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Mechanisms for Improved Insulin Sensitivity by Branched-chain Amino Acids Deprivation

This report explores the role of leucine deprivation in enhancing insulin sensitivity and glucose metabolism. Research investigates the effects of individual branched-chain amino acids (BCAAs) on insulin resistance and genetic factors regulating insulin sensitivity. Findings highlight the potential of leucine deprivation in improving insulin sensitivity under normal and insulin-resistant conditions through mTOR/S6K1 signaling. Mechanisms of action include activation of GCN2 and AMPK pathways.

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Mechanisms for Improved Insulin Sensitivity by Branched-chain Amino Acids Deprivation

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  1. Mechanisms for Improved Insulin Sensitivity by Branched-chain Amino Acids Deprivation Reporter : Fei Xiao, PhD Shanghai Institute for Nutritional Sciences, Chinese Academia of Sciences

  2. Background Prevalence of diabetes

  3. Insulin signaling Insulin Receptor, IR Insulin Receptor Substrate, IRS AKT Nature. 2001, 414:799-806

  4. Background Insulin resistance: a physiological condition where insulin becomes less effectiveat lowering blood glucose a common feature of many metabolic diseases

  5. Background Various strategies to treat insulin resistance The DPP Research Group, NEJM,2002

  6. Background Branched-chain amino acids (BCAAs) L-isoleucine L-valine L-leucine

  7. The role of leucine in insulin sensitivity Increased serum leucine level: * Improves the whole body glucose metabolism Diabetes 56:1647-1654, 2007 * Does not alter susceptibility to diet-Induced obesity J. Nutr. 139: 715–719, 2009. * Increases insulin resistance in models of obesity ？ Cell Metab 9:311-326, 2009 Diabetes 54:2674-2684, 2005

  8. Research interest of our work Genetic factors Nutrient (BCAAs) X sensing Metabolism regulation Metabolic diseases (insulin sensitivity/glucose metabolism)

  9. Outline Part Ⅰ The role of leucine deprivation in insulin sensitivity Part Ⅱ Effects of individual BCAAs on insulin sensitivity and glucose metabolism in mice Part Ⅲ Looking for new genes regulating insulin sensitivity by leucine deprivation model

  10. Part Ⅰ The role of leucine deprivation in insulin sensitivity

  11. Part Ⅰ In Our Lab Fat mass Lipolysis in WAT UCP1 in BAT Leucine deprivation ？ CNS food intake Serum Insulin Blood Glucose Normal Cell Metab5:103-114, 2007 Diabetes59:17-25

  12. Part Ⅰ Hypothesis Leucine deprivation may improve insulin sensitivity

  13. Part Ⅰ Experimental Design • Control • (-)leu • Pair-fed control control (-)leu 85% control 14d 7d 0d Mice were acclimated to control diet for 7 days Change different diets Collect tissues

  14. Part Ⅰ Result 1: (-) leu improves insulin sensitivity in vivo pf (-) leu ctrl 1.5 200 0.6 Fasting Fasting Serum Insulin (ng/ml) 150 # 1 0.4 HOMA-IR * # Blood Glucose (mg/dl) 100 # * * 0.5 0.2 50 0 0 0 *: p<0.05 vs. control #: p<0.05 vs.pf

  15. Part Ⅰ Result 2: (-) leu improves insulin sensitivity in vivo ctrl (-) leu pf ITT GTT 500 200 400 150 * # 300 * * # Blood Glucose (mg/dl) 100 # Blood Glucose (mg/dl) * * 200 # * # * * 50 # 100 0 0 0 20 40 60 80 100 120 0 20 40 60 80 100 120 Time (min) Time (min) *: p<0.05 vs. control #: p<0.05 vs.pf

  16. Part Ⅰ Result 3: (-) leu improves insulin sensitivity in vivo Liver WAT Muscle ctrl (-) leu ctrl (-) leu ctrl (-) leu Ins - + - + - + - + - + - + p-IR t-IR p-AKT t-AKT (-) leu + Ins ctrl + Ins 200 * 300 300 * * * * * 200 200 Arbitrary Units 100 100 100 0 0 0 p-AKT p-AKT p-AKT p-IR p-IR p-IR *: p<0.05 vs. control

  17. Part Ⅰ Results 4 :(-) leu improves insulin sensitivity under insulin-resistance conditions HFD ctrl db/db (-) leu HFD (-) leu db/db ctrl C ctrl WT 250 600 ITT ITT 200 Blood Glucose (mg/dl) Blood Glucose (mg/dl) 400 150 * # * # 100 * # * * * 200 * * * 50 * * * * * * * 0 0 0 20 40 60 80 100 120 100 0 20 40 60 80 120 Time (min) Time (min) *: p<0.05 vs. HFD #: p<0.05 vs. ctrl *: p<0.05 vs. ctrl db/db #: p<0.05 vs. ctrl WT

  18. Part Ⅰ Summary 1 leucine deprivation improves insulin sensitivity under normal and insulin-resistant conditon Mechanisms ?

  19. Part Ⅰ Role of mTOR/S6K1 signaling in insulin sensitivity mTOR： mammalian target of rapamycin S6K1：ribosomal protein S6 kinase 1 Nature 431:200-205, 2004

  20. Part Ⅰ Results 5 :(-) leu increases insulin sensitivity by decreasing mTOR/S6K1 signaling in vivo On a leucine-deficient diet A B Liver - Ad-CA-S6K1 + Ad-CA-S6K1 (-) leu ctrl p-mTOR 200 ITT 150 Blood Glucose (mg/dl) t-mTOR * * 100 * p-S6K1 50 t-S6K1 0 p-S6 0 20 40 60 80 100 120 Time (min) t-S6 *: p<0.05 vs. control

  21. Part Ⅰ Leucine deprivation ? GCN2 p-mTOR /p-S6K1 p-IR/p-IRS/p-AKT GCN2 General control nonderepressible (GCN)2 ● A serine protein kinase ● Function as a sensor for amino acid deprivation ●

  22. Part Ⅰ * * * Results 6:(-) leu increases insulin sensitivity by activation of GCN2 Liver Gcn2+/+ Gcn2-/- (-) leu ctrl 150 ITT p-GCN2 100 Blood Glucose (mg/dl) t-GCN2 50 0 0 20 40 60 80 100 120 Time (min) * 200 Arbitrary Units 100 0 *: p<0.05 vs. control

  23. Part Ⅰ AMPK AMP-activated protein kinase ● Energy sensor ● Target of many drugs ● Leucine deprivation ? GCN2 AMPK p-mTOR /p-S6K1 p-IR/p-IRS/p-AKT

  24. Part Ⅰ Results 7 :(-)leu improves insulin sensitivity via activation of AMPK HepG2 HepG2 Liver Ins + + - - +leu -leu ctrl (-) leu - + - + DN-AMPK - DN-AMPK + Ins p-AMPK p-IR + DN-AMPK + Ins t-AMPK t-IR 150 p-IRS1 (Tyr612) 100 * * Arbitrary Units t-IRS1 * 50 * 200 p-AKT * Arbitrary Units 0 100 t-AKT p-IR p-IRS1 p-Akt 0 t-AMPK p-ACC t-ACC *: p<0.05 vs. control

  25. Part Ⅰ Summary2 Leucine deprivation increases hepatic insulin sensitivity via GCN2/mTOR/S6K1 and AMPK pathways model Leucine deprivation p-AMPK p-GCN2 p-mTOR /p-S6K1 p-IR/p-IRS/p-AKT

  26. Part Ⅰ Conclusion One Elucidate the mechanisms underlying increased insulin sensitivity by leucine deprivation ● GCN2/mTOR/S6K1 and AMPK pathways Demonstrate a novel function for GCN2 in the regulation of insulin sensitivity ● The paper titled “leucine deprivation increases hepatic insulin sensitivity via GCN2/mTOR/S6K1 And AMPK pathways” was published in Diabetes, 60:746-756,2011.

  27. How about the other two branched-chain amino acids ? L-valine (val) L-isoleucine (ile)

  28. Part Ⅱ Effects of individual branched-chain amino acids on insulin sensitivity and glucose metabolism in mice

  29. Part Ⅱ Results 8: (-)val and (-)ile improves insulin sensitivity in vivo B A (-) val (-) ile ctrl ctrl 500 200 500 200 GTT ITT ITT GTT 400 400 150 150 * 300 300 100 Blood Glucose (mg/dl) Blood Glucose (mg/dl) Blood Glucose (mg/dl) Blood Glucose (mg/dl) * 100 200 200 * * * 50 * * 50 100 * * * * 100 * * * * * * * 0 0 0 0 0 40 80 120 0 40 80 120 0 40 80 120 0 40 80 120 Time (min) Time (min) Time (min) Time (min)

  30. Part Ⅱ Result 9: (-)val and (-)ile decrease mTOR/S6K1 and increase AMPK signaling Liver Liver (-) Val (-) Ile ctrl ctrl p-mTOR p-mTOR t-mTOR t-mTOR p-S6K1 p-S6K1 t-S6K1 t-S6K1 p-S6 p-S6 t-S6 t-S6 p-AMPK p-AMPK t-AMPK t-AMPK * 200 200 * Arbitrary Units * Arbitrary Units 100 100 * * * * * 0 0 p-s6 p-s6 p-s6k1 p-s6k1 p-mTOR p-mTOR p-AMPK p-AMPK

  31. Part Ⅱ Results 10: Effects of individual BCAA deficiency on glucose metabolism (-) ile (-) val ctrl Fasting Fasting 0.4 150 1 * * * * 100 * * HOMA-IR Blood Glucose (mg/dl) Serum Insulin (ng/ml) 0.5 0.2 50 0 0 0 *: p<0.05 vs. control

  32. Part Ⅱ Results 11: Effects of individual BCAA deficiency on glucose metabolism ctrl （-）leu (-) val (-) ile Fed Fed 1.5 200 200 * * * * 150 1 Relative mRNA (%) Blood Glucose (mg/dl) Serum Insulin (ng/ml) 100 100 * 0.5 * * * 50 0 0 0 pepck g6pase *: p<0.05 vs. control

  33. Part Ⅱ Results 12: BCAA deprivation for 1 day improves whole body insulin sensitivity ctrl (-) BCAA (-) leu (-) val (-) ile 200 200 200 * * Blood Glucose (mg/dl) Blood Glucose (mg/dl) Blood Glucose (mg/dl) 100 100 100 * * * * * * * * * * 0 0 0 0 40 80 120 0 40 80 120 0 40 80 120 Time (min) Time (min) Time (min) *: p<0.05 vs. control

  34. Part Ⅱ Conclusion Two Leucine deprivation represents a general effect of BCAAs on regulation of insulin sensitivity ● The effect of BCAAs deprivation differs in glucose metabolism ● The paper titled “Effects of individual branched-chain amino acids deprivation on insulin sensitivity and glucose metabolism in mice ” was published in Metabolism, 2014.

  35. Part Ⅲ Looking for new genes regulating insulin sensitivity by leucine deprivation model (gene chip)

  36. Part Ⅲ Hepatic Gene Chip of lecine-deprived male mice liver * 800 600 Prolactin receptor (PRLR) PrlR mRNA level 400 200 0 con (-) leu

  37. Part Ⅲ Prolactin：A hormone best known for its role in lactation. PRLR: Present in nearly all organs and tissues. Numerous biological functions of PRLR have been identified. (Regulates glucose levels by modulating the secretion of insulin） a direct effect on insulin sensitivity ？ Prolactin Receptor (PRLR)

  38. Part Ⅲ working model Insulin sensitivity Insulin resistance Leucine deprivation db/db PRLR GCN2/ mTOR/S6K p-STAT5 p-IR / p-AKT Insulin sensitivity Normal condition

  39. Part Ⅲ Conclusion Three Identify a novel function for hepatic PRLR in the regulation of insulin sensitivity ● Provide important insights in the nutritional regulation of PRLR expression ● The paper titled “PRLR Regulates Hepatic Insulin Sensitivity in Mice via STAT5” was published in Diabetes, 62:3103-3113,2013.

  40. Acknowledgments Our lab: Feifan Guo, Ph.D Chunxia Wang, Ph.D Junjie Yu , Ph.D Shanghai Chen Kai Li Hao Liu Yajie Guo Jiali Deng Yuzhong Xiao Yalan Deng Previous members: Ying Cheng, PhD Qian Zhang, Ph.D Ying Du , Ph.D Tingting Xia, Ph.D Qingshu Meng Zhiying Huang Bin Liu Houkai Li, PhD Ziquan Li, Ph.D Douglas cavener (Penn State Univ) Brad lowell (Harvard Med School) Xiang Gao (Nanjing Univ) Yong Liu (INS, CAS) Hongguang Sheng (CAS clinical center)

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