| Obesity is a chronic metabolic disease caused by the imbalance of energy metabolism,which leads to the accumulation of excess energy in fat.It is also seriously impairing the life quality and longevity of modern humans.However,there is no effective drug for the prevention or treatment of obesity and its associated metabolic diseases.Therefore,it is of great significance to reveal the pathogeny of obesity and the molecular mechanism of adipose tissue metabolism,in order to solve this public health problem.In the development of obesity,adipose tissue plays an important role in regulating energy balance.In adults and rodents,there are two major categories,white adipose tissue?WAT?and brown adipose tissue?BAT?.Recent studies have found that a new type of adipocyte is diffusely distributed in white adipose tissue,which is called beige adipocyte.Beige adipocytes are produced by white adipose tissue browning,share similar characteristics with brown adipocytes:more mitochondrias and high expression of uncoupling protein 1?UCP1?.UCP1 can uncouple the electron transfer of mitochondrial inner membrane and ATP generation,thereby dissipating a large amount of energy in the form of heat,improving heat production and resisting the occurrence of obesity.Current researches have shown that immune cells in adipose tissue play an important role in regulating adipose tissue thermogenesis.In addition,lipid decomposition and glucose utilization play vital roles in the regulation of browning.The browning of subcutaneous fat not only resists high-fat diet induced obesity by promoting lipolysis,but also increases the uptake and utilization of glucose.Therefore,studying the detailed mechanism of white fat browning will provide important clues for the treatment of obesity and its associated metabolic diseases.Cysteinyl aspartate specific proteinase?Caspase-1?is a key member for the inflammasome and can cleave protein precursors to generate active interleukin-1??IL-1??and interleukin-18?IL-18?.Recent studies have found that Caspase-1 has a wide range of substrate specificity,far beyond the scope of inflammation,which suggests that Caspase-1 may play functions independent of inflammasome.And it has been reported that Caspase-1 can cleave enzymes involved in glycolytic pathways.Most of the existing studies are revolving around obesity and inflammasome comprised of Caspase-1.Studies have shown that Caspase-1 is closely related to lipid metabolism and obesity,but whether Caspase-1 is involved in the browning of white fat induced by cold stimulation in normal mice has not been reported.In this study,cold exposure or treatment with?3-adrenoceptor agonist CL316.243 induced browning of white fat.Wild type?WT?and caspase-1-/-mice were used to explore the relationship and mechanism between Caspase-1 and white fat browning.The results showed that the expression of Caspase-1 was significantly reduced in the subcutaneous white adipose tissue when the mice were induced browning of white fat.Under cold exposure,white adipose tissues from caspase-1-/-mice were more prone to browning.Detection of IL-1?,macrophages polarization,and inflammation-related pathways revealed that promotion of white fat browning in caspase-1-/-mice does not depend on the inflammasome-mediated inflammatory response.We found that activated cyclic adenosine monophosphate?c AMP?signaling led to decreased caspase-1 expression by luciferase report assay.Furthermore,we found that Caspase-1 deficiency could directly upregulate the protein level of pyruvate kinase?glycolysis pathway rate-limiting enzyme?in adipocytes,promote intracellular glycolysis level,and increase the expression of UCP1.In conclusion,Caspase-1 deficiency can promote subcutaneous fat browning and improve heat production level by promoting glycolytic signaling pathways.This study could pave the path for discovering novel strategy to prevent and therapy obesity and metabolic syndrome. |
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