Adipose Tissue Inflammation in Obesity Robert W. O’Rourke, M.D. Associate Professor Co-Director, Bariatric Surgery Program Department of Surgery Oregon

Adipose Tissue Inflammation in Obesity

Robert W. O’Rourke, M.D.Associate ProfessorCo-Director, Bariatric Surgery ProgramDepartment of SurgeryOregon Health & Science UniversityPortland, Oregon

Support: American Surgical Association NIH-NIDDK

What is Inflammation?• Response to trauma, infection• Response to daily cell turnover, “wear and tear”• Exogenous (non-self) and endogenous (self) stimuli

2004

“Inflammation is The Root Cause of ALL Major Diseases”

Systemic inflammation in obesity

Hotasimigil et al. Science 1993

Zhang et al. Nature 1994

Shi et al. JCI 2006

Toll-like receptors: Central innate immunity mediators

Obesity-related inflammation

1. Obesity-related inflammation originates and is based in adipose tissue

2. Adipose tissue inflammation has systemic effects and is a primary or contributing cause of virtually all obesity related co-morbidities

3. Hypoxia is a prime candidate for a root cause of adipose tissue inflammation

Inflammation in obesity begins in adipose tissue

Akagiri et al.,J Clin Biochem Nutr 2008

Kintscher et al., Arterioscler Thromb Vasc Biol 2008

TNF-IL-1IL-6IL-1RaIFN-gCCL2PPAR- Growth-hormone secretogogue receptorAdipsinResistinAcylation stimulation proteinAgouti proteinAngiotensin II ProstaglandinsAdiponectinmacrophage migration inhibitory factorSPARC) leptin

Bcl-3IGF-1IGF-2NFkBLIGHTHVEMGM-CSFG-CSFHMOX-1IL-1Toll-like receptorsVEGFIL-17IL-23ComplementICAMVCAMMCAMMAPKMatrix metalloproteases…

Adipose tissue is a central regulator of metabolism and an immune and endocrine organ

Cytokines and adipokines

TNF-IL-6IL-8IL-1bIFN-CCL2

IL-10IL-1Ra

Inflammation

Body weight

Glucose homeostasis

“Pro-inflammatory”, diabetogenic

“Anti-inflammatory”, Insulin-mimetic

leptinresistinPYY

adiponectin

Cytokines Adipokines

IL-10IL-1Ra

leptinResistinPYY

0 200 400 600 800 1000FSC-H: Forward Scatter

0

200

400

600

800

1000S

SC

-H: S

ide

Sca

tter

SVF FractionAdipocyte Fraction

The Adipose Tissue Stromovascular Cell Fraction (SVF)

Adipose tissue macrophages are central mediators of inflammation in obesity

ATM increased in obesity and in VAT

(Cancello et al. Diabetes 2006, Curat et al. Diabetologia 2006, O’Rourke et al. Int J Obes 2009, )

Macrophages are a primordial metabolic cell: phylogenetically one of the oldest cell types, capacity for transdifferentiation to adipocytes, fibroblasts, other cells

Permana et al., BBRC 2006

Xu et al., JCI 2003

Kanda et al., JCI 2006

Adipose tissue macrophages: how do they get there and why are they important?

Recruited to sites of inflammation- adipocyte death/damage as trigger?

What ATM mediates homing to adipose tissue?

Primary source of inflammatory cytokine mediators

Key mediators of insulin resistance in adipocytes

DIABETES

DIABETES

NO DIABETES

Obesity

Obesity, Macrophages k/o

Lean, + Macrophages

Macrophage homing molecule tissue-specific knock-in and knock-out mice

Kamei et al. JBC 2006Weisberg et al. JCI 2006

The M1 - M2 Macrophage Model

M1:Acute Infection, trauma

M2:Scavenging,Tissue remodeling

Pathogenic tissue macrophage subpopulations;Tailoring macrophage phenotype

Lumeng et al.J Clin Invest 2007

Patsouris et al. Cell Metabolism 2008

Novel F4/80+CD11c+ obesity-specific ATM population

Designer macrophages?

0 102 103 104 105

CD14

0

102

103

104

105

CD

16

26.8

1.2

13.5

8.7

4.99

CD14+CD16-

CD14+CD16dim

CD14+CD16+

CD14+allCD14-CD16+

p=0.266

p=0.000

p=0.012

Inflammatory ATM subpopulations

It’s not all about macrophages…

“DIO VAT-associated T cells show severely biased T cell receptor Va repertoires, suggesting antigen-specific expansion”

O’Rourke et al., Int J Obes 2009

Winer et al., Nature Medicine 2009

T-cells, NK cells increased in VAT cw SAT, IFN- regulates inflammation

Wu et al., Circulation 2007

Adipose tissue T-cells increased in obesity

Kintscher et al., Arter Thromb Vasc Biol 2008

“T-cell infiltration…a primary event in AT inflammation and…insulin resistance”





How Does Adipose Tissue Inflammation “Go Systemic”?

Schoelson et al. JCI 2006

1. Portal Communication

2. Humoral effects of cytokines, adipokines

Adipose tissue

Liver 3. Systemic effects of excess FFA, i.e. lipotoxicity

4. Infiltration of macs, lymphos in non-AT tissue beds

Plus:5. CNS-peripheral interactions6. Shift in glucose/FA metabolism balance

The physiologic systems regulating inflammation, weight regulation, and diabetes are phylogenetically related

Arkan et al. Nat Med 2005

Agwunobi et al., J. Clin Endocrinol Metab 2000

Yuan et al. Science 2001

Stimulation of innate immune response with LPS >> insulin resistance

Aspirin, disruption of NFkB reverse insulin resistance

NFkB mediates insulin resistance

Williamson et al. BMJ 1901

Inflammation and diabetes

• ATM, liver macrophages, NKT cells, other tissue lymphocytes

• Adipose tissue effects on liver, muscle, other tissue glucose homeostasis via portal and humoral effects

• Beta cell, muscle, liver lipotoxicity

Cancer and Inflammation

Hepatocellular carcinoma

Inflammatory bowel disease

Chronic Pancreatitis

Barrett’s esophagus

Primary sclerosing cholangitis, viral hepatitis

Colorectal carcinoma

Pancreatic adenocarcinoma

Esophageal adenocarcinoma

Chronic H. pylori infection

Gastric adenocarcinoma, lymphoma

Chronic asbestos, silica irritation

Mesothelioma, lung cancer

1863: Rudolf Virchow proposed link between cancer and inflammation

Inflammation, obesity, and cancer

• Inflammatory processes involve fundamental cellular homeostasis systems, including proliferation, apoptosis, necrosis…

• Increased cellular damage, turnover secondary to chronic inflammation

• Specific cellular and molecular mediators:

1. Insulin, IGF-1: Diabetes is an independent risk factor for CA

2. Cytokines, adipokines: TNF-, leptin, adiponectin

3. Steroids: testosterone, estrogen, progesterone

4. Multiple downstream signaling pathways: mTOR, MAPK-Ras-Raf, Akt, JNK, NfkB…

Obesity-related cancer: Anabolism and Inflammation

• Caloric excess >>

• Increased nutrient delivery to cells >>

• Increased pro-proliferative signals: insulin, IGF, other growth factors >>

• Increased activation of pro-proliferation, anti-apoptotic signaling mediators (mTOR, JNK, Akt)

• All in the context of increased inflammatory mediators inducing chronic cell/DNA damage

Atherosclerosis, hypertension, and inflammation

Li et al. Nat Med 2002

Macrophages and T-cells mediate plaque progression

Atherosclerosis mayhave an infectious etiology

Insulin regulates vascular physiology and is implicated in hypertension,atherosclerosis

Other Co-morbidities and Inflammation

• Steatohepatitis• Hypertension• Sleep apnea

• Asthma• Allergy

• and more…

“Inflammation is The Root Cause of All Major Diseases”





Adipose tissue hypoxia: the evidence

• Direct measurement of tissue pO2

• Chemical tracers e.g. pimonidazole

• Hypoxia-inducible genes

n=8AD 143, 144, 146-151

Reviews:Trayhurn et al., Br J Nutr 2008Ye, Int J Obes 2009

Adipocyte hypoxia

O2

1. Hypoxia-inducible gene expression

2. Endoplasmic reticulum stress

3. Mitochondrial/oxidative stress

Surviving hypoxic adipocytes

Deadadipocytes

Recruitment of scavenging lymphocytes, activation of inflammatory danger responses: TLR, PAMPs, DAMPs

Adipocyte diameter

Obese Lean Obese Lean

VAT SAT

* p=0.017

p=0.448

*p=0.020

*p=0.003

c/w data from others:Drolet et al. Int J Obes 2008Tchoukalova et al. Am J Clin Nut 2008Winkler et al. Eur J Endocrinol 2003

Adipose tissue capillary density

ATBF decreased in human obesity:Jansson et al. Eur J Clin Invest 1998Blaak et al. Metabolism 1995

In vivo measurement of tissue pO2

Blood content

VAT

SAT

In vitro study of hypoxia

Obese adipose tissue is more susceptible to hypoxia induced inflammation…

…and stress gene transcription

*

* **

*

What’s the point?Hypoxia-based therapy…

N H H + SP6

*p=0.006 *p=0.011

Regazetti et al. Diabetes 2009

Transduction of 3T3L1 adipocytes with HIF-1 siRNA attenuates in vitro insulin resistance

Small molecule inhibition of JNK in primary human adipose tissue SVF attenuates in vitro inflammation

…cytokine-based therapy…

2007

p=0.020

Thank you




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Adipose Tissue Inflammation in Obesity Robert W. O’Rourke, M.D. Associate Professor Co-Director, Bariatric Surgery Program Department of Surgery Oregon