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ALYSSA HASTY, PHDASSISTANT PROFESSOR
MOLECULAR PHYSIOLOGY & BIOPHYSICS
Metabolic Impact of Adipose Tissue
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The Simplified Model
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Obesity Trends Among U.S. Adults between 1985 and 2002
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
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
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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
cancer-related 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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Central obesityGlucose intolerance
HypertensionInsulin resistance
High TGLow HDL-C
Small, dense LDL particles
The Metabolic Syndrome
©1998 PPS
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0
5
10
15
20
25
30
CHD Previous MI Previous Stroke
WITH Metabolic Syndrome
All Subjects
NGT
IFG/IGT
Type 2 Diabetes
(n=3,928)(n=1,808)
(n= 685)(n=1,430)
Without Metabolic Syndrome
0
5
10
15
20
25
30
CHD Previous MI Previous Stroke
Prevalence of CHD, MI, and Stroke in Relation to the Presence of Metabolic Syndrome
Isomaa et al. 2001. Diabetes Care. 24:683-689.
Pre
vale
nce
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Traditional CHD Risk Factors
Elevated Plasma CholesterolReduced Plasma HDL LevelsDiabetesHypertensionSmokingAge
Lipid Lowering only results in a relative risk reduction of 30%
New MarkersInflammatoryAdipokines
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New Inflammatory Markers to assess Risk
CRP IL-6 TNF Serum Amyloid ANon-esterified fatty acids
Adipose tissue is an important source of inflammatory cytokine production
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White Adipose Tissue (WAT)
Many different adipose tissue beds throughout the whole organism
Many distinct cell types: adipocytes, pre-adipocytes, fibroblasts, macrophages, vascular cells
Heterogeneous metabolic capabilities, depending on visceral or subcutaneous location of fat depot
Secrete adipokines with systemic effects
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J. Magn. Reson. Imaging Vol.21, 4 Pages: 455-462
Gender Differences in Adipose Tissue Distribution
Female Male
Original Image
SCATSubcutaneous Adipose
TissueHIGHLIGHTED WHITE
VATVisceral Adipose
TissueHIGHLIGHTED WHITE
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White Adipose Tissue
WAT is comprised of 2 Fractions:
1) adipocytes2) SVF which consists of: preadipocytes endothelial cells macrophages
WAT is central to energy storage in the body and the mobilization of this energy store is highly regulated.
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Preadipocyte Mature adipocyte
http://www.hsph.harvard.edu/GSHLAB/adipos.html
Basic Adipose Tissue Expansion
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Adipocyte Growth:Hypertrophy vs. Hyperplasia
Hypertrophy (increase in size) “Lipogenesis” 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
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Hormones, Adipokines, enzymes, molecules and other factors reportedly associated with Adipose Tissue
-1 acid glycoprotein (AGP) 3-hydroxysteroid dehydrogenase (3HSD) 3-HSD 5 reductase 7 hydroxylase 11HSD 17HSD 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 VI3 Complement factor C3 and B
• 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
• Nitric oxide synthase• Nuclear factors• Omentin• Osteonectin (secreted protein, acidic and rich
in cystein/SPARC)• Pentraxin-3• p85phosphatidylinositol 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-• UDP-glucuronosyltransferase A242B15• Uncoupling proteins• Vascular endothelial growth• Visceral adipose tissue-derived serpin• Visfatin (pre- cell colony-enhancing factor
[PBEF])Bays H & Ballantyne C; Future Lipidol 2006; 1(4): 389-420
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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
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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
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Control of Release of FFA From White Adipose Tissue
WATDietLipid storage
Lipolysis
Starvation
Insulin
Free Fatty Acid
Insulin Resistance
Liver
Triglycerides
PhospholipidsKetonebodies
Hypertriglyceridemia Atherosclerosis
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Secretory Products of Adipose Tissue
AdiposeTissue
IGF-1IGFBP
TNF-αInterleukinsTGF βFGFEGF
Fatty AcidsLactateAdenosineProstaglandinsGlutamine
Unknown Factors
PAI-1Angiotensinogen
Ang II
Estrogen
Adiponectin
Resistin
BoneMorphogenic
Protein
Adapted from: Roth, J, et al, Obesity Research, Vol 12, supplement Nov 2004:88S-101S
Leptin
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Adipokines
Vascular Disease Related Angiotensinogen PAI-1
Insulin Resistance Related ASP (Acylation-stimulating protein) TNF IL-6 Resistin Leptin Adiponectin
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Angiotensinogen (AGE)
Links obesity with hypertensionPositive correlation of blood pressure with
AGE levelsPrimarily produced in liver, but also by WATDeficiency partially protects against diet-
induced obesity
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Plasminogen Activator Inhibitor 1 (PAI-1)
Impairment of fibrinolytic system contributes to cardiovascular complications of obesity
WAT is main tissue source of PAI-1Produced by pre-adipocytes, primarily in
visceral WATActs to inhibit fibrinolysis (is pro-thrombotic)Also influences cell migration and angiogenesisCould impair pre-adipocyte migration leading
to WAT growth
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TNF
Proinflammatory cytokineProduced by adipocytes and
macrophages in WATOver-expressed in obesityLink between TNF and insulin
resistanceAlters insulin signaling and MAPK
pathways in vitro and in vivo
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IL-6
10-30% of circulating IL-6 is from WATHighly correlated with body mass and
inversely related to insulin sensitivityAlters insulin signaling in the liverIL-6 KO mice develop mature-onset obesity
and glucose intolerance
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Resistin
Discovered in 2001Expressed in adipocytes in mice and in
macrophages in humansIncreased in obesityRecombinant resistin
Promotes insulin resistance in mice Decreased insulin stimulated glucose uptake in
WAT
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Visfatin
Discovered in 2004Specifically expressed in visceral fat as
opposed to subcutaneous fatBinds to insulin receptor on an allosteric
site to insulinCan mimic insulin in down-stream insulin
signaling pathwaysPlasma levels are 1/100th level of insulin
and not controlled by nutritional statusThese original findings were not
reproducible, and the paper was later recalled!
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Leptin
Secreted by adipocytesRegulates food intake – satiety factorLeptin receptor is expressed in hypothalamus
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ob/ob and db/db mouse models
Spontaneous mutations first noted in 1950morbid obesity (3x normal weight)hyperinsulinemia (50-fold increase)hyperglycemiaInfertileslightly increased cholesterol
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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
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Parabiosis: ob/ob with wild type
Wild Type ob/ob
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Parabiosis: ob/ob with wild type
Wild type Ob/ob Suppressed weightgain in ob/ob mouse
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Parabiosis between wt and db/db
Wild type db/db
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Parabiosis between wt and db/db
Wild type db/db
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Parabiosis between wt and db/db
Wild type db/db
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Parabiosis between wt and db/db
Wild type db/db RIP
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1994: Cloning of Leptin
167 aa protein belonging to cytokine family
Circulates free or bound soluble receptor
Expressed in WAT, stomach and placenta84% homology between mouse and
human leptinLeptin administration to ob/ob mice
alleviates all aspect associated with the deficiency in mice
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Possible Physiologic Roles of Leptin
ObesityAnorexiaDiabetesReproductionBone Mass Immune System
GlomerulosclerosisHematopoeisis Agingsweet-sensing
modulatorAngiogenic activityHypertension
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Adiponectin (Acrp 30, AdipoQ)
Discovered in mid-1990’sProtein highly expressed in adipocytes
and circulates at high concentrationsCollagenous tail and globular headPlasma concentrations are reduced in
obesity and insulin resistanceTNF and IL-6 inhibit adiponectin
expressionAdministration of recombinant
adiponectin ameliorates IR in obese and lipodystrophic mice
Adiponectin is anti-atherogenic
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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
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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
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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
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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
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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
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Together, ATGL and HSL are responsible for >95% of TG hydrolysis from WAT
Lipolysis of TG in WAT
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Perilipins
Found within phospholipid monolayer surrounding neutral lipid containing lipid vacuole
Phosphorylated by PKA on multiple residuesPrevent lipolysis under basal conditions
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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
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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
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Yeaman, Biochem. J 379:11
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Osuga. 2000. PNAS 97:787
Hormone Sensitive Lipase deficient mice
Mice do NOT become obese
Mice have increased Diacylglycerol in their WAT and muscle
Adipocytes in BAT were enlarged (5-fold)
BAT mass was enlargedMales were sterileWAT retained 40% of
TG lipase activity
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Perilipin Knockout mice
Decreased adipose tissue mass
High levels of basal lipolysis
Resistant to diet-induced obesity
Javier Martinez-Botas Nature Genetics 26, 474 - 479 (2000)
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Mechanism for Hormone-mediated lipolysis
Hormones include catecholamines, adrenaline, and noradrenaline
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 PKAPKA phosphorylates HSL and perilipin
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Gs/cAMP/PKA/HSL Pathway to Lipolysis
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Kimmel, Biochimie 87: 45-49
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Flex Time: Adipose Tissue Macrophages