Roger J. Davis. Metabolic Stress Signaling by the JNK Pathway

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1 Roger J. Davis Metabolic Stress Signaling by the JNK Pathway

2 Age-adjusted Percentage of U.S. Adults with Diagnosed Diabetes or Obesity Diabetes Obesity (BMI 30 kg/m 2 ) <4.5% % % % >9.0% <14.0% % % % >26.0% see

3 Diabetes: Problem Scope USA: *Dall TM. Health Affairs, 2010 ~24 million Americans afflicted (>8%), incidence increasing Expensive! In $218B* Compared to those without the disease, patients with T2D and T1D see physicians 2.9 and 3.5 diabetes times more during frequently their lifetime Leading cause of kidney failure, blindness, amputations, and a major contributor to Narayan premature et al mortality Diabetes Care 29: , in 3 Americans born in 2000 are expected to develop

4 JNK, Obesity & Insulin Resistance JNK is activated by eating a high fat diet JNK-deficient mice are resistant to the effects of a high fat diet The Jackson Labs

5

6 PP2A PP6 PP2A PP2C MKP

7 Obesity-induced insulin resistance - Role of MLK

8 Scaffold proteins can assemble a JNK signaling module MKKK MKK JIP1 MLK MKK7 MAPK JNK

9 JIP1 and the metabolic stress response Diabetes: JIP1 MLK MKK7 JNK The human JIP1 Ser59Asn allele segregates with diabetes. JIP1-deficient mice are resistant to obesity -induced JNK activation and insulin resistance. Response to obesity requires MLK, MKK7 & JNK.

10 JIP1 scaffold protein 1) JIP1 scaffold protein contributes to JNK-mediated metabolic stress responses 2) JIP1 organizes large multi-protein complexes 3) JIP1 complexes are dynamically regulated - Phosphorylation - Kinesin-mediated transport

11 Mechanism of JNK-regulated Obesity and Insulin Resistance JNK in peripheral tissues regulates insulin sensitivity. A central mechanism accounts for JNK-regulated obesity.

12 How does JNK make you obese?

13 JNK and the hypothalamic-pituitary axis

14 Mechanism of JNK-regulated Obesity

15 JNK in the anterior pituitary gland causes obesity without changing food consumption 1 H-MRS Analysis

16 JNK causes decreased energy expenditure

17 Gene Expression Analysis Differentially expressed genes - liver and brown fat significant enrichment of thyroid hormone responsive genes Anterior pituitary gland Increased Thyroid Stimulating Hormone (TSH) expression

18 JNK suppresses the thyroid hormone axis

19 Pharmacological inhibition of Thyroid hormone release prevents the effects of JNK-deficiency on obesity

20 JNK suppresses TSH expression No change in pitiuitary transcription factors known to regulate TSH expression

21 JNK promotes AP1-dependent gene expression

22 What is Dio2? Dio2 converts the pro-hormone T4 to the active form T3 Critically required for local thyroid hormone signaling. Dio2 is required for feed-back inhibiton of TSH expression in the anterior pituitary gland by T4. Increased TSH expression by the anterior pituitary gland may be caused by failure of T4-mediated repression of TSH expression.

23 JNK is required for T4-mediated repression of TSH expression by the anterior pituitary gland JNK in the hypothalamus also regulates the thyroid hormone axis. JNK is required for T4- mediated repression of thyroglobulin releasing hormone (TRH). JNK-regulated Dio2 expression in the hypothalamus (tanycytes) may provide a mechanism.

24 Dio2 TRH JNK and Obesity JNK promotes diet-induced obesity by suppressing the hypothalamic-pituitarythyroid axis

25 How does JNK promote insulin resistance?

26 Insulin Resistance: tissue interactions

27 Obesity-induced chronic diseases Handschin et al, Nature 2008; 454:

28 Obesity-induced inflammation in adipose tissue Adipocyte ATM; Adipose Tissue Macrophage Odegaard et al, Annu Rev Patol Mech Dis 2011; 6:275

29 Jnk1 -/- Jnk2 -/- Macrophages Control LPS F WT F KO pser 63 -cjun

30 Macrophage JNK-deficiency does not prevent obesity

31 Macrophage-specific JNK deficiency prevents diet-induced hyperglycemia & hyperinsulinemia

32 Macrophage JNK causes glucose and insulin intolerance Glucose injection Insulin injection Glucose tolerance test Insulin tolerance test

33 Macrophage JNK promotes insulin resistance GIR; Glucose infusion rate HIA; Hepatic insulin action HGP; Hepatic glucose production

34 Macrophage JNK suppresses insulin-stimulated AKT

35 JNK Promotes Macrophage Infiltration of Adipose Tissue

36 Macrophage JNK promotes chemokine signaling

37 Obesity-induced inflammation in adipose tissue Adipocyte ATM; Adipose Tissue Macrophage Odegaard et al, Annu Rev Patol Mech Dis 2011; 6:275

38 Macrophage Polarization M1 (Classically activated macrophages) IFN-g and endotoxin IL12-mediated Th1 immune response Pro-inflammatory cytokines CD11C, TNF M2 (Alternatively activated macrophages) IL4 or IL13 (M2a) Immune Complex (M2b) IL10 or TGFb (M2c) Th2 immune response Resolution of acute inflammation Regulation of tissue homeostasis Arg-1, Mgl1, Mrc1, IL10

39 JNK Promotes Macrophage Infiltration of Adipose Tissue M1 M2

40 Macrophage polarization in vitro BMDM GM-CSF IFNg, LPS IL4, IL13 IC+LPS IL10 M1 M2a M2b M2c FACS CD11c CD206,CD301 CD86 Gene Expression Ccr7, Cd11c, Il1b, Tnfa, Il6,Ccl2, Ccl5 Arg1, CD206, CD301 Il1b, Tnfa, Il6, Il10

41 Macrophage JNK is not required for M2a polarization

42 Macrophage JNK is required for M1 polarization

43 JNK controls M1 Macrophage Polarization Adipocyte ATM; Adipose Tissue Macrophage Odegaard et al, Annu Rev Patol Mech Dis 2011; 6:275

44 Metabolic stress signaling by JNK 1) JNK targets Dio2 to regulate obesity. 2) JNK1 in peripheral tissues (fat, muscle) controls insulin sensitivity. 3) JNK promotes macrophage-mediated inflammation. - M1 polarization - Tissue infiltration

45 Metabolic Stress 1) JNK responds to metabolic stress 2) JNK-mediated inflammation contributes to disease: - Diabetes - Cardiovascular disease - Cancer 3) Opportunity for therapeutic intervention

46 Acknowledgments Tammy Barrett Seda Barutcu Vicky Benoit Shashi Kant Julie Cavanagh-Kyro Nomeda Girnius Myoung Sook Han Norm Kennedy Caroline Morel Kasmir Ramo Santiago Vernia Ping Xu Clamp assays Jason Kim

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