University of Michigan, Ph.D.
The obesity epidemic is considered one of the most serious threats to public health in the 21st century, impacting 36% of the United States and 18% of the world’s adult populations (Body Mass Index or BMI over 30). Obesity creates significant health risks for a variety of associated metabolic disorders including type 2 diabetes and cardiovascular diseases. Indeed, around 9% of U.S. and world populations have diabetes. Asian countries including Korea are not safe from obesity epidemics. Though only 3.8% of Koreans have a BMI over 30, alarmingly 10.1% of Korean adults have diabetes due to being overweight and obese. Unfortunately, there are only limited medication and treatment options available to manage patients’ body weight and blood glucose levels over their entire life. Thus, finding new and effective ways to treat obesity and diabetes is critical.
Our body weight is largely determined by the balance between energy intake (through food consumption) and energy expenditure (in the form of exercise or thermogenesis). Leptin, a hormone secreted from adipose (fat) tissue, is a major regulatory factor for both food intake and energy expenditure by acting on the central nervous system, in particular the hypothalamus. However, in obese condition leptin fails to properly control our body weight, which is called leptin resistance. It is leptin resistance to lead to obesity.
Glucose homeostasis is mainly regulated by insulin, a hormone secreted from the pancreas. Insulin increases glucose uptake into the muscle and fat tissues and suppresses new glucose production from the liver, therefore insulin consequently maintains proper glucose levels in our blood. However, obesity leads to insulin resistance and ultimately type 2 diabetes.
Our current understanding of the cellular and molecular mechanisms of leptin and insulin signaling and their resistance during obesity’s progression still remains elusive, which prevents the development of new and effective therapeutics for obesity and diabetes.
Among endeavors to expand our knowledge on energy and glucose homeostasis, recent studies have demonstrated that endoplasmic reticulum (ER) stress is severely elevated in the metabolically crucial hypothalamus, liver and adipose tissues during obesity’s progression. Moreover, increased ER stress leads to leptin and insulin resistance while interventions to decrease ER stress reverse them. For example, chemical chaperones (such as 4-PBA and TUDCA) reduce ER stress and, in turn, promote leptin and insulin sensitivities in obese and diabetic animal models as well as in human patients. These strongly suggest that signaling events during ER stress play a pivotal role on various metabolic regulations and can be promising therapeutic targets to treat various metabolic diseases.
ER stress and metabolic disorders
Cells under ER stress employ signaling events called the “unfolded protein response” (UPR) to restore ER homeostasis. Among signaling molecules in UPR, X-box binding protein 1 (XBP1s) is one of key signaling molecules and has been shown to play a crucial role in the hypothalamus, liver and pancreatic β cells’ metabolic regulation. There is “cross-talk” between XBP1s and other signaling molecules including p38 MAPK, IKKβ, Brd7, PI3K and FoxO1. Furthermore, XBP1s interactome is critically involved in metabolic homeostasis. These findings clearly demonstrate that ER stress and its related signaling pathways are critically important in metabolic regulation.
Our research interests stem from the existence of various interactions surrounding UPR and their critical involvement in metabolic homeostasis, and their subsequent potentials as therapeutics toward obesity, type 2 diabetes and other metabolic disorders. We identify novel interactions between UPR and other signaling pathways and investigate their roles in metabolic homeostasis. Our research currently focuses on the following topics.
1. Identification of novel crosstalk between UPR and other signal transduction pathways (UPR interactome)
2. Identification of novel post-translational modifications (PTMs) on UPR signaling molecules (such as phosphorylation and ubiquitination)
3. Investigation of the physiological role of crosstalk and PTMs of UPR on energy, glucose and lipid metabolism
4. Investigation of the pathophysiological role of crosstalk and PTMs of UPR on the development of obesity, type 2 diabetes and other metabolic disorders.
- Liu, J., Ibi, D., Taniguchi, K. Lee, Jaemin, Herrema, H., Akosman, B., Mucka, P., Salazar Hernandez, M.A., Uyar, M.F., Park, S.W., Karin, M., Ozcan, U. Inflammation improves glucose homeostasis through IKKβ-XBP1s Interaction. Cell 2016, 167(3):1052-1066.
- Lee, Jaemin*, Liu, J.*, Feng, X.*, Salazar Hernandez, M.A., Mucka, P., Ibi, D., Choi, J-W., Ozcan,U. Withaferin A is a Leptin Sensitizer with Strong Anti-diabetic Properties in Mice. Nature Medicine 2016, 22(9): 1023-1032. *co-first authors.
- Liu, J.*, Lee, Jaemin*, Salazar Hernandez, M.A., Mazitschek, R. Ozcan, U. Treatment of obesity with celastrol. Cell 2015, 161(5): 999-1011. * co-first authors
- Lee, Jaemin, Ozcan, U. Unfolded protein response signaling and metabolic diseases. Journal of Biological Chemistry 2014, 289(3): 1203-1211.
- Herrema, H., Lee, Jaemin, Zhou, Y., Copps, KD., White, MF., Ozcan, U. IRS1Ser307 phosphorylation does not mediate mTORC1-induced insulin resistance. Biochemical and Biophysical Research Communications 2014, 443(2): 689-693.
- Wright, J., Wang, X., Haataja, L., Kellogg, AP., Lee, Jaemin, Liu, M., Arvan, P. Dominant protein interactions that influence the pathogenesis of conformational diseases. Journal of Clinical Investigation 2013, 123(7): 3124-3134.
- Lee, Jaemin*, Sun, C.*, Zhou, Y., Lee, J., Gokalp, D., Herrema, H., Park, SW., Davis, RJ., Ozcan, U. p38 MAPK-mediated Regulation of Xbp1s is Crucial for Glucose Homeostasis. Nature Medicine 2011, 17(10): 1251-1260. *co-first authors
- Lee, Jaemin, Di, Jeso. B., Arvan, P. Maturation of Thyroglobulin Region-I. Journal of Biological Chemistry 2011, 286(38): 33045-33052.
- Lee, Jaemin, Arvan, P. Repeat Motif-containing Regions within Thyroglobulin. Journal of Biological Chemistry 2011, 286(30): 26327-26333.
- Zhou, Y., Lee, J., Reno, CM., Sun, C., Park, SW., Chung, J., Lee Jaemin, Fisher, SJ., White, MF., Biddinger, SB., Ozcan, U. Regulation of Glucose Homeostasis through a XBP-1-FoxO1 Interaction. Nature Medicine 2011, 17(3): 356-365.
- Park, SW., Zhou, Y., Lee, Jaemin, Lee, J., Ozcan, U. Sarco(endo)plasmic Reticulum Ca2+-ATPase 2b is a Major Regulator of Endoplasmic Reticulum Stress and Glucose Homeostasis in Obesity. Proceedings of the National Academy of Sciences 2010, 107(45): 19320-19325.