Our study suggests that insulin signal pathway is subjected to a negative feedback regulation. The molecules involved in the feedback regulation include serine kinases, such as JNK, mTOR, GSK-3B, S6K, and Akt. FFAs and inflammation mediators are able to activate one or more of these kinases in the feedback loop to induce insulin resistance. This conclusion is supported by our observations published in the past few years, which include: (a) JNK and IKK was able to phosphorylate IRS-1 at Ser307/312 (1); (b) Aspirin was able to protect IRS-1 function by inhibiting multiple serine kinases including JNK, IKK, Akt, and mTOR (2); (c) FFAs, such as palmitic and lenoleic acids, were able to activate IKK/NF-kB (3); (d) FFAs inhibited insulin signal transduction through IRS-1 serine phosphorylation by IKK and JNK (4). In the latest study, we demonstrated that NF-kB inhibited the transcriptional activity of PPARg through transcriptional cofactors (5).

  Current studies are designed to understand the molecular mechanism of crosstalk of insulin pathway with inflammation pathway, with fatty acid signaling pathway, and with signaling pathway of bioactive botanicals.  Our hypothesis is summarized in the illustration (below). Following are some focuses in our research:

1.  Regulation of IKK (Inhibitor kB kinase) and JNK by FFAs.

2.  Regulation of PPARg and IRS-1 by IKK and MAPK (mitogen-activated protein kinases).

3.  Regulation of IKK, and MAPK by bioactive botanicals.

  We believe that adipocytes serve as a sensor as well as a regulator of nutrients/energy balance. Functional failure of adipocytes is a result of oversupply of nutrients/energy. When energy is oversupplied in the body, adipocytes undergo changes to adapt to the oversupply. When the degree of oversupply exceeds the capacity of compensation in adipose tissue, adipocytes will suffer functional failure, which is characterized by changes in adipopkine profile and development of insulin resistance. Insulin resistance in adipocyte is an early event of systemic insulin resistance.  

  To understand insulin resistance, we are focusing on adipocytes and trying to understand how adipocyte failure happens.  In the study, two questions are asked: (1) How chronic inflammation is induced in adipose in obese condition. In this regard, the signal pathway of fatty acids is investigated in adipocytes. (2) Whether the serine kinases (IKK, MAPKs, and PKCs) play a role in translation of fatty acid signal into functional failure in adipocytes. To this end, inhibition of IRS-1 and PPARg function by these kinases is under investigation. A variety of molecular, cellular and animal models are used in the study. Free fatty acids (palmitic and linoleic acids) and inflammatory cytokines (TNF-a) are used to induce insulin resistance in adipocytes. Dietary obese C57BL/6J mice, JNK1-/- mice, PKCtheta-/- mice, ob/ob mice, SIRT1-/- mice and p50-/- mice are used to investigate the crosstalk among the signaling pathways. Integration of signal transduction and transcriptional regulation is one of the focuses in mechanistic study.  Transcriptional cofactors are studied for the crosstalk of NF-kB and PPARg. Molecular strategies, such as RNAi (RNA interference), ChIP (chromatin immunoprecipitation), and gene knockout, are used in the study. 

  Another aspect of our research is related to the cellular and molecular mechanisms of a Chinese herbal medicine. This medicine is a botanical product and has an insulin-sensitizing effect. We will identify the molecular target and the bioactive components of this medicine.

  Research in this laboratory is supported by grants from the National Institutes of Health and American Diabetes Association.

Selected References: 

1. Gao Z, Hwang D, Bataille F, Lefevre M, York D, Quon M, Ye J.  Serine phosphorylation of insulin receptor substrate 1 (IRS-1) by inhibitor kB kinase (IKK) complex. J Biol Chem 2002;277:48115-48121.
2. Gao Z, Zuberi A, Quon M, Dong Z, Ye J.  Aspirin Inhibits TNF-induced Serine phosphorylation of IRS-1 through Targeting Multiple Serine Kinases. J Biol Chem 2003;278:24944-24950.
3. Lee JY, Ye J, Gao Z, Youn HS, Lee WH, Zhao L, Sizemore N, Hwang DH.  Reciprocal modulation of Toll-like receptor-4 signaling pathways involving MyD88 and phosphatidylinositol 3-kinases/AKT by saturated and polyunsaturated fatty acids. J Biol Chem 2003;278:37041-37051.
4. Gao Z, Zhang X, Zuberi A, Hwang D, Quon MJ, Lefevre M, Ye J.  Inhibition of Insulin Sensitivity by Free Fatty Acids Requires Activation of Multiple Serine Kinases in 3T3-L1 Adipocytes. Mol Endocrinol 2004;18:2024-2034.
5. Gao Z, He Q, Peng B, Chiao P, Ye J.  Regulation of nuclear translocation of HDAC3 by IkBa is required for TNF-inhibition of PPARg function. J Biol Chem 2006;281(7):4540-7. Epub 2005 Dec 21.