FAM3A drives uncoupling of muscle lipid accumulation and insulin resistance depending on insulin receptor.

Obesity-associated insulin resistance (IR) is closely related to intramyocellular lipid accumulation in skeletal muscle. FAM3 metabolism regulating signaling molecule A (FAM3A) is expressed and secreted in almost all tissues. However, its biological roles and underlying mechanisms remain largely unknown. Here, we reported that abnormal lipid metabolism decreased the FAM3A level. To investigate the function of FAM3A, a transgenic mouse strain was generated, in which FAM3A protein was overexpressed systemically. Proteomic analyses revealed that proteins related to lipid metabolic processes, specifically fatty acid (FA) synthesis complex enzymes and adiponectin were upregulated in the skeletal muscles of the FAM3A-transgenic mice compared with those in the skeletal muscles of the wild-type control mice. Furthermore, a positive correlation between FAM3A and adiponectin levels was observed in patient plasma samples. FAM3A transgene or FAM3A injection in high-fat diet (HFD)-fed mice led to increased levels of muscular srebp1, fas, acc, and acly expression, De novo FA biosynthesis, and lipid accumulation compared with those in matched controls. However, FAM3A transgene or FAM3A injection suppressed IR and inflammation and promoted glucose consumption in HFD-fed mice. Moreover, these functions of FAM3A were attenuated by the inhibition of PPARα. Notably, the inhibition of the insulin receptor abolished the linkage of FAM3A and PPARα as well as their downstream metabolic effects. Taken together, these findings suggest that increasing FAM3A expression in the body may represent a unique opportunity to avoid IR in individuals with obesity induced by high lipid levels.