chanisms for Improved Insulin Sensitivity Branched-chain Amino Acids

chanisms for Improved Insulin Sensitivity Branched-chain Amino Acids

chanisms for Improved Insulin Sensitivity Branched-chain Amino Acids Deprivation Reporter : Fei Xiao, PhD Shanghai Institute for Nutritional Sciences, Chinese Academia of Sciences Background Prevalence of diabetes Insulin signaling Insulin Receptor, IR Insulin Receptor Substrate, IRS AKT Nature. 2001, 414:799-806 Background Insulin resistance: a physiological condition where insulin becomes less effective at lowering blood glucose a common feature of many metabolic diseases

Background Various strategies to treat insulin resistance The DPP Research Group, NEJM,2002 Background Branched-chain amino acids (BCAAs) L-leucine L-isoleucine L-valine 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: 715719, 2009. * Increases insulin resistance in models of obesity Cell Metab 9:311-326, 2009 Diabetes 54:2674-2684, 2005 Research interest of our work

Nutrient (BCAAs) X sensing Metabolism regulation Metabolic diseases (insulin sensitivity/glucose metabolism) Genetic factors Outline Part The role of leucine deprivation in insulin sensitivity The role of leucine deprivation in insulin sensitivity Part Effects of individual BCAAs on insulin sensitivity Effects of individual BCAAs on insulin sensitivity and glucose metabolism in mice Part Looking for new genes regulating insulin Looking for new genes regulating insulin sensitivity by leucine deprivation model Part The role of leucine deprivation in insulin sensitivity The role of leucine deprivation in insulin sensitivity Part The role of leucine deprivation in insulin sensitivity In Our Lab Fat mass

Lipolysis in WAT UCP1 in BAT Leucine deprivation CNS food intake Serum Insulin Blood Glucose Normal Cell Metab 5:103-114, 20 Diabetes 59:17-25 Part The role of leucine deprivation in insulin sensitivity Hypothesis Leucine deprivation may improve insulin sensitivity Part The role of leucine deprivation in insulin sensitivity Experimental Design Control (-)leu Pair-fed

control (-)leu 85% control control 0d Mice were acclimated to control diet for 7 days 7d Change different diets 14d Collect tissues Part The role of leucine deprivation in insulin sensitivity Result 1: (-) leu improves insulin sensitivity in vivo 100 50 0 # * 0.6 0.4

0.2 1.5 Fasting # * HOMA-IR 150 Fasting Serum Insulin (ng/ml) Blood Glucose (mg/dl) 200 pf (-) leu ctrl 1 0.5 0

*: p<0.05 vs. control 0 #: p<0.05 vs. pf # * Part The role of leucine deprivation in insulin sensitivity Result 2: (-) leu improves insulin sensitivity in vivo GTT 500 400 300 200 100 0 * # * * #* 0 20 40 60 80 100120

(-) leu Blood Glucose (mg/dl) Blood Glucose (mg/dl) ctrl pf ITT 200 150 100 #* * # 50 0 0 20 40 60 80 100120 Time (min) Time (min) *: p<0.05 vs. control * #

* # #: p<0.05 vs. pf Part The role of leucine deprivation in insulin sensitivity Result 3: (-) leu improves insulin sensitivity in vivo Liver ctrl Ins - + WAT ctrl (-) leu + + (-) leu + Muscle ctrl (-) leu + +

p-IR t-IR p-AKT t-AKT Arbitrary Units ctrl + Ins 300 200 * * * 200 (-) leu + Ins * 300 * * 200

100 100 100 0 0 0 p-IR p-AKT p-IR p-AKT p-IR *: p<0.05 vs. control p-AKT Part The role of leucine deprivation in insulin sensitivity HFD (-) leu HFD ctrl

Blood Glucose (mg/dl) C 250 ITT 200 150 100 50 0 * * * * * * * 0 20 40 60 80 100 120 Time (min) *: p<0.05 vs. HFD #: p<0.05 vs. ctrl Blood Glucose (mg/dl)

Results 4 :(-) leu improves insulin sensitivity under insulin-resistance conditions ctrl db/db (-) leu db/db ctrl WT 600 ITT 400 200 0 #* * # # * * * * * * * 0 20 40 60 80 100 120 Time (min) *: p<0.05 vs. ctrl db/db #: p<0.05 vs. ctrl WT Part The role of leucine deprivation in insulin sensitivity

Summary 1 leucine deprivation improves insulin sensitivity under normal and insulin-resistant conditon Mechanisms ? Part The role of leucine deprivation in insulin sensitivity Role of mTOR/S6K1 signaling in insulin sensitivity mTOR mammalian target of S6K1rapamycin ribosomal protein S6 kinase 1 Nature 431:200-205, 2004 Part The role of leucine deprivation in insulin sensitivity Results 5 :(-) leu increases insulin sensitivity by decreasing mTOR/S6K1 signaling in vivo Liver ctrl (-) leu p-mTOR t-mTOR p-S6K1 t-S6K1 p-S6 t-S6 B

Blood Glucose (mg/dl) A On a leucine-deficient diet - Ad-CA-S6K1 + Ad-CA-S6K1 200 ITT 150 100 * * * 50 0 0 20 40 60 80 100 120 Time (min) *: p<0.05 vs. control Part The role of leucine deprivation in insulin sensitivity GCN2

General control nonderepressible (GCN)2 A serine protein kinase Function as a sensor for amino acid deprivation Leucine deprivation p-mTOR /p-S6K1 p-IR/p-IRS/p-AKT ? GCN2 Part The role of leucine deprivation in insulin sensitivity Liver ctrl (-) leu p-GCN2 Arbitrary Units t-GCN2 200 Blood Glucose (mg/dl) Results 6:(-) leu increases insulin sensitivity

by activation of GCN2 Gcn2+/+ 150 100 ITT * * * 50 0 * 100 0 Gcn2-/- *: p<0.05 vs. control 0 20 40 60 80 100 120 Time (min) Part The role of leucine deprivation in insulin sensitivity AMPK

AMP-activated protein kinase Energy sensor Target of many drugs Leucine deprivation ? AMPK GCN2 p-mTOR /p-S6K1 p-IR/p-IRS/p-AKT Part The role of leucine deprivation in insulin sensitivity Results 7 :(-)leu improves insulin sensitivity via activation of AMPK HepG2 ctrl (-) leu +leu -leu Arbitrary Units p-AMPK t-AMPK

HepG2 Ins DN-AMPK p-IR t-IR p-IRS1 (Tyr612) t-IRS1 200 100 * * 0 p-AKT t-AKT t-AMPK p-ACC t-ACC *: p<0.05 vs. control - +

+ - + + - DN-AMPK + Ins + DN-AMPK + Ins Arbitrary Units Liver 150 100 50 * * * 0 p-IR p-IRS1 p-Akt Part The role of leucine deprivation in insulin sensitivity Summary2 Leucine deprivation increases hepatic insulin sensitivity

via GCN2/mTOR/S6K1 and AMPK pathways model Leucine deprivation p-GCN2 p-AMPK p-mTOR /p-S6K1 p-IR/p-IRS/p-AKT Part The role of leucine deprivation in insulin sensitivity 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. How about the other two branched-chain amino acids ? L-valine (val)

L-isoleucine (ile) Part Effects of individual BCAAs on insulin sensitivity Effects of individual branched-chain amino acids on insulin sensitivity and glucose metabolism in mice Part Effects of individual BCAAs on insulin sensitivity lts 8: (-)val and (-)ile improves insulin sensitiv in vivo GTT 400 300 * 200 100 0 * 0 * * 40 80 120

Time (min) 200 ITT 150 100 50 * * 0 0 * * * 40 80 120 Time (min) ctrl 500 GTT 400

* 300 200 100 0 * 0 * * 40 80 120 Time (min) (-) ile Blood Glucose (mg/dl) 500 B (-) val Blood Glucose (mg/dl) ctrl Blood Glucose (mg/dl)

Blood Glucose (mg/dl) A 200 ITT 150 100 50 0 * ** * 0 * 40 80 120 Time (min) Part Effects of individual BCAAs on insulin sensitivity Result 9: (-)val and (-)ile decrease mTOR/S6K1 and increase AMPK signaling Liver ctrl (-) Ile 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 200 t-AMPK 200

100 * * * 0 m p- TO R k s6 p 1 * s6 p M A p PK

Arbitrary Units Arbitrary Units Liver ctrl (-) Val 100 * * * * 0 m p- TO R k s6 p 1

s6 p M A p PK Part Effects of individual BCAAs on insulin sensitivity Results 10: Effects of individual BCAA deficiency on glucose metabolism * * 50 0 *: p<0.05 vs. control 0.4 1 * 0.2 0

* HOMA-IR 100 Serum Insulin (ng/ml) Blood Glucose (mg/dl) Fasting Fasting 150 (-) ile (-) val ctrl * 0.5 0 * Part Effects of individual BCAAs on insulin sensitivity

Results 11: Effects of individual BCAA deficiency on glucose metabolism - leu ctrl 0 * *: p<0.05 vs. control 1.5 1 0.5 0 * * Relative mRNA (%) 50 * Serum Insulin (ng/ml) Blood Glucose (mg/dl)

200 100 (-) ile Fed Fed 150 (-) val 200 * * 100 0 * pepck * g6pase

Part Effects of individual BCAAs on insulin sensitivity Results 12: BCAA deprivation for 1 day improves whole body insulin sensitivity 100 * * * * 0 0 40 80 120 Time (min) *: p<0.05 vs. control (-) BCAA (-) val 200 *

100 * * * 0 0 40 80 120 Time (min) Blood Glucose (mg/dl) (-) leu 200 Blood Glucose (mg/dl) Blood Glucose (mg/dl) ctrl (-) ile 200

* 100 * * * 0 0 40 80 120 Time (min) Part Effects of individual BCAAs on insulin sensitivity 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. Part Looking for new genes regulating insulin Looking for new genes regulating insulin sensitivity by leucine deprivation model (gene chip) Part Looking for new genes regulating insulin Hepatic Gene Chip of lecine-deprived male mice - leu/con Gene number Upregulate more than twice 984 Downregulate more than twice 1163 Prolactin receptor (PRLR) PrlR mRNA level liver 800

600 400 200 0 * con (-) leu Part Looking for new genes regulating insulin Prolactin Receptor (PRLR) 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 Part Looking for new genes regulating insulin working model Insulin sensitivity Insulin resistance Leucine deprivation

db/db PRLR p-STAT5 p-IR / p-AKT Insulin sensitivity Normal condition GCN2/ mTOR/S6K Part Looking for new genes regulating insulin 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. 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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