Am J Physiol Endocrinol Metab. 2024 Apr 03.
Shijun Wei,
Yu Song,
Zhengbin Li,
Ai Liu,
Yunfang Xie,
Shang Gao,
Hongbiao Shi,
Ping Sun,
Zekun Wang,
Yecheng Jin,
Wenjie Sun,
Xi Li,
Jiangxia Li,
Qiji Liu.
OBJECTIVE: Obesity has become a major risk of global public health. SMEK1 is also known as a regulatory subunit of protein phosphatase 4 (PP4). Both PP4 and SMEK1 have been clarified many metabolic functions, including regulating the hepatic gluconeogenesis and glucose transporter gene expression in yeast. Whether SMEK1 participates in obesity and the broader metabolic role in mammals is unknown. Thus we investigated the function of SMEK1 in white adipose tissue and glucose uptake.
METHODS: GWAS/GEPIA/GEO database was used to analyze the correlation between SMEK1 and metabolic phenotypes/lipid metabolism related genes/obesity. Smek1 KO mice were generated to identify the role of SMEK1 in obesity and glucose homeostasis. Cell culture and differentiation of SVFs and 3T3-L1 were used to determine the mechanism. 2-NBDG was used to measure the glucose uptake. Compound C was used to confirm the role of AMPK.
RESULTS: We elucidated that SMEK1 was correlated to obesity and adipogenesis. Smek1 deletion enhanced adipogenesis in both SVFs and 3T3-L1. Smek1 KO protected mice from obesity, had protective effects on metabolic disorders including insulin resistance and inflammation. Smek1 KO mice have lower level of fasting serum glucose, we found that SMEK1 ablation promoted glucose uptake by increased p-AMPKα(T172) and the transcription of Glut4, when the effect on AMPK-regulated glucose uptake was due to the PP4 catalytic subunits (PPP4C).
CONCLUSION: Our findings reveal a novel role of SMEK1 in obesity and glucose homeostasis, providing a potential new therapeutic target for obesity and metabolic dysfunction.
Keywords: AMP-activated protein kinase; Adipogenesis; Glucose uptake; Obesity; SMEK1