Abstract
Insulin receptor signaling is crucial for white adipose tissue (WAT) function. Consequently, lack of insulin receptor (IR) in WAT results in a diabetes-like phenotype. Yet, causes for IR downregulation in WAT of patients with diabetes are not well understood. By using multiple mouse models of obesity and insulin resistance, we identify a common downregulation of IR with a reduction of mRNA expression of selenoproteins Txnrd3, Sephs2, and Gpx3 in gonadal adipose tissue. Consistently, GPX3 is also decreased in adipose tissue of insulin-resistant and obese patients. Inducing Gpx3 expression via selenite treatment enhances IR expression via activation of the transcription factor Sp1 in 3T3-L1 preadipocytes and improves adipocyte differentiation and function. Feeding mice a selenium-enriched high-fat diet alleviates diet-induced insulin resistance with increased insulin sensitivity, decreased tissue inflammation, and elevated IR expression in WAT. Again, IR expression correlated positively with Gpx3 expression, a phenotype that is also conserved in humans. Consequently, decreasing GPx3 using siRNA technique reduced IR expression and insulin sensitivity in 3T3-L1 preadipocytes. Overall, our data identify GPx3 as a potentially novel regulator of IR expression and insulin sensitivity in adipose tissue.
Highlights
The steadily increasing occurrence of obesity with concomitant insulin resistance and adipocyte dysfunction constitutes a serious health problem worldwide
We show that a combination of hyperglycemia, long-term insulin resistance, and obesity, but not short-term insulin resistance, in a variety of animal models, is linked to reduced insulin receptor (IR) and selenoprotein Gpx3, selenophosphate synthetase 2 (Sephs2), and thioredoxin reductase 3 (Txnrd3) mRNA expression in adipose tissue
To determine whether obesity, altered leptin, or insulin caused a reduction of IR expression in adipose tissue, we investigated IR expression in gonadal white adipose tissue of obese, diabetic, and ovariectomy-induced insulin-resistant mice (16 weeks of age) and C57BL/6N mice fed an high-fat diet (HFD) for 3 days or 12 weeks
Summary
The steadily increasing occurrence of obesity with concomitant insulin resistance and adipocyte dysfunction constitutes a serious health problem worldwide. A common feature is the presence of low-grade inflammation and oxidative stress in tissues of obese, insulin-resistant animals and patients [1]. More than 40 years ago, it was observed that insulin receptor (IR) expression is downregulated in obese humans and diabetic patients [5, 6] This downregulation is present in adipocytes of patients with diabetes and insulin-resistant animals [7, 8]. Loss of IR expression in adipose tissue results in both diabetes and a marked reduction in white adipose tissue mass [10] These data indicate that counteracting the decline in IR expression and finely balancing oxidants during obesity development can improve metabolism
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
