Diabetes is a leading cause of morbidity and death in the United States. Obesity is a major risk factor for the most common form of diabetes; type 2 diabetes which is characterized by resistance to the actions of insulin. Recently a nuclear hormone receptor, PPAR-gamma, has emerged as a critical regulator of both adipocyte differentiation and glucose metabolism, and hence a potential link between obesity and diabetes. PPAR-gamma is induced during adipocyte differentiation, and is highly abundant in fat cells. PPAR-gamma ligands, such as the exciting new class of antidiabetic drugs called thiazolidinediones (TZDs), enhance insulin action. A major goal of this laboratory is to understand the relationships between PPAR-gamma activity, adipogenesis and insulin resistance. We have discovered a novel secreted protein called resistin that adipocyte-specific and down-regulated by TZDs in vitro and in vivo. Resistin circulates in mouse blood and serum resistin levels are elevated in mice fed a high fat diet leading to obesity and insulin resistance. Resistin administration impairs glucose tolerance, and neutralization of resistin improves hyperglycemia and insulin resistance in mice with diet induced obesity. We hypothesize that resistin is a mediator of insulin resistance associated with obesity, and that anti-diabetic effects of TZDs are due in part to down-regulation of resistin levels. These hypotheses will be directly tested in the experiments proposed in this project.
Specific Aim 1 is to develop improved reagents for exploring resistin physiology. These include improved assays and recombinant protein expression that will be critical to future studies.
Specific Aim 2 is to determine the phenotype of mice over-expressing resistin. We hypothesize that elevated levels of circulating resistin will lead to impaired glucose tolerance that is at least partially refractory to TZD treatment. Resistin will be expressed at high levels in mice using multiple strategies including administration of recombinant resistin, infection with adeno-associated virus, and transgenic techniques. Glucose tolerance, insulin action, and other metabolic parameters will be assessed, as will the effect of TZD treatment.
Specific Aim 3 is to determine the phenotype of mice lacking a functional resistin gene. We hypothesize that mice without resistin will be resistant to obesity-induced insulin resistance in dietary and/or genetic models, and/or will have impaired responsiveness to TZDs. The resistin gene will be ablated in mice, and glucose tolerance, insulin action, and other metabolic parameters will be determined in mice with deletions of one or both alleles of the resistin gene. Together, the proposed studies will address critical questions about the role of resistin as a link between obesity, diabetes, and the mechanism of action of antidiabetic TZDs. These studies have important implications for our society in which diabetes and obesity are rampant.
| Kim, Yong Hoon; Marhon, Sajid A; Zhang, Yuxiang et al. (2018) Rev-erb? dynamically modulates chromatin looping to control circadian gene transcription. Science 359:1274-1277 |
| Juliana, Christine A; Yang, Juxiang; Cannon, Corey E et al. (2018) A PDX1-ATF transcriptional complex governs ? cell survival during stress. Mol Metab 17:39-48 |
| Barnoud, Thibaut; Budina-Kolomets, Anna; Basu, Subhasree et al. (2018) Tailoring Chemotherapy for the African-Centric S47 Variant of TP53. Cancer Res 78:5694-5705 |
| Plikus, Maksim V; Guerrero-Juarez, Christian F; Ito, Mayumi et al. (2017) Regeneration of fat cells from myofibroblasts during wound healing. Science 355:748-752 |
| Juliana, Christine A; Yang, Juxiang; Rozo, Andrea V et al. (2017) ATF5 regulates ?-cell survival during stress. Proc Natl Acad Sci U S A 114:1341-1346 |
| Ediger, Benjamin N; Lim, Hee-Woong; Juliana, Christine et al. (2017) LIM domain-binding 1 maintains the terminally differentiated state of pancreatic ? cells. J Clin Invest 127:215-229 |
| Jang, Jessica C; Li, Jiang; Gambini, Luca et al. (2017) Human resistin protects against endotoxic shock by blocking LPS-TLR4 interaction. Proc Natl Acad Sci U S A 114:E10399-E10408 |
| Carr, Rotonya M; Dhir, Ravindra; Mahadev, Kalyankar et al. (2017) Perilipin Staining Distinguishes Between Steatosis and Nonalcoholic Steatohepatitis in Adults and Children. Clin Gastroenterol Hepatol 15:145-147 |
| Park, Hyeong Kyu; Kwak, Mi Kyung; Kim, Hye Jeong et al. (2017) Linking resistin, inflammation, and cardiometabolic diseases. Korean J Intern Med 32:239-247 |
| Ackermann, Amanda M; Zhang, Jia; Heller, Aryel et al. (2017) High-fidelity Glucagon-CreER mouse line generated by CRISPR-Cas9 assisted gene targeting. Mol Metab 6:236-244 |
Showing the most recent 10 out of 220 publications
