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Jianping Ye, M.D.

Professor of Molecular Biology
Chief, Antioxidant and Gene Regulation Lab
Professor

Department/Laboratory:
Antioxidant and Gene Regulation
Phone:
(225) 763-3163
Fax:
(225) 763-3030
Send E-mail 
 

EDUCATION

M.D., Beijing Medical University, Beijing, PR China, 1989, Medicine

RESEARCH INTERESTS

Our research is conducted to understand the molecular mechanism of insulin resistance in obesity. One of the goals is to understand initiation and impact of inflammation in adipose tissue. The study is concentrated on the NF-kB signaling pathway. We made the initial observation of oxygen reduction in fat tissue of obese mice, and reported hypoxia as a risk factor for NF-kB activation in adipose tissue for the chronic inflammation in obesity. To test NF-kB activity on glucose metabolism, we modified NF-kB activity in adipose tissue by over expression or knockout of the p65 subunit. Activation of NF-kB leads to an increase in adipose inflammation, energy expenditure and thermogenesis in aP2-p65 mice. The energy expenditure makes the mice resistant to diet-induced obesity and insulin resistance. The disassociation of inflammation and insulin resistance in aP2-p65 mice leads us to investigate mechanism of energy expenditure upon NF-kB activation. Our studies suggest that the inflammation has beneficial effects on obesity through induction of energy expenditure and adipose tissue remodeling. The view has contributed to the revision of inflammation concept in obesity. The view provides a mechanism for the weight gain in patients with anti-inflammatory therapies, and an answer to the poor efficacy of anti-inflammation therapies in the control of insulin resistance in clinical trials.

1. Adipose tissue hypoxia as a trigger of chronic inflammation: We have been actively investigating adipose chronic inflammation since 2001. In 2007, we published the first report of decreased oxygen pressure in adipose tissue of obese mice, and demonstrated hypoxia activity in the induction of chronic inflammation in obesity (Ye, et al, 2007). In the study, we observed the hypoxia in three ways (oxygen pressure, chemical hypoxia prober and hypoxia response genes), demonstrated hypoxia activities in the activation of transcription factors (NF-kB and HIF-1) for induction of pro-inflammatory cytokines in adipocytes and macrophages. We reported that hypoxia inhibits adiponectin expression and induces leptin expression in adipocytes. In the cellular mechanism of hypoxia, we reported that angiogenic deficiency contributes to the adipose tissue hypoxia in obesity (Pang, et al, 2008). We observed that macrophages play an important role in the regulation of adipose angiogenesis. Now, adipose tissue hypoxia has been a major concept of adipose inflammation in obesity in the initiation of inflammation as well as ER stress, oxidative stress, adipocyte death (Yin, et al, 2009), etc. Our study suggests that HIF-1 is not a good marker of hypoxia in adipose tissue since HIF-1 is also activated by other factors in obesity such as insulin and adipocyte differentiation (He, et al, 2011).

1. Ye J, Gao Z, Yin J, He Q. Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice. Am J Physiol Endocrinol Metab. 2007 Oct;293(4):E1118-28. PubMed PMID: 17666485.
2. Pang C, Gao Z, Yin J, Zhang J, Jia W, Ye J. Macrophage infiltration into adipose tissue may promote angiogenesis for adipose tissue remodeling in obesity. Am J Physiol Endocrinol Metab. 2008 Aug;295(2):E313-22. PubMed PMID: 18492768; PubMed Central PMCID: PMC2519760.
3. Yin J, Gao Z, He Q, Zhou D, Guo Z, Ye J. Role of hypoxia in obesity-induced disorders of glucose and lipid metabolism in adipose tissue. Am J Physiol Endocrinol Metab. 2009 Feb;296(2):E333-42. PubMed PMID: 19066318; PubMed Central PMCID: PMC2645021.
4. He Q, Gao Z, Yin J, Zhang J, Yun Z, Ye J. Regulation of HIF-1a activity in adipose tissue by obesity-associated factors: adipogenesis, insulin, and hypoxia. Am J Physiol Endocrinol Metab. 2011 May;300(5):E877-85. PubMed PMID: 21343542; PubMed Central PMCID: PMC3093977.

2. Beneficial activities of inflammation in obesity: Classically, chronic inflammation is believed to generate detrimental effects on glucose metabolism through induction of insulin resistance. Our studies suggest that inflammation inhibits insulin signaling pathway of adipocytes through activation of IKK/NF-kB pathway in cellular models (Zhang, et al, 2008, 2013). To test NF-kB in adipose tissue, we made the first line of transgenic mice with NF-kB activation in fat tissue by overexpressing the p65 subunit (Tang, et al, 2010). The phenotype studies reveals that in vivo, NF-kB activation is coupled with an increase in energy expenditure in mice. The energy expenditure protects the transgenic mice from obesity and insulin resistance. These observations lead to identification of the beneficial effects of inflammation in obesity. The thermogenic effect of NF-kB provides a mechanism to two important effects of anti-inflammation therapies in patients: (a) the weight gain in patients under anti-inflammation therapies; (b) disappointed effects of anti-inflammation medicines in the improvement of insulin sensitivity in clinical trials. To test NF-kB activity further, we made the first line of fat NF-kB inactivation mice by knocking out the p65 subunit (Gao, et al, 2015). The study suggests that the NF-kB inactivation is not able to block the chronic inflammation and insulin resistance in obese mice. The study demonstrates that NF-kB is required for protection of adipocytes from apoptosis in obesity.

1. Zhang J, Gao Z, Yin J, Quon MJ, Ye J. S6K directly phosphorylates IRS-1 on Ser-270 to promote insulin resistance in response to TNF-(alpha) signaling through IKK2. J Biol Chem. 2008 Dec 19;283(51):35375-82. PubMed PMID: 18952604; PubMed Central PMCID: PMC2602883.
2. Tang T, Zhang J, Yin J, Staszkiewicz J, Gawronska-Kozak B, Jung DY, Ko HJ, Ong H, Kim JK, Mynatt R, Martin RJ, Keenan M, Gao Z, Ye J. Uncoupling of inflammation and insulin resistance by NF-kappaB in transgenic mice through elevated energy expenditure. J Biol Chem. 2010 Feb 12;285(7):4637-44. PubMed PMID: 20018865; PubMed Central PMCID: PMC2836069.
3. Zhang J, Gao Z, Ye J. Phosphorylation and degradation of S6K1 (p70S6K1) in response to persistent JNK1 Activation. Biochim Biophys Acta. 2013 Dec;1832(12):1980-8. PubMed PMID: 23816567; PubMed Central PMCID: PMC3825840.
4. Gao Z, Zhang J, Henagan TM, Lee JH, Ye X, Wang H, Ye J. P65 inactivation in adipocytes and macrophages attenuates adipose inflammatory response in lean but not in obese mice. Am J Physiol Endocrinol Metab. 2015 Mar 15;308(6):E496-505. PubMed PMID: 25564477; PubMed Central PMCID: PMC4360014.

3. Induction of energy metabolism by natural products: Butyric acid is a major product of gut microbiota during fermentation of dietary fibers in the large gut. We made the initial observation that dietary supplementation of butyric acid induces energy expenditure to protect mice from insulin sensitivity and dietary obesity (Gao, et al, 2009). In a subsequent study, we found that butyric acid induces FGF21 expression in liver to promote the energy metabolism (Li, et al, 2012). Butyric acid has been a major signaling molecule in the biological activities of gut microbiota. In addition, we investigated the mechanism of berberine activity in the regulation of metabolism. Berberin is a single molecule compound originally identified in Chinese herbs. Synthetic berberine is widely used in the treatment of type 2 diabetes in China and many counties in the world. The metabolic action is related to activation of AMPK by berberine. However, the mechanism of AMPK activation was not known. We published the initial report that berberine activates AMPK through inhibition of ATP production in cells (Yin, et al, 2008).

1. Yin J, Gao Z, Liu D, Liu Z, Ye J. Berberine improves glucose metabolism through induction of glycolysis. Am J Physiol Endocrinol Metab. 2008 Jan;294(1):E148-56. PubMed PMID: 17971514; PubMed Central PMCID: PMC2464622.
2. Gao Z, Yin J, Zhang J, Ward RE, Martin RJ, Lefevre M, Cefalu WT, Ye J. Butyrate improves insulin sensitivity and increases energy expenditure in mice. Diabetes. 2009 Jul;58(7):1509-17. PubMed PMID: 19366864; PubMed Central PMCID: PMC2699871.
3. Li H, Gao Z, Zhang J, Ye X, Xu A, Ye J, Jia W. Sodium butyrate stimulates expression of fibroblast growth factor 21 in liver by inhibition of histone deacetylase 3. Diabetes. 2012 Apr;61(4):797-806. PubMed PMID: 22338096; PubMed Central PMCID: PMC3314370.

Complete list of Published Works (>140) in MyBibliography: current h-index is 57 with 10400 citations at Google scholar.
http://www.ncbi.nlm.nih.gov/sites/myncbi/1Z1snxv2lmvkz/bibliography/47604258/public/?sort=date&direction=ascending

For more information, please visit my lab webpage at http://labs.pbrc.edu/generegulation/

SELECTED PUBLICATIONS

Following are selected from >140 total peer-reviewed publications. For detail information, please visit my lab webpage: http://labs.pbrc.edu/generegulation/

Mumphrey MB, Hao Z, Townsend RL, Patterson L, Munzberg H, Morrison CD, Ye J, and Berthoud HR: Eating in mice with gastric bypass surgery causes exaggerated activation of brainstem anorexia circuit. International Journal of Obesity (Accepted March 11, 2016). PMID: 26984418

Hao Z, Mumphrey MB, Townsend RL, Morrison CD, Munzberg H, Ye J, and Berthoud HR: Reprogramming of defended body weight after Roux-En-Y gastric bypass surgery in diet-induced obese mice. Obesity 24(3):654-60, 2016. PMID: 26847390

Lu H, Gao Z, Zhao Z, Weng J, and Ye J. Transient hypoxia reprograms differentiating adipocytes for enhanced insulin sensitivity and triglyceride accumulation. International Journal of Obesity 40(1):121-8, 2016. PMID: 26219415

Karkeni E, Astier J, Tourniaire F, El Abed M, Romier B, Gouranton E, Lin W, Borel P, Salles J, Walrand S, Ye J, and Landrier JF: Obesity-associated inflammation induces microRNA-155 expression in adipocytes and adipose tissue: outcome on adipocyte function. J Clin Endocrinol Metab 101(4):1615-26, 2016. PMID: 26829440

Ke B, Zhao Z, Ye X, Gao Z, Manganiello V, Wu B, and Ye J. Inactivation of NF-?B p65 (RelA) in liver improved insulin sensitivity and inhibited cAMP/PKA pathway. Diabetes 64:3355-3362, 2015. PMID: 26038580

Gao Z, Zhang J, Henagan TM, Lee JH, Ye X, Wang Hui, and Ye J: p65 inactivation in adipocytes and macrophages attenuates adipose inflammatory response in lean but not in obese mice. American journal of physiology-Endocrinology and metabolism. 308(6):E496-505, 2015. PMID: 25564477

Wang H, and Ye J: Regulation of energy balance by inflammation: Common theme in physiology and pathology. Rev Endocr Metab Disord. 16(1):47-54, 2015. (review article)

Hao Z, Münzberg H, Rezai-Zadeh K, Keenan M, Coulon D, Lu H, Berthoud HR, Ye J: Leptin deficient ob/ob mice and diet-induced obese mice responded differently to Roux-en-Y bypass surgery. International Journal of Obesity 39(5):798-805, 2015. PMID: 25349056

Ye J, Hao Z, Mumphrey MB, Townsend RL, Patterson LM, Stylopoulos N, Münzberg H, Morrison CD, Drucker DJ,Berthoud HR. GLP-1 receptor signaling is not required for reduced body weight after RYGB in rodents. Am J Physiol Regul Integr Comp Physiol 306: R352–R362, 2014. PMID: 24430883

Yin J, Lee JH, Zhang J, Gao Z, Polotsky VL, and Ye J: Regulation of Hepatocyte Growth Factor Expression by NF-kB and PPARg in Adipose Tissue. American journal of physiology-Endocrinology and metabolism 306:E929–E936, 2014. PMID: 24569592

Ye J, McGuinness OP: Inflammation during obesity is not all bad: Evidence from animal and human studies. Am J Physiol Endocrinol Metab 304:E466-E477, 2013

Hao Z, Zhao Z, Berthoud H-R, and Ye J. Development and Verification of a Mouse Model for Roux-en-Y Gastric Bypass Surgery with a Small Gastric Pouch. PLoS One 8:e52922, 2013.

Li H, Gao Z, Zhang J, Ye X, Xu A, Ye J, Jia W: Sodium Butyrate Stimulates Expression of Fibroblast Growth Factor 21 in Liver by Inhibition of Histone Deacetylase 3. Diabetes 61:797-806, 2012.

Xu F, Burk D, Gao Z, Yin J, Zhang X, Weng J, Ye J: Angiogenic Deficiency and Adipose Tissue Dysfunction Are Associated with Macrophage Malfunction in SIRT1-/- Mice. Endocrinology 153:1706-1716, 2012.

Zhang J, Henagan TM, Gao Z, Ye J: Inhibition of glyceroneogenesis by Histone Deacetylase 3 Contributes to Lipodystrophy in Mice with Adipose Tissue Inflammation. Endocrinology 152 1829-1838, 2011.

Tang T, Zhang J, Yin J, Staszkiewicz J, Gawronska-Kozak B, Mynatt R, Martin RJ, Keenan M, Gao Z, Ye J: Uncoupling of Inflammation and Insulin Resistance by NF-kB in Transgenic Mice through Induction of Energy Expenditure. J Biol Chem 285:4637-4644, 2010

Xu F, Gao Z, Zhang J, Rivera CA, Yin J, Weng J, Ye J: Lack of SIRT1 (mammalian sirtuin 1) Activity Leads to Liver Steatosis in the SIRT1+/- Mice: A Role of Lipid Mobilization and Inflammation. Endocrinology 151 2504-2514, 2010

Gao Z, Yin J, J. Z, He Q, McGuinness OP, Ye J: Inactivation of NF-kB P50 Leads to Insulin Sensitization in liver through Post-Translational Inhibition of p70S6K. J. Biol. Chem. 284:18368-18376 2009

Yin J, Zuberi A, Gao Z, Liu D, Liu Z, Ye J: Shilianhua extract inhibits GSK-3{beta} and promotes glucose metabolism. Am J Physiol Endocrinol Metab 296:E1275-E1280, 2009

Gao Z, Yin J, Zhang J, Pope CR, Martin RJ, Cefalu WT, Ye J: Butyrate Improves Insulin Sensitivity and Increases Energy Expenditure in Mice. Diabetes 58:1509-1517 2009

Ye J: Emerging Role of Adipose Tissue Hypoxia in Obesity and Insulin Resistance. International Journal of Obesity 33:54-66, 2009. (Review article)

Jun Yin, Zhanguo Gao, Qing He, and Jianping Ye. Potential role of hypoxia in obesity-induced disorder of glucose and lipid metabolism in adipose tissue. American Journal of Physiology-Endocrinology & Metabolism 296:E333-E342, 2009.

Zhang J, Gao Z, Yin J, Quon M, and Ye J: S6K Directly Phosphorylates IRS-1 on Ser270 to Promote Insulin Resistance in Response to TNF-a Signaling Through IKK2. Journal of Biological Chemistry 283:35375-35382, 2008.

Can Pang, Zhanguo Gao, Jun Yin, Jin Zhang, Weiping Jia and Jianping Ye: Macrophage Infiltration into Adipose Tissue May Promote Angiogenesis for Adipose Tissue Remodeling in Obesity. American Journal of Physiology-Endocrinology & Metabolism 295:313-322, 2008.

Jun Yin, Hanjie Zhang and Jianping Ye. Traditional Chinese Medicine in Treatment of Metabolic Syndrome. Endocrine, Metabolic and Immune Disorders-Drug Targets 8:99-111, 2008. (Review article)

Jun Yin, Zhanguo Gao, Dong Liu, Zhijun Liu and Ye J: Berberine Improves Glucose Metabolism through Induction of Glycolysis. American Journal of Physiology-Endocrinology & Metabolism. 294:E148-156, 2008.

Ye J, Gao Z, Yin J and He Q: Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice. American Journal of Physiology-Endocrinology & Metabolism. 293:E1118-E1128, 2007.

Yan J, Gao Z, Yu G, Weng? J and Ye J: Nuclear Corepressor is Required for Phosphoenolpyruvate Carboxykinase Inhibition by TNF-a. Molecular Endocrinology 21:1630-1641, 2007.

Jianping Ye: Role of Insulin in the Pathogenesis of Free Fatty Acid-Induced Insulin Resistance in Skeletal Muscle. Endocrine, Metabolic and Immune Disorders-Drug Targets. 7:65-74, 2007. (review article)

Gao Z, Wang Z, Zhang X, Butler A, Zuberi A, Gawronska-Kozak B, Lefevre M, York D, Ravussin E, Berthoud HR, Cefalu WC and Ye J: Inactivation of PKCtheta Leads to Increased Susceptibility to Dietary Insulin Resistance in Mice. American Journal of Physiology-Endocrinology & Metabolism 292:E84-E91, 2007.

Gao Z, He Q, Peng B, Chiao P and Ye J: Regulation of Nuclear Translocation of HDAC3 by IkBalpha Involves in TNF-inhibition of PPARgamma Function. Journal of Biological Chemistry 281:4540-4547, 2006.

Gao Z, Chiao P, Zhang X, Zhang XH, Lazar MA, Seto E, Young HA and Ye J: Coactivators and Corepressors of NF-kB in IkB alpha Gene Promoter. Journal of Biological Chemistry 280:21091-21098, 2005.

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. 18(8):2024-34, 2004

Gao Z, Zuberi A, Quon MJ, Dong Z, Ye J. Aspirin inhibits serine phosphorylation of insulin receptor substrate 1 in tumor necrosis factor-treated cells through targeting multiple serine kinases. J Biol Chem. 278(27):24944-50, 2003.

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-kinase/AKT by saturated and polyunsaturated fatty acids. J Biol Chem. 278(39):37041-51, 2003. ^ top