Transcript Slide 1

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
and paracrine factors
24-22
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
abnormal function
obstructive sleep apnea
hypoventilation syndrome
Nonalcoholic fatty liver
disease
steatosis
steatohepatitis
cirrhosis
Gall bladder disease
Idiopathic intracranial
hypertension
Stroke
Cataracts
Coronary heart disease
Diabetes
Dyslipidemia
Hypertension
Severe pancreatitis
Gynecologic abnormalities
Cancer
abnormal menses
infertility
polycystic ovarian syndrome
breast, uterus, cervix
colon, esophagus, pancreas
kidney, prostate
Osteoarthritis
Skin
Gout
Phlebitis
venous stasis
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
Brown adipocyte
Multilocular 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
PGC-1a
Fat storage &
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
VLDL
Adipose tissue
LPL
Chylomicrons
(lymphatic circulation)
TG
Lipases
LPL
NEFA
TG
Intestinal absorption
Essays Biochem. 2006;42:89-103.
CO2
FA
Muscle,
myocardium,
kidney cortex,
etc.
Fatty acid and glucose metabolism in white adipocytes
b1- b2- b3- AR
a2-AR
IR
Glucose
VLDL CL
ASP
NH2
LPL
NH2
AC
Gs
CD36
FAT
GLUT4
Gi
IRS
ATP
GLUT4
PDE 3B
PI3-K
cAMP
Glucose 6-P
5' AMP
PKB
PKA
ATGL
HSL
Pyruvate
ALBP
Glycerol 3-P
Acetyl-CoA
HSL
P
Perilipins
Fatty acids
Fatty acids
DGAT
Triglycerides
Fatty acids
Lipolysis in human white adipocytes
FFA glycerol
Natriuretic peptide
receptor A
Insulin
receptor
?
Aquaporin 7
ALBP-FA
GC
MGL
AMPK
HSL
PI3-K
PKG
?
PKB
HSL
cGMP
IRS
triglycerides
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
+ acids
Esterification
Gut
+
Glycerol
3-phophate
Glucose
Glut4
Pancreas
+
Insulin
Triglycerides
- +
Lipases
Fatty
Acids
+
Glycerol
Catecholamines
ANP, BNP
To liver,
muscle
To liver
Adrenergic control of metabolism in brown fat cells
b 1, b 2, b 3
A
C
Plasma
membrane
Gs
Mitochondrial biogenesis
(PGC1)
cAMP
PKA
UCP1 transcription
UCP1
activation
Lipolysis (FA)
b oxidation
T
H
E
R
M
O
G
E
N
E
S
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
esterification
FA
Triglycerides
b oxidation
FA
FA
FA
esterification
Glycerol-3P
Glycerol-3P
Glucose, amino acids,
lactate, pyruvate
Glycerol, glucose
Triglycerides
Deleterious effects of an excess of nonesterified fatty acids
SNS activity
Triglycerides
Myocardial
performance
Increased
lipolysis
Thrombosis
VLDL secretion
NEFA
Glucose
utilisation
Antilipolytic
effect
HDL-C
Insulin
resistance
LDL particle size
Glucose
production
Glucose
intolerance
Hyperinsulinemia
Hypertension
Role of fatty acids in obesity complications
Subcutaneous adipose tissue
Vessels
Thrombosis
Visceral adipose tissue
Portal and visceral FA
Abdominal FA
Heart
Myocardial
performance
FA hepatic flux
Skeletal
muscle
Liver
Non alcoholic
steatohepatitis
Increased synthesis
of TG-rich VLDL
Hepatic
glucose
production
Glucose
utlization
Pancreas
Glucose intolerance
Insulin resistance
Hyperlipidemia
Obesity complications
Hyperinsulinemia
Nicotinic
acid
Potential therapeutic strategies associated with
fatty acid metabolism
HM74a
Inducers
Ligands
A
C
Gi
PGC1a
Inhibitors
Nuclear
receptors
cAMP
PKA
Fat
mass?
ATGL
Lipid
utilization
HSL
Lipolysis
Antilipolysis as a strategy to combat the
metabolic syndrome
A combination of PGC-1a inducers and nuclear receptor
ligands may constitute a strategy to combat obesity
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
Endothelial cells
Monocytes
Preadipocytes
Adipocytes
Adipose tissue development : beyond adipocyte
differentiation
Mature
Preadipocytes
adipocytes
ADIPOCYTE
HYPERTROPHY
& HYPERPLASIA
Endothelial
cells
Mature
adipocytes
ANGIOGENESIS
INFLAMMATION
Macrophages Preadipocytes
Cellular origin of the peptides secreted
by human adipose tissue
Adipocytes  Adipokines
Leptin
Adiponectin
Serum amyloids
Retinol binding protein 4 (RBP4)
Apelin
FIAF/PGAR
Stromavascular fraction cells
 cytokines & chemiokines
Monocyte chemoattractant protein 1 (MCP1)
Macrophage inflammatory protein (MIP)
Tumor necrosis a (TNFa)
Interleukins 1b, 6, 8, 10, ….
Chemiokines
Resistin
Apelin
…
Crosstalk between the cells
Hypertrophy of adipocytes
& triglyceride overload
Adiponectin
ADIPOCYTE
NEFA
others
Leptin
MCP-1
MIP-1a
others

preadipocyte
NEFAs
TNF-a
others
Activation and
infiltration of
macrophages

HYPERTROPHIED
ADIPOCYTE
TNF-a
MCP-1
IL-1b
others
Cytokines
TNF-a
MIP-1a
MCP-1
others

FA,
Other metabolites,
Adipokines,
…
Glycerol
Lipolysis
Triglycerides
FA
FA
FA
b oxidation
FA esterification
Glycerol-3P
TNFa,
Cytokines,
Chemiokines,
…
Systemic and local roles of adipose tissue macrophages
activation
monocytes
Bone
marrow
adhesion
transmigration
PECAM-1, ICAM-1
PECAM-1, ICAM-1
MCP-1
proteases
systemic effects:
low-grade
inflammatory state
endothelial dysfunction
insulin resistance
leptin/adiponectin
interplay
differentiation
macrophages
retention
TNF-a, IL-6, IL-8
MCP-1, resistin,
visfatin……
Adipocyte
VEGF
M-SCF
MIF
LPA….
proinflammatory cytokines
reactive oxygen species (ROS)
local effects:
angiogenesis,
neovascularization
adipose growth
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
IL-6
TNF-a
Liver
macrophages
Secretions :
Leptin
Adiponectin
RBP4
Skeletal
muscle
utilisation
glucose
Non alcoholic CRP
steatohepatitis PAI1
Glucose intolerance
Insulin resistance
Obesity complications
TNF-a, IL-6…
Other target tissues
Vessels
atherosclerosis,
hypertension
To summarize : …
Obesity
Fatty acids,
Adipokines,
Other peptides
Lipid
mediators,
Adipokines
Fatty acids,
Adipokines,
Other peptides
Insulin resistance
Diabetes, cardiovascular disease,…
Abbreviations
Used: I
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
Used: 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
Used: 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