis

Obesity and its metabolic syndrome have a complex etiology and widespread prevalence,posing a serious threat to the health of all humans.Obesity is manifested by excessive or abnormal fat accumulation,and adipose tissue is an important organ for the energy balance of lipid metabolism.At present,it has been found that human adipose tissue can be broadly divided into three categories: white adipose tissue,which is responsible for energy storage;and brown adipose tissue,which is responsible for heat production;and another type of adipose tissue is beige adipose tissue,which is found in white adipose tissue and has brown-like adipocyte characteristics.In recent years,studies have shown that enhancing the function of brown adipose tissue,promoting the browning of white adipose tissue,that is,promoting the differentiation and development of beige adipose tissue,can enhance the energy metabolism of the body,alter the balance between energy intake and expenditure,which is recognized as a kind of obesity therapeutic thought with significant potential.REGγ is a member of the 11 s proteasome activator family,which is involved in ubiquitin-and ATP-independent protein degradation pathway.REGγ-proteasome regulation of physiological and pathological processes in various signaling pathways is gradually being revealed.However,the biological function of REGγ in adipose tissue is currently unknown.It is observed in this dissertation that,compared with wild-type mice,REGγ whole body knockout mice alleviate the excessive fat deposition and metabolism decline due to aging.The REGγ adipose tissue specific knockout mice,constructed by Cre-Lox P system,have increased basal metabolic rate,and can resist obesity and metabolic disorders induced by high fat diet.Furthermore,our research found that there is a cell autonomous approach,and that the loss of REGγ enhanced adipogenic differentiation of brown and beige adipocytes,increased the expression of thermogenic genes and mitochondrial functional genes,and improved mitochondrial function and cellular metabolism.Molecular mechanism studies showed that REGγ could interact with PKAcα and mediate its degradation,thereby affecting CREB1 phosphorylation,and negatively regulating the transcriptional expression of downstream thermogenic genes such as UCP1,PGC1α and others.In summary,this dissertation has identified REGγ as a key negative regulator of brown and beige adipose tissue function,and elucidated the molecular mechanism of REGγ negative regulation of brown and beige adipose tissue function through PKACREB signal axis.These results provide a basis for further understanding of lipid metabolism,and for the development of therapies of obesity and metabolic disorders targeting REGγ-proteasome.