Transcript Adipose Tissue

Metabolic Impact of Adipose
Tissue
ALYSSA HASTY, PHD
ASSISTANT PROFESSOR
MOLECULAR PHYSIOLOGY & BIOPHYSICS
The Simplified Model
Obesity Trends Among U.S. Adults
between 1985 and 2002
Definitions:
 Obesity: having a very high amount of body fat in
relation to lean body mass, or Body Mass Index
(BMI) of 30 or higher
 Body Mass Index (BMI): a measure of an adult’s
weight in relation to his or her height, specifically
the adult’s weight in kilograms divided by the
square of his or her height in meters
Diseases Associated with Obesity
Diabetes: 80% related to obesity
Hypertension: prevalence is >40% in obesity
Heart disease: 70% related to obesity
Cancer: Obesity accounts for 15-20% of cancerrelated deaths
 Death: Obese individuals have a 50-100%
increased risk of death from all causes
compared to lean individuals (most of this
risk is due to cardiovascular disease)
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The Metabolic Syndrome
Central obesity
Glucose intolerance
Hypertension
Insulin resistance
High TG
Low HDL-C
Small, dense LDL particles
©1998
PPS
Prevalence of CHD, MI, and Stroke in Relation to the
Presence of Metabolic Syndrome
WITH Metabolic
Syndrome
30
25
20
All Subjects
NGT
IFG/IGT
Type 2 Diabetes
(n=3,928)
(n=1,808)
(n= 685)
(n=1,430)
15
10
5
0
30
CHD
Previous MI
Previous Stroke
25
Without Metabolic
Syndrome
20
15
10
5
0
CHD
Previous MI
Previous Stroke
Isomaa et al. 2001. Diabetes Care. 24:683-689.
Traditional CHD Risk Factors
 Elevated Plasma Cholesterol
 Reduced Plasma HDL Levels
 Diabetes
 Hypertension
 Smoking
 Age
New Markers
Inflammatory
Adipokines
Lipid Lowering only results in a relative risk
reduction of 30%
New Inflammatory Markers to assess Risk
 CRP
 IL-6
 TNFa
 Serum Amyloid A
 Non-esterified fatty acids
Adipose tissue is an important source of
inflammatory cytokine production
White Adipose Tissue (WAT)
 Many different adipose tissue beds throughout the
whole organism
 Many distinct cell types: adipocytes, preadipocytes, fibroblasts, macrophages, vascular cells
 Heterogeneous metabolic capabilities, depending
on visceral or subcutaneous location of fat depot
 Secrete adipokines with systemic effects
Gender Differences in Adipose Tissue
Distribution
Female
Male
Original Image
SCAT
Subcutaneous Adipose
Tissue
HIGHLIGHTED WHITE
VAT
Visceral Adipose
Tissue
HIGHLIGHTED WHITE
J. Magn. Reson. Imaging Vol.21, 4 Pages: 455-462
White Adipose Tissue
WAT is comprised of
2 Fractions:
1) adipocytes
2) SVF which consists of:
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preadipocytes
endothelial cells
macrophages
WAT is central to energy
storage in the body and
the mobilization of this
energy store is highly
regulated.
Basic Adipose Tissue Expansion
Preadipocyte
Mature adipocyte
http://www.hsph.harvard.edu/GSHLAB/adipos.html
Adipocyte Growth:
Hypertrophy vs. Hyperplasia
 Hypertrophy (increase in size)
“Lipogenesis”
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Result of excess triglyceride accumulation in
existing adipocytes
 Hyperplasia (increase in number)
 ‘adipogenesis’ results from the recruitment of new
adipocytes from precursor cells in adipose tissue
and involves proliferation and differentiation
Hausman et al. Obesity Reviews (2001) 2, 239-254
Hormones, Adipokines, enzymes, molecules and other factors reportedly associated with Adipose Tissue
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a-1 acid glycoprotein (AGP)
3a-hydroxysteroid dehydrogenase (3aHSD)
3-HSD
5a reductase
7a hydroxylase
11HSD
17HSD
Acylation-stimulatin protein (ASP or C3adesArg)
Adenosine
Adipocyte differentiation factor (ADF)
Adipogenin
Adiponectin
Adiponutrin
Adipohilin (adipose differentiation-related protein
[ADRP])
Adipose protein 2 (aP2 or adipocyte-specific fatty
acid-binding protein, otherwise known as 422
protein)
Adipose triglyceride lipase (ATGL)
Adipsin (ADN; complement factor D, C3
convertase activator and properdin factor D)
Agouti protein
Androgens
Angiotensin I and II
Angiotensin-converting enzyme (ACE)
Angiotensinogen (AGT)
Annexin (lipocortin)
Apelin
Aoplipoproteins E, C1 and D
Aquaporin 7 (AQP7)
Autotaxin (lyosphospholipase D)
Bone morphogenic protein (BMP)
C-reactive protein (CRP)
Calumenin
Calvasculin
Cathepsin D and G
Ceramide
Cholesteryl ester transfer protein (CETP)
Chymase
Collagen Type VIa3
Complement factor C3 and B
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Cytochrome p450-dependent aromatase
(P450arom)
E2F proteins
Ecto-nucleotide
pyrophosphatase/phosphodiesterase 1
Eicosanoids
Endothelin
Entactin/nidogen
Eotaxin
Epidermal growth factor
Estrogen
Fasting-induced adipose factor
Fatty acid translocase
Fatty acid transport protein
Fibroblast growth factor
Free Fatty Acids
Galectin-12
Gelsolin
Glucose transporter 4
Glutamine
Glycerol
Haptoglobin
Hippocampal cholinergic neurostimulating
peptide
Hormone-sensitive lipase
Insulin-like growth factor
Insulin-like growth factor binding protein
Interleukin-1, -6, -8, and -10
Interleukin-1 receptor antagonist
Lactate
Leptin
Lipin
Lipocalins
Lipoprotein lipase
Lysophospholipid
Macrophage migration inhibitory factor
Metalloproteases
Metallothionein
Monobutyrin
Monocyte chemoattractant protein-1
Necdin
Nerve growth factor
Neuronatin
Bays
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Nitric oxide synthase
Nuclear factors
Omentin
Osteonectin (secreted protein, acidic and rich
in cystein/SPARC)
Pentraxin-3
p85aphosphatidylinositol 3-kinase
Perilipins
Phosphoenolpyruvate carboxykinase
Phospholipid transfer protein
Pigment epithelium-derived factor
Plasminogen activator inhibitor
Pre-adipocyte factor-1
Prolactin
Protein kinases
Protease inhibitors (e.g., cystatin C and
Colligin-1)
Prostaglandin E, I2 and F2 prostacyclins
(PGI2/PGF2)
Regulated on activation, normal T-cell
expressed and secreted (RANTES)
Renin
Resistin (FIZZ3 or serine/cystein-rich
adipocyte-specific secretory factor [ADSF])
Resistin-like molecules
Retinol
Retinol-binding protein
Sergin protease inhibitors
Serum amyloid A
Stearoyl-CoA desaturase
Stromal cell-derived factors (e.g., stromal
cell-derived factor 1 precursor or pre-B
growth stimulating factor)
Tissue factor
Tonin
Transforming growth factor-
Tumor necrosis factor-a
UDP-glucuronosyltransferase A242B15
Uncoupling proteins
Vascular endothelial growth
Visceral adipose tissue-derived serpin
Visfatin (pre- cell colony-enhancing factor
[PBEF])
H & Ballantyne C; Future Lipidol 2006; 1(4): 389
Free Fatty Acids (FFA)
 Adipose tissue serves as a buffer for FFA levels
following feeding (similar to the way liver buffers
blood glucose levels)
 FFA are released from WAT when systemic energy
needs are not being met
 FFA levels are a predictor of future development of
type 2 diabetes
Effects of elevated plasma FFA levels
 Insulin resistance in muscle
 Inhibition of normal function of insulin to
suppress hepatic glucose production
 Impair insulin-stimulated glucose uptake
 FFA are substrate for hepatic triglyceride
synthesis leading to increased plasma VLDL and
triglyceride levels
 Impair endothelial function
Control of Release of FFA From White Adipose Tissue
Lipid storage
Diet
WAT
Starvation
Lipolysis
Insulin Resistance
Insulin
Free Fatty Acid
Liver
Ketone
bodies
Phospholipids
Triglycerides
Hypertriglyceridemia
Atherosclerosis
Secretory Products of Adipose Tissue
Resistin
Bone
Morphogenic
Protein
IGF-1
IGFBP
TNF-α
Interleukins
TGF β
FGF
EGF
Adipose
Tissue
Adiponectin
Fatty Acids
Lactate
Adenosine
Prostaglandins
Glutamine
Unknown Factors
Estrogen
Ang II
Angiotensinogen
PAI-1
Leptin
Adapted from: Roth, J, et al, Obesity Research, Vol 12, supplement Nov 2004:88S-101S
Adipokines
 Vascular Disease Related
 Angiotensinogen
 PAI-1
 Insulin Resistance Related
 ASP (Acylation-stimulating protein)
 TNFa
 IL-6
 Resistin
 Leptin
 Adiponectin
Angiotensinogen (AGE)
 Links obesity with hypertension
 Positive correlation of blood pressure with AGE
levels
 Primarily produced in liver, but also by WAT
 Deficiency partially protects against diet-induced
obesity
Plasminogen Activator Inhibitor 1 (PAI-1)
 Impairment of fibrinolytic system contributes to
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cardiovascular complications of obesity
WAT is main tissue source of PAI-1
Produced by pre-adipocytes, primarily in visceral WAT
Acts to inhibit fibrinolysis (is pro-thrombotic)
Also influences cell migration and angiogenesis
Could impair pre-adipocyte migration leading to WAT
growth
TNFa
 Proinflammatory cytokine
 Produced by adipocytes and macrophages in
WAT
 Over-expressed in obesity
 Link between TNFa and insulin resistance
 Alters insulin signaling and MAPK pathways in
vitro and in vivo
IL-6
 10-30% of circulating IL-6 is from WAT
 Highly correlated with body mass and inversely
related to insulin sensitivity
 Alters insulin signaling in the liver
 IL-6 KO mice develop mature-onset obesity and
glucose intolerance
Resistin
 Discovered in 2001
 Expressed in adipocytes in mice and in macrophages in
humans
 Increased in obesity
 Recombinant resistin
 Promotes insulin resistance in mice
 Decreased insulin stimulated glucose uptake in WAT
Visfatin
 Discovered in 2004
 Specifically expressed in visceral fat as opposed
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to subcutaneous fat
Binds to insulin receptor on an allosteric site to
insulin
Can mimic insulin in down-stream insulin
signaling pathways
Plasma levels are 1/100th level of insulin and not
controlled by nutritional status
These original findings were not reproducible,
and the paper was later recalled!
Leptin
 Secreted by adipocytes
 Regulates food intake – satiety factor
 Leptin receptor is expressed in hypothalamus
ob/ob and db/db mouse models
 Spontaneous mutations first noted in 1950
 morbid obesity (3x normal weight)
 hyperinsulinemia (50-fold increase)
 hyperglycemia
 Infertile
 slightly increased cholesterol
Leptin and Leptin Receptor
 Both
ob/ob and db/db mice
originally developed from
spontaneous mutations
 The genes mutated in these mice
were later identified as leptin and
its receptor
 ob/ob and db/db mice are
obese, hyperphagic,
hyperglycemic, and
hyperinsulinemic and are
commonly used models for
studies of diabetes
ob/ob
littermate
Parabiosis: ob/ob with wild type
Wild Type
ob/ob
Parabiosis: ob/ob with wild type
Wild type
Ob/ob
Suppressed weight
gain in ob/ob mouse
Parabiosis between wt and db/db
Wild type
db/db
Parabiosis between wt and db/db
Wild type
db/db
Parabiosis between wt and db/db
Wild type
db/db
Parabiosis between wt and db/db
Wild type
db/db
RIP
1994: Cloning of Leptin
 167 aa protein belonging to cytokine family
 Circulates free or bound soluble receptor
 Expressed in WAT, stomach and placenta
 84% homology between mouse and human
leptin
 Leptin administration to ob/ob mice
alleviates all aspect associated with the
deficiency in mice
Possible Physiologic Roles of Leptin
 Obesity
 Glomerulosclerosis
 Anorexia
 Hematopoeisis
 Diabetes
 Aging
 Reproduction
 sweet-sensing modulator
 Bone Mass
 Angiogenic activity
 Immune System
 Hypertension
Adiponectin (Acrp 30, AdipoQ)
 Discovered in mid-1990’s
 Protein highly expressed in adipocytes and
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circulates at high concentrations
Collagenous tail and globular head
Plasma concentrations are reduced in obesity
and insulin resistance
TNFa and IL-6 inhibit adiponectin expression
Administration of recombinant adiponectin
ameliorates IR in obese and lipodystrophic
mice
Adiponectin is anti-atherogenic
Mobilization of Triglycerides Stored
in Adipose Tissue
Low levels of glucose in the
blood trigger the
mobilization of
triglycerides through the
action of epinephrine and
glucagon.
cAMP pathway activate
hormone sensitive lipase
to cause hydrolysis of
triglycerides into glycerol
and FFA
Modulators of Triglyceride
Synthesis and Storage
 Insulin – promotes conversion of carbohydrates into
triglycerides
 Epinephrine: activates release of fatty acids from
adipose tissue
 Glucagon: stimulates release of fatty acids from
adipose tissue
 Pituitary Growth Hormone
 Adrenal Cortical Hormones
Lipoprotein Lipase
 LPL: lipolytic activity in the capillary bed; hydrolyzes
NEFA from lipoproteins (chylomicrons and VLDL)
 Secreted by adipocytes, macrophages, muscle but
active in capillary endothelial beds
 Has catalytic activity, but also functions as ligand for
anchoring of lipoproteins to cell surface
Hormone Sensitive Lipase
 lipolytic activity inside adipocytes
 releases NEFA from storage when energy is needed
 Hydrolyses TG but also cholesteryl esters, retinyl
esters and steroid esters
Triglyceride
 Glycerol backbone
with 3 fatty acid
chains
 Fatty acids can be
similar or varied
 Stored in cytosol of
adipocytes
 Carbon atoms are
more reduced than
sugars – thus
provide more energy
Lipolysis of TG in WAT
Together, ATGL and HSL are responsible for >95%
of TG hydrolysis from WAT
Perilipins
 Found within phospholipid monolayer surrounding
neutral lipid containing lipid vacuole
 Phosphorylated by PKA on multiple residues
 Prevent lipolysis under basal conditions
Fatty Acid Binding Proteins
(FABP: ap2 and mal-1)
 Expressed in WAT, liver, intestine, heart, and
brain
 Sequester fatty acids in cytosol to protect cell from
harmful effects of intracellular-FFA
 Interact with HSL to favor translocation of lipid
from cytosol to lipid droplet
 Ap2-/- mice do develop diet-induced obesity, but
do not develop IR or diabetes
Hormone Stimulated Lipolysis Paradigm
 Lipolytic stimulation leads to phosphorylation of
HSL and perilipin by PKA
 Phosphorylation of perilipin causes them to lose
their lipolysis-blocking capability
 Phosphorylation of HSL promotes its translocation
from the cytosol to the lipid droplet
 Required for maximal TG storage in WAT
Yeaman, Biochem. J 379:11
Hormone Sensitive Lipase deficient mice
 Mice do NOT become
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obese
Mice have increased
Diacylglycerol in their
WAT and muscle
Adipocytes in BAT were
enlarged (5-fold)
BAT mass was enlarged
Males were sterile
WAT retained 40% of TG
lipase activity
Osuga. 2000. PNAS
97:787
Perilipin Knockout mice
 Decreased adipose
tissue mass
 High levels of basal
lipolysis
 Resistant to dietinduced obesity
Javier Martinez-Botas Nature Genetics 26, 474 - 479 (2000)
Mechanism for Hormone-mediated lipolysis
 Hormones include catecholamines, adrenaline, and
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Receptors are called G-protein coupled receptors
called β-adrenergic receptors
When activated, they transmit signals to adenylyl
cyclase leading to cAMP production
cAMP activates PKA
PKA phosphorylates HSL and perilipin
Gs/cAMP/PKA/HSL Pathway to Lipolysis
Kimmel, Biochimie 87: 45-49
Flex Time: Adipose Tissue Macrophages