Mechanisms underlying insulin resistance
The overall goal of research in my lab is to determine the cellular and molecular mechanisms for insulin resistance in obesity and type 2 diabetes. Major research interests include 1) discovering the mechanisms by which novel adipocyte-associated molecules alter insulin action and fuel metabolism in other tissues; 2) determining the molecular mechanisms that render obesity a risk factor for type 2 diabetes and 3) identifying novel cell signaling pathways involved in the regulation of food intake, body weight, and glucose homeostasis. Our work has had a major impact on understanding the critical role of the adipocyte as an endocrine organ. We have used genomic approaches with adipose tissue from genetically engineered mice to discover novel adipocyte-associated molecules such as retinol binding protein 4 which have proven to be important markers and mechanisms for insulin resistance and diabetes in humans. Most recently, we demonstrated that elevated retinol binding protein 4 causes insulin resistance by activating both the innate and adaptive immune systems in adipose tissue. We also recently showed that de novo lipogenesis in adipocytes has a major role in regulating systemic insulin sensitivity in humans and rodents. My lab also established a critical role for the AMP-activated protein kinase pathway in leptin action in both the hypothalamus and peripheral tissues. In addition, in collaboration with Ben Neel, we demonstrated the importance of protein tyrosine phosphatase 1B in modulating leptin and insulin action in neural and peripheral circuits that regulate adiposity and fuel homeostasis. Through these studies, we developed a strong interest in identifying metabolites, especially novel lipids and lipid profiles, which regulate insulin sensitivity and glucose metabolism.
1. Xue B, Pulinikunnil P, Murano I, Bence KK, He H, Minokoshi Y, Asakura K, Lee A, Haj F, Furukawa N, Balschi JA, Cinti S, Neel BG, Kahn BB. Neuronal PTP1B deficiency results in Inhibition of hypothalamic AMPK and isoform-specific activation of AMPK in peripheral tissues. Mol. Cell. Bio. 2009, 29:4563-4573. PMCID: PMC27725736
2. Norseen J, Hosooka T, Hammarstedt A, Yore MM, Kant S, Aryal P, Kiernan UA, Phillips DA, Maruyama H, Kraus BJ, Usheva A, Davis RJ, Smith U, Kahn BB. RBP4 inhibits insulin signaling in adipocytes by inducing pro-inflammatory cytokines in macrophages through a JNK- and TLR4-dependent and retinol-independent mechanism. Mol Cell Biol 2012, 32:2010-2019. PMCID: PMC3347417
3. Yang Q, Eskurza I, Kiernan UA, Phillips DA, Bluher M, Graham TE, Kahn BB. Quantitative measurement of full-length and C-terminal proteolyzed RBP4 in serum of normal and insulin resistant humans using a novel mass spectrometry immunoassay (qMSIA). Endocrinology 2012, 153(3):1519-1527. PMCID: PMC3281532
4. Herman MA, Peroni OD, Villoria J, Schön MR, Abumrad NA, Blüher M, Klein S, Kahn BB. A novel ChREBP isoform in adipose tissue regulates systemic glucose metabolism. Nature 2012, 484:333-338. PMCID: PMC3341994
5. Dagon Y, Hur E, Zheng B, Cantley LC, Kahn BB. p70S6-kinase phosphorylates AMPK on serine 491 to mediate leptin’s effect on food intake. Cell Metabolism 2012, 16:104-112. PMCID: PMC3407689
6. Zemany L, Kraus BJ, Norseen J, Saito T, Peroni OD, Johnson RL, Kahn BB. Downregulation of STRA6 in adipocytes and adipose stromovascular fraction in obesity and effects of adipocyte-specific STRA6 knockdown in vivo. Molecular and Cellular Biology 2014, 34:1179-1186. PMCID: In process.
7. Moraes-Vieira PM, Yore MM, Dwyer PM, Syed I, Aryal P, Kahn BB. RBP4 activates antigen-presenting cells leading to adipose tissue inflammation and systemic insulin resistance. Cell Metabolism 2014, 4:512- 526. PMCID: In process.
8. Kraus D*, Yang Q*, Kong D, Banks AS, Zhang L, Rodgers JT, Pirinen E, Pulinilkunnil TC, Gong F, Yang Y-C, Chen Y, Sauve AA, Asara JM, Peroni OD, Monia BP, Bhanot S, Alhonen L, Puigserver P, Kahn BB. Nicotinamide N-methyltransferase (NNMT) knockdown protects against diet-induced obesity. Nature. 2014;508(7495):258-62.PMCID: In process.