Effects of Tissue-Specific Manipulation of Nuclear Receptor Interacting Protein 1 on Metabolism and Longevity

Presentation Number: SAT 576
Date of Presentation: April 1st, 2017

Rong Yuan*, Xundi Chen and Jared Osland
Southern Illinois University, Springfield, IL

Abstract

Nuclear receptor protein 1 (NRIP1) is a key regulator of metabolism. Global knockout of Nrip1 significantly improves glucose tolerance and enhances insulin sensitivity. We previously reported that Nrip1 might also be involved in the regulation of aging. We recently confirmed that the global deletion of Nrip1 could significantly extend longevity in mice. However, it has also been reported that global deletion of Nrip1 has deleterious effects, including reduced female fertility, increased risk of colon and liver cancer, and impaired memory. Therefore, in targeting Nrip1 to improve metabolism and extend longevity, the effects of tissue-specific Nrip1 manipulation need to be investigated. To select the targets for tissue-specific deletion, we measured the mRNA expression of Nrip1 in different tissues/organs of mice, at 4, 8, 12, and 21 months of age, as well as in mice under 60% diet restriction and in control mice. The results showed that, in white fat tissue, Nrip1 expression is significantly elevated in aging, but suppressed under diet restriction (p<0.05). Interestingly, the expression pattern is opposite in skeletal muscle, in which the expression of Nrip1 decreased with aging but was elevated under diet restriction. Therefore, we hypothesized that deletion of Nrip1 in white adipose and skeletal muscle might have positive and negative effects, respectively, on metabolism and healthspan. Using the Cre-loxP method, we successfully deleted Nrip1 in white adipose tissue and skeletal muscle. Glucose and insulin tolerance tests, along with glucose simulation assays, were then employed to test the effects on metabolism. Our results showed that deletion of Nrip1 in white adipose tissue significantly increased glucose tolerance, while the deletion of Nrip1 in skeletal muscle significantly reduced glucose tolerance. Significant change was not found by insulin tolerance testing. However, the glucose stimulation study indicated that the deletion of Nrip1 in skeletal muscle significantly reduced insulin sensitivity. The lifespan study found that Nrip1 deletion in skeletal muscle reduced median lifespan by 15%, while the deletion in white adipose tissue increased median lifespan by 10%. Log Rank tests show p < 0.05 for both groups. These results suggest that deletion of Nrip1 in white adipose tissue improves metabolism and extends longevity; but, the deletion of Nrip1 in skeletal muscle has negative effects on metabolism and longevity.

 

Nothing to Disclose: RY, XC, JO