Physiopathology of obesity and current

theories on the association between an excess

of fat mass and insulin resistance
Prof. Dominique Langin

Inserm
Institut National de la Santé
et de la Recherche Médicale
 Contents

Slides

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 24-22

and paracrine factors

Summary 33

Abbreviations used 34-36

Fat stores, adipose tissue and
complications of obesity
 Fat mass, adipose tissue and energy stores

Liver triglycerides = 450 kcal

Muscle triglycerides =
Liver glycogen = 400 kcal 3000 kcal

Muscle glycogen =
2500 kcal

Adipose tissue triglycerides =

120,000 kcal

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

 Anatomical distribution of adipose tissue
Subcutaneous adipose tissue :
- abdominal
- femoral

Intraabdominal adipose tissue :

- visceral (mesenteric and omental)
- retroperitoneal (perirenal and perigonadic)

Other depots :
- intra and intermuscular
- perivascular
- epicardiac

Different physiological and pathogenic roles of the fat depots

Heterogeneous distribution of adipose tissue and risks of
metabolic and cardiovascular complications
The apple The pear

Visceral vs.
subcutaneous
obesity

Gender differences

Differences in risk for

complications

Dyslipidemia, type 2 diabetes,

hypertension, coronary heart disease, …
Nature. 2006 444:881-7
 Medical Complications of Obesity

Pulmonary disease Idiopathic intracranial

abnormal function hypertension
obstructive sleep apnea Stroke
hypoventilation syndrome
Cataracts
Nonalcoholic fatty liver Coronary heart disease
disease
Diabetes
steatosis
steatohepatitis Dyslipidemia
cirrhosis Hypertension

Gall bladder disease Severe pancreatitis

Gynecologic abnormalities Cancer
abnormal menses breast, uterus, cervix
infertility colon, esophagus, pancreas
polycystic ovarian syndrome kidney, prostate

Osteoarthritis
Phlebitis
Skin venous stasis
Gout
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
Multilocular adipocyte
Brown adipocyte Lipid storage and mobilization (++)
Mitochondria (+++)
Fatty acid oxidation (+++)
Respiratory chain (+++)
UCP1 (+++)

PGC-1a (+++)

White adipocyte Unilocular adipocyte ( 200µm)

Lipid storage and mobilization (+++)
Mitochondria (+)
Fatty acid oxidation (+)
Respiratory chain (+)
UCP1 (0)

PGC-1a (+)
 Transcriptional control of adipocyte differentiation

SREBP1c / ADD1

PPAR b RXRa
PPAR g

C/EBP b/d C/EBP a

Wnt signaling
GATA 2 & 3
proliferation differentiation

fat cell-specific
gene expression

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

 Thermogenesis Fat storage &
PGC-1a mobilization
Endocrine organ

PRDM16

Genes Dev, 2000, 14, 1293-1307 Biochem J. 2006 398:153-68

Metabolism and pathogenic action
of fatty acids
 Overview of fatty acid metabolism

Alternate fuel source

for brain and other organs Liver
TG NEFA
Ketone bodies
and CO2
Adipose tissue
VLDL
TG
LPL
Lipases

Chylomicrons
(lymphatic circulation) LPL
NEFA
TG

Intestinal absorption FA Muscle,

CO2 myocardium,
kidney cortex,
Essays Biochem. 2006;42:89-103. etc.
Fatty acid and glucose metabolism in white adipocytes

IR
b1- b2- b3- AR a2-AR Glucose VLDL CL
NH2 ASP LPL
NH2

AC GLUT4 CD36
FAT
Gs Gi
IRS
ATP GLUT4
PDE 3B PI3-K
cAMP
Glucose 6-P
5' AMP
PKB
PKA Pyruvate
Fatty acids
ALBP Acetyl-CoA
ATGL Glycerol 3-P
HSL HSL
Fatty acids
P
Perilipins DGAT

Triglycerides Fatty acids

 Lipolysis in human white adipocytes
FFA glycerol
Natriuretic peptide
receptor A ?
Aquaporin 7
Insulin ALBP-FA
receptor GC
AMPK MGL

IRS
cGMP

HSL
HSL triglycerides
PI3-K PKG
?
PKB PDE-3B

PKA

b1/2-AR,
Others ?

a2-AR, HM74A, A1 receptor, EP3

receptor, Y1 receptor Pharmacol. Res. 2006 53:482-91
Coordination of the regulation of fat deposition and fat
mobilization in white adipose tissue
Fed Fasting
Triglycerides LPL
Fatty
Gut + acids
Esterification
+ Triglycerides
Glycerol
- + Catecholamines
3-phophate ANP, BNP
Lipases

Glucose
Fatty To liver,
Glut4
+ Acids muscle
+
Glycerol
To liver

Pancreas Insulin
 Adrenergic control of metabolism in brown fat cells

b 1, b 2, b 3

A Plasma membrane
C
Gs
T
Mitochondrial biogenesis H
(PGC1) E
R
M
cAMP PKA UCP1 transcription O
G
UCP1 E
N
activation E
Lipolysis (FA) S
b oxidation I
S
 Differences in the fate of fatty acids between brown
and white fat cells
White adipocyte Brown adipocyte

Glycerol Glycerol

FA FA
Glycerol
Glycerol FA

Lipolysis Lipolysis
FA FA
FA
FA FA
FA Triglycerides b oxidation Triglycerides
FA FA
esterification esterification
Glycerol-3P
Glycerol-3P
Glucose, amino acids,
lactate, pyruvate Glycerol, glucose
Deleterious effects of an excess of nonesterified fatty acids
SNS activity

Triglycerides Myocardial Increased

performance
lipolysis
Thrombosis

Antilipolytic
effect HDL-C
VLDL secretion
NEFA Insulin
resistance
Glucose LDL particle size
utilisation
Glucose
production

Glucose
intolerance Hyperinsulinemia
Hypertension
 Role of fatty acids in obesity complications
Subcutaneous adipose tissue
Visceral adipose tissue Vessels
Thrombosis

Heart
Portal and visceral FA Abdominal FA Myocardial
performance

FA hepatic flux

Liver Skeletal
muscle
Non alcoholic Hepatic
Glucose
steatohepatitis glucose
utlization
production
Pancreas
Increased synthesis
of TG-rich VLDL Hyperinsulinemia
Glucose intolerance
Insulin resistance
Hyperlipidemia

Obesity complications
 Potential therapeutic strategies associated with
Nicotinic
acid fatty acid metabolism
HM74a
Inducers Ligands

A
C
Gi
PGC1a
Nuclear
Inhibitors cAMP receptors

PKA
Fat Lipid
mass? utilization
ATGL HSL

Lipolysis A combination of PGC-1a inducers and nuclear receptor

Antilipolysis as a strategy to combat the ligands may constitute a strategy to combat obesity
metabolic syndrome
Trends Endocrinol Metab 2006 ;17 :314-320. Trends Endocrinol Metab 2003;14 :439-441.
 Diversity of adipose tissue cell
types and production of endocrine
and paracrine factors
 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)

Macrophages
Lymphocytes Monocytes Preadipocytes
Endothelial cells
Adipocytes
 Adipose tissue development : beyond adipocyte
differentiation

Mature Preadipocytes
adipocytes Endothelial Mature
cells adipocytes
ADIPOCYTE
HYPERTROPHY
& HYPERPLASIA

ANGIOGENESIS

INFLAMMATION
Macrophages Preadipocytes
 Cellular origin of the peptides secreted
by human adipose tissue
Adipocytes  Adipokines Stromavascular fraction cells
 cytokines & chemiokines

Monocyte chemoattractant protein 1 (MCP1)

Leptin
Macrophage inflammatory protein (MIP)
Adiponectin
Tumor necrosis a (TNFa)
Serum amyloids
Interleukins 1b, 6, 8, 10, ….
Retinol binding protein 4 (RBP4)
Chemiokines
Apelin
Resistin
FIAF/PGAR
Apelin
…
 Crosstalk between the cells

Hypertrophy of adipocytes
& triglyceride overload Adiponectin ADIPOCYTE
NEFA
 others
Leptin MCP-1
MIP-1a
TNF-a
others
MCP-1
HYPERTROPHIED preadipocyte IL-1b
ADIPOCYTE others

TNF-a
 others
NEFAs

TNF-a
MIP-1a
Activation and MCP-1
infiltration of

Cytokines others
macrophages
 FA,
Other metabolites,
Adipokines,
…
Glycerol

Lipolysis
FA FA
Triglycerides
FA
b oxidation
FA esterification

Glycerol-3P

TNFa,
Cytokines,
Chemiokines,
…
 Systemic and local roles of adipose tissue macrophages

monocytes activation adhesion endothelial dysfunction

Bone insulin resistance
transmigration
marrow
PECAM-1, ICAM-1 PECAM-1, ICAM-1

leptin/adiponectin
MCP-1 interplay
proteases
differentiation
systemic effects:
low-grade
macrophages Adipocyte
inflammatory state
retention VEGF
M-SCF
local effects:
MIF angiogenesis,
LPA…. neovascularization
TNF-a, IL-6, IL-8 adipose growth
proinflammatory cytokines
MCP-1, resistin, reactive oxygen species (ROS)
visfatin……
Curr. Opin. Clin. Nutr. Metab. Care, 2005, 8: 347
Adipose tissue infiltration by macrophages in obesity

J. Clin. Invest. 2006;116:33-35

J. Intern. Med. 2007;262:422-430
Role of adipokines and cytokines in obesity complications
Subcutaneous adipose tissue
Visceral adipose tissue

macrophages
IL-6
TNF-a Secretions :
Leptin
Adiponectin
RBP4

Liver Skeletal TNF-a, IL-6…

muscle

utilisation
glucose Other target tissues
Non alcoholic CRP Vessels
steatohepatitis PAI1 Glucose intolerance atherosclerosis,
Insulin resistance hypertension

Obesity complications
 To summarize : …

Obesity
Lipid
Fatty acids, mediators, Fatty acids,
Adipokines, Adipokines Adipokines,
Other peptides Other peptides

Insulin resistance

Diabetes, cardiovascular disease,…

 AC Adenylyl cyclase
Abbreviations
ADD1/SREBP1 =SREBP1c (see below)
Used: I 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 ICAM Intercellular adhesion molecule

Used: II 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 PPAR (α etc) Peroxisome proliferator-activated receptors

Used: III 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