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Abstract
Proper regulation of energy storage in adipose tissue is crucial for maintaining insulin sensitivity and molecules contributing to this process have not been fully revealed. Here we show that type II transmembrane protein tenomodulin (TNMD) is upregulated in adipose tissue of insulin-resistant versus insulin-sensitive individuals, who were matched for body mass index (BMI). TNMD expression increases in human preadipocytes during differentiation, whereas silencing TNMD blocks adipogenesis. Upon high-fat diet feeding, transgenic mice overexpressing Tnmd develop increased epididymal white adipose tissue (eWAT) mass, and preadipocytes derived from Tnmd transgenic mice display greater proliferation, consistent with elevated adipogenesis. In Tnmd transgenic mice, lipogenic genes are upregulated in eWAT, as is Ucp1 in brown fat, while liver triglyceride accumulation is attenuated. Despite expanded eWAT, transgenic animals display improved systemic insulin sensitivity, decreased collagen deposition and inflammation in eWAT, and increased insulin stimulation of Akt phosphorylation. Our data suggest that TNMD acts as a protective factor in visceral adipose tissue to alleviate insulin resistance in obesity.
Highlights
Proper regulation of energy storage in adipose tissue is crucial for maintaining insulin sensitivity and molecules contributing to this process have not been fully revealed
Among several differentially expressed genes identified, we focused on tenomodulin (TNMD), a type II transmembrane protein, due to its high and predominant expression in human adipose tissue, noted by others[31,32]
It was previously demonstrated that white adipose tissue and primary adipocytes have the highest expression of TNMD among human tissues[31]
Summary
Proper regulation of energy storage in adipose tissue is crucial for maintaining insulin sensitivity and molecules contributing to this process have not been fully revealed. Many genome-wide association studies revealed that single-nucleotide polymorphisms in the TNMD gene are associated with various metabolic characteristics such as BMI, serum low-density lipoprotein levels and inflammatory factors[35,36,37] Though these studies indicate a potential role for TNMD in human adipose tissue, the function of TNMD has not been evaluated. By gene silencing and generating a transgenic mouse line, we demonstrate that TNMD is required for adipocyte differentiation, and overexpression of Tnmd in adipose tissue protects mice from obesity-induced systemic insulin resistance. These data suggest that adipocyte TNMD is a protective factor that enhances insulin sensitivity in obesity, potentially via promoting hyperplasia and beneficial lipid storage in the visceral adipose tissue
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