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