InsermInstitut National de la Santéet de la Recherche Médicale

Physiopathology of obesity and current theories on the association between an excess

of fat mass and insulin resistance

Prof. Dominique Langin

ContentsContents

Fat stores, adipose tissue and complications of obesity 3-7

White and brown adipose tissues: Adipocyte differentiation 8-13

Metabolism and pathogenic action of fatty acids 14-23

Diversity of adipose tissue cell types and production of endocrine 24-22and paracrine factors

Summary 33

Abbreviations used 34-36

Slides

Fat stores, adipose tissue and complications of obesity

Fat mass, adipose tissue and energy stores

Data for a 70 kg lean subject. Subject with morbid obesity : x 8 TG

Adipose tissue triglycerides = Adipose tissue triglycerides =

120,000 kcal120,000 kcal

Muscle triglycerides =

3000 kcal

Liver triglycerides = 450 kcal

Liver glycogen = 400 kcal

Muscle glycogen =

2500 kcal

Subcutaneous adipose tissue :- abdominal- femoral

Intraabdominal adipose tissue :- visceral (mesenteric and omental)- retroperitoneal (perirenal and perigonadic)

Other depots :- intra and intermuscular- perivascular- epicardiac

Anatomical distribution of adipose tissueAnatomical distribution of adipose tissue

Different physiological and pathogenic roles of the fat depots

Heterogeneous distribution of adipose tissue and risks of metabolic and cardiovascular complications

Heterogeneous distribution of adipose tissue and risks of metabolic and cardiovascular complications

Visceral vs. subcutaneous

obesity

Gender differences

Differences in risk for complications

Dyslipidemia, type 2 diabetes, hypertension, coronary heart disease, …

The apple The pear

Nature. 2006 444:881-7

Pulmonary diseasePulmonary diseaseabnormal functionabnormal functionobstructive sleep apneaobstructive sleep apneahypoventilation syndromehypoventilation syndrome

Nonalcoholic fatty liver Nonalcoholic fatty liver diseasediseasesteatosissteatosissteatohepatitissteatohepatitiscirrhosiscirrhosis

Coronary heart diseaseCoronary heart disease

DiabetesDiabetes

DyslipidemiaDyslipidemia

HypertensionHypertension

Gynecologic abnormalitiesGynecologic abnormalitiesabnormal mensesabnormal mensesinfertilityinfertilitypolycystic ovarian syndromepolycystic ovarian syndrome

OsteoarthritisOsteoarthritis

SkinSkin

Gall bladder diseaseGall bladder disease

CancerCancerbreast, uterus, cervixbreast, uterus, cervixcolon, esophagus, pancreascolon, esophagus, pancreaskidney, prostatekidney, prostate

PhlebitisPhlebitisvenous stasisvenous stasis

GoutGout

Medical Complications of Obesity

Idiopathic intracranial Idiopathic intracranial hypertensionhypertension

StrokeStroke

CataractsCataracts

Severe pancreatitisSevere pancreatitis

White and brown adipose tissues

Adipocyte differentiation

White adipose tissue

For letter symbols, see slide 36

WAT

BAT

For letter symbols, see slide 36

Characteristics of brown and white adipocytes

White adipocyte Unilocular adipocyte ( 200µm)Lipid storage and mobilization (+++)Mitochondria (+)Fatty acid oxidation (+)Respiratory chain (+)UCP1 (0)

PGC-1 (+)

Brown adipocyteMultilocular adipocyteLipid storage and mobilization (++)Mitochondria (+++)Fatty acid oxidation (+++)Respiratory chain (+++)UCP1 (+++)

PGC-1 (+++)

proliferation

fat cell-specific gene expression

differentiation

Transcriptional control of adipocyte differentiation

Wnt signalingGATA 2 & 3

SREBP1c / ADD1

C/EBP /

PPAR

C/EBP

RXRPPAR

J. Lipid Res., 2002, 43, 835-860

Genes Dev, 2000, 14, 1293-1307

Thermogenesis Fat storage &mobilizationEndocrine organ

PGC-1

Biochem J. 2006 398:153-68

PRDM16

Metabolism and pathogenic action of fatty acids

Alternate fuel sourcefor brain and other organs Liver

Ketone bodiesand CO2

VLDL Adipose tissue

TG LPL Lipases

Chylomicrons(lymphatic circulation)

Intestinal absorption Muscle,myocardium,kidney cortex,

etc.

LPL

TG

CO2

FA

TG NEFA

NEFA

Overview of fatty acid metabolism

Essays Biochem. 2006;42:89-103.

Triglycerides

CL

Fatty acids

DGAT

CD36 FAT

ASP LPL

VLDL

Fatty acids

ATP

CO

OH

NH2

2-AR1- 2- 3- AR

AC

cAMP

PKA

5' AMP

COOH

NH2

GiGs

Perilipins

HSL HSL

ALBP

P

Pyruvate

Glucose

Glucose 6-P

Glycerol 3-P

GLUT4

Acetyl-CoA

Fatty acids

GLUT4PDE 3B

IR

IRS

PI3-K

PKB

Fatty acid and glucose metabolism in white adipocytes

ATGL

cAMP

2-AR, HM74A, A1 receptor, EP3 receptor, Y1 receptor

PKA

PerilipinPDE-3B

FFA

1/2-AR,Others ?

triglyceridesPKG

Natriuretic peptide receptor A

cGMP

ALBP-FAGC

AC

Gs

Gi

HSLIRS

PI3-K

PKB

Insulinreceptor

HS

L

?

ATGL

glycerol

AMPK MGL

Aquaporin 7?

Lipolysis in human white adipocytes

Pharmacol. Res. 2006 53:482-91

Pancreas

Fed Fasting

Gut

Triglycerides

Coordination of the regulation of fat deposition and fat

mobilization in white adipose tissue

Triglycerides

LPL

Glut4

Glucose

Glycerol3-phophate

FattyAcids

+Glycerol To liver

To liver,muscle

Insulin

Esterification

Fattyacids

+

+

+

Lipases

- Catecholamines

ANP, BNP

+

1, 2, 3

cAMP PKA

AC

Gs

Plasma membrane

Mitochondrial biogenesis (PGC1)

UCP1 transcription

Lipolysis (FA)

UCP1 activation

oxidation

THERMOGENESIS

Adrenergic control of metabolism in brown fat cells

Differences in the fate of fatty acids between brown

and white fat cells

FAFA

Glycerol

Lipolysis

FA esterification

FA

Glycerol

TriglyceridesFA

Glycerol-3P

FA

Glycerol

FA

oxidation

FA

Glycerol

Triglycerides

White adipocyte Brown adipocyte

Glycerol-3P

Glucose, amino acids, lactate, pyruvate

Lipolysis

FA esterification

FA

Glycerol, glucose

FA

Hyperinsulinemia

Hypertension

Insulinresistance

Increased lipolysis

HDL-C

LDL particle size

Glucose production

Glucose utilisation

Glucose intolerance

VLDL secretion

Triglycerides

Thrombosis

Myocardial performance

SNS activity

Antilipolytic

effect

NEFA

Deleterious effects of an excess of nonesterified fatty acids

Obesity complications

Increased synthesis of TG-rich VLDL

Visceral adipose tissue

Glucose intoleranceInsulin resistance

Hyperlipidemia

Liver

Hepatic glucose

production

Glucoseutlization

Skeletalmuscle

Pancreas

FA hepatic flux

Portal and visceral FA

Hyperinsulinemia

VesselsThrombosis

HeartMyocardialperformance

Role of fatty acids in obesity complicationsSubcutaneous adipose tissue

Abdominal FA

Non alcoholic steatohepatitis

A combination of PGC-1 inducers and nuclear receptor

ligands may constitute a strategy to combat obesity

PGC1

Lipid utilization

Fat mass?

Nuclearreceptors

LigandsInducers

Potential therapeutic strategies associated with fatty acid metabolism

HM74a

cAMP

AC

Gi

HSL

PKA

Lipolysis

ATGL

Nicotinicacid

Inhibitors

Antilipolysis as a strategy to combat the

metabolic syndrome

Trends Endocrinol Metab 2003;14 :439-441.Trends Endocrinol Metab 2006 ;17 :314-320.

Diversity of adipose tissue cell types and production of endocrine

and paracrine factors

Macrophages

Adipocytes

PreadipocytesEndothelial cells

MonocytesLymphocytes

Cell types in white adipose tissue

- adipocytes (lipid-filled cells) 30%- preadipocytes and fibroblasts- matrix of collagen fibres- blood vessels (capillaries/endothelial cells)- immune cells (monocytes/macrophages, lymphocytes)

ADIPOCYTE HYPERTROPHY

& HYPERPLASIA

ADIPOCYTE HYPERTROPHY

& HYPERPLASIA

ANGIOGENESISANGIOGENESIS

INFLAMMATIONINFLAMMATIONMacrophages

Mature adipocytes

Preadipocytes

Endothelial cells

Mature adipocytes

Preadipocytes

Adipose tissue development : beyond adipocyte differentiation

Cellular origin of the peptides secreted by human adipose tissue

Adipocytes Adipokines Stromavascular fraction cells cytokines & chemiokines

Monocyte chemoattractant protein 1 (MCP1)Macrophage inflammatory protein (MIP)Tumor necrosis (TNF)Interleukins 1, 6, 8, 10, ….ChemiokinesResistinApelin…

LeptinAdiponectinSerum amyloidsRetinol binding protein 4 (RBP4)ApelinFIAF/PGAR

Hypertrophy of adipocytes& triglyceride overload

Activation andinfiltration of

macrophages

Adiponectin

TNF-MIP-1MCP-1others

MCP-1MIP-1others

TNF-others

TNF-MCP-1IL-1others

NEFAothers

HYPERTROPHIEDADIPOCYTE

ADIPOCYTE

MacrophageNEFAs

Leptin

Cytokines

preadipocyte

Crosstalk between the cells

FA,Other metabolites,Adipokines,…

TNF,Cytokines,Chemiokines,…

FA

Glycerol-3P

FA

Glycerol

FA

oxidation

Lipolysis

FA esterification

Triglycerides

monocytes activation adhesion

transmigration

differentiation

VEGFM-SCFMIFLPA….

retention

macrophages

leptin/adiponectininterplayMCP-1

proteases

proinflammatory cytokinesreactive oxygen species (ROS)

Adipocyte

endothelial dysfunctioninsulin resistance

PECAM-1, ICAM-1PECAM-1, ICAM-1

local effects:angiogenesis,

neovascularizationadipose growth

systemic effects:low-grade

inflammatory state

Systemic and local roles of adipose tissue macrophages

Curr. Opin. Clin. Nutr. Metab. Care, 2005, 8: 347

TNF-, IL-6, IL-8MCP-1, resistin,

visfatin……

Bone marrow

Adipose tissue infiltration by macrophages in obesity

J. Clin. Invest. 2006;116:33-35J. Intern. Med. 2007;262:422-430

Role of adipokines and cytokines in obesity complications

IL-6TNF-

Liver

utilisation glucose

Skeletalmuscle

macrophages

Other target tissues Vessels

atherosclerosis, hypertension

Secretions :LeptinAdiponectinRBP4

TNF-, IL-6…

Non alcoholic CRPsteatohepatitis PAI1

Visceral adipose tissueSubcutaneous adipose tissue

Obesity complications

Glucose intoleranceInsulin resistance

Fatty acids,Adipokines,Other peptides

Insulin resistance

Lipid mediators,Adipokines

Fatty acids,Adipokines,Other peptides

Diabetes, cardiovascular disease,…

Obesity

To summarize : …

AC Adenylyl cyclase

ADD1/SREBP1 =SREBP1c (see below)

ALBP Adipocyte lipid binding protein

AMPK AMP-activated protein kinase

ANP Atrial natriuretic peptide

AR (α, etc) Adrenoreceptors

ASP Acylation stimulating protein

ATGL Adipose triglyceride lipase

BNP Brain natriuretic peptide

C/EBP (α etc) CCAAT enhancer binding protein

CBP/p300 CREB- (cAMP response element binding protein) binding transcriptional adaptor protein

CD36/FAT Gene for long-chain FA transport in the plasma membrane

CL Cholesterol

CRP C-reactive protein

DGAT Diacylglycerol acyltransferase

FIAF Fasting-induced adipose factor

GATA 2 &3 Transcription factors binding to the GATA sequence

Gi, Gs Guanine binding proteins (i = inhibiting, s = stimulating)

HDL High-density lipoprotein

HM74A The nicotinic acid receptor GPR109A

HSL Hormone-sensitive lipase

Abbreviations Abbreviations Used: IUsed: I

Abbreviations Abbreviations Used: IIUsed: II

ICAM Intercellular adhesion molecule

IL Interleukin

IR Insulin receptor

IRS Insulin receptor substrate

LPA Lysophosphatidic acid

LPL Lipoprotein lipase

MCP1 Monocyte chemotactic protein 1

MGL Monoglyceride lipase

MIP Macrophage migration inhibitory factor

M-SCF Membrane-bound stem cell factor

NEFA Non-esterified fatty acids

P13-K Phosphatidylinositide 3-kinase

PAI1 Plasminogen activator inhibitor-1

PCAF p300/CBP-associated factor

PDE 3B Phosphodiesterase 3B

PECAM Platelet/endothelial cell adhesion molecule 1

PGAR = FIAF

PGC (1, α, etc) Peroxisome-proliferator-activated receptor-gamma co-activator

PKA Protein kinase A

PKB Protein kinase B

PKG Protein kinase G

Abbreviations Abbreviations Used: IIIUsed: III

PPAR (α etc) Peroxisome proliferator-activated receptors

RBP4 Retinol binding protein 4

RXR (α etc) Retinoid X receptor

SNS Sympathetic nervous system

SRC1 Steroid receptor coactivator-1

SREBP1c Sterol Regulatory Element Binding Protein 1c

TG Triglyceride

TNF Tumour necrosis factor

UCP-1 Uncoupling protein 1

VEGF Vascular endothelial growth factor

VLDL Very low density lipoprotein

Wnt Wingless-type MMTV* integration site family member (signaling pathway) *Mouse mammary tumour virus

Slides 8,9

C Cytosol

D Droplet (Lipid droplet)

F Fibroblast

L Lipid

M Mitochondrion

N Nucleus