PATOPHYSIOLOGY OF

OBESITY

Putu Moda Arsana

FKUB, 2015
Eat to

Live to Eat!
Live!

“EAT TO LIVE” “LIVE TO EAT”

Intake = Expenditure Intake > Expenditure
Weight Stable Obese
Prevalences of obesity among adults
in Indonesia similar to the US
in terms of the number and gender
HEALTH CONSEQUENCES OF OBESITY
Sedentariness/Overnutrition

Mental Mechanical Metabolic

- depression - osteoarthritis - diabetes
- anxiety - obstructive sleep apnea - dyslipidemia
- personality disorder - reflux disease - fatty liver
- self esteem - urinary incontenance - hypertension
- etc. - intertrigo - cancer
- etc. - PCOS
- gall bladder
- infertility
- etc.

Hormones / Adipokines / Inflammation

PATHOPHYSIOLOGY OF
OBESITY
 ISN’T OBESITY SIMPLE?

Genetics

Environmental Environmental
Determinants Determinants
+/- +/-
Energy Energy
In Out

Energy Regulation is Complex!

FACTORS CONTRIBUTING TO
OBESITY
Lifestyle Psychosocial Biomedical
• Poor diet • Depression • Genetics
• Skipping meals • Anxiety • Metabolism
• Sugary soft drinks • Binge eating • Intrauterine
• Poor sleep • Social events growth
• Stress • Medications
• Snacking
• Etc. • Etc.
• Alcohol
• Sedentariness
• Etc.
 SELECTED MEDICATIONS THAT CAN
CAUSE WEIGHT GAIN
• Psychotropic medications • Diabetes medications
• Tricyclic antidepressants • Insulin
• Monoamine oxidase • Sulfonylureas
inhibitors
• Thiazolidinediones
• Specific SSRIs
• Highly active antiretroviral therapy
• Atypical antipsychotics
• Lithium • Tamoxifen

• Specific anticonvulsants • Steroid Hormones

• β-adrenergic receptor blockers • Glucocorticoids
• Progestational steriods

13/26
SSRI=Selective Serotonin Reuptake Inhibitor.
INGESTIVE BEHAVIOUR
Homeostatic System

Hunger: Satiety:
Need for Calories Sense of “Fullness”

Hedonic System

Appetite: Reward:
Need for Foods Sense of Pleasure
 PATOFISIOLOGI
DISLIPIDEMIA
Dr Putu Moda Arsana SpPD - KEMD
Department of Internal Medicine
Brawijaya University
M a l a n g
LIPID

• Molekul organik yang tidak larut dalam

air
• Sebagian besar terdiri dari hidro karbon
• Dibagi menjadi :
Lipid sederhana : asam lemak
Lipid kompleks : Ester asam lemak
( gabungan antara asam lemak dengan
alkohol; monoacylglycerol atau
triacylglycerol )
FUNGSI LIPID

• Sebagai sumber dan cadangan

energi
• Membentuk tekstur tubuh
• Fungsi pelindung mekanik
• Bahan untuk sintesis hormon
• Bahan untuk sintesis dinding sel
• Bahan untuk sintesis prostaglandin
dll
SUMBER LIPID

• Diet / makanan ( eksogen )

• Sintesis oleh tubuh ( endogen )
TRANSPORTASI LIPID

• Jalur eksogen ( mengangkut lipid yang

berasal dari diet )
• Jalur endogen ( mengangkut lipid yang
berasal dari sintesis oleh hati )
⇒ Lipid diangkut oleh Lipoprotein
LIPOPROTEIN

• Kompleks lipid dengan protein

• Terdiri dari :
Fosfolipid
Apolipoprotein
Kholesterol bebas
Kholesterol ester
Trigliserida
 LIPOPROTEIN
• Untuk transportasi Lipid ( Trigliserida
dan kholesterol )
• Bentuk bentuk Lipoprotein :
Chylomicrons
Very Low Density Lipoprotein ( VLDL )
Intermediate Density Lipoprotein ( IDL )
Low Density Lipoprotein ( LDL )
High Density Lipoprotein ( HDL )
Lipoprotein Classes and Inflammation

Chylomicrons, LDL HDL

VLDL, and
their catabolic
remnants
> 30 nm 20–22 nm 9–15 nm
Potentially anti-
Potentially proinflammatory
inflammatory
Doi H et al. Circulation 2000;102:670-676; Colome C et al. Atherosclerosis 2000;
149:295-302; Cockerill GW et al. Arterioscler Thromb Vasc Biol
1995;15:1987-1994.
 Exogenous Endogenous
Dietary Bile
lipids acids
+
Cholesterol

Peripheral
tissues

Chylomicron
Chylomicron remnant

Capillaries Capillaries
LDLR
ApoB
ApoE
FFA FFA
ApoC’s

Muscle Adipose Muscle Adipose

REVERSE CHOLESTEROL TRANSPORT

Macrophage

IDL
CE LDL LDLR
TP
LCAT
VLDL
Liver

Nascent TP
CE Mature
HDL HDL
LDLR

Small Chylomicrons
intestine Free CE
cholesterol

Peripheral cells Apo AI TG

 REVERSE CHOLESTEROL
TRANSPORT

Bile
A-I
FC
A-I
CE LCAT CE
CE FC
FC ABC1
SR-BI Nascent
HDL Macrophage

Liver Mature HDL

ABC1 = ATP-binding cassette protein 1; A-I = apolipoprotein A-I;

CE = cholesteryl ester; FC = free cholesterol;
LCAT = lecithin:cholesterol acyltransferase;
SR-BI = scavenger receptor class BI
 INTESTINAL CHOLESTEROL ABSORPTION

Intestinal Biliary Dietary

epithelial cell cholesterol cholesterol
Through
lymphatic
system to the
liver MTP
CM Cholesteryl esters Luminal
cholesterol
ACAT excretion Bile
(esterification)
acid
ABCG5 Micellar
ABCG8
cholesterol

Free
cholesterol uptake

Bays H et al. Expert Opin Pharmacother 2003;4:779-790.

CHOLESTEROL ABSORPTION

Lymph Enterocyte Intestinal

Lumen

Cholesterol

ACAT NPC1L1

Cholesteryl
Ester ABCG5/G8
 TRIGLYCERIDE ABSORPTION

Lymph Enterocyte Intestinal

Lumen

2 Fatty Acid
+
Monoglyceride

DGAT

Triglyceride
APA ITU DISLIPIDEMIA ?
• Total cholesterol ↑
• LDL – cholesterol ↑
• Trigliserida ↑
• ( Small dense – LDL ↑ )
• ( Non HDL – cholesterol ↑ )
• HDL – cholesterol ↓
 TWO TYPES OF LIPIDS

LIPIDS IN BLOOD

TOTAL CHOLESTEROL TRIGLYCERIDES (TG)

GOOD CHOLESTEROL BAD CHOLESTEROL

HDL 1 and HDL 2 LDL, VLDL (TG), Lp(a)
HASIL PEMERIKSAAN LIPID

LIPIDS ESTIMATED

TOTAL CHOLESTEROL (TC) TRIGLYCERIDES (TG)

Chylomicro
HDLc LDLc VLDLc VLDL
ns

Post Prandial Puasa

 NORMAL LIPID PROFILE

• Total Cholesterol < 200

• TG ‘Ugly’ Lipid < 150
• ‘Bad’ Cholesterols LDL < 100
• HDL ‘Good’ cholesterol > 50
• VLDL is Ugly TG ÷ 5 < 30
• Lp(a) ‘Deadly’ cholesterol < 20
 HOW TO INTERPRET LIPID
PROFILE REPORT?
A. Total Cholesterol 200
HDL Cholesterol (Soldiers) - Good 50
Non HDL Cholesterol(Culprits) 150
LDL Cholesterol – Bad fellows
100
Lipoprotein(a) – Deadly fellows
20
VLDL Cholesterol (1/5 of TG)- Ugly
30
B. Triglycerides
150
Normal Lipid Profile
INTERPRET THIS LIPID PROFILE
REPORT
A. Total Cholesterol 240
HDL Cholesterol (Soldiers) - Good 50
Non HDL Cholesterol(Culprits) 190
LDL Cholesterol – Bad fellows 140
Lipoprotein(a) – Deadly fellows
20
VLDL Cholesterol (1/5 of TG)- Ugly
30
B. Triglycerides
150
Hyper cholesterolemia ↑LDL, HDL, TG, Lp(a) - N
 INTERPRET THIS LIPID
PROFILE REPORT
A. Total Cholesterol 200
HDL Cholesterol (Soldiers) - Good
50
Non HDL Cholesterol(Culprits) 150
LDL Cholesterol – Bad fellows
70
Lipoprotein(a) – Deadly fellows
20
VLDL Cholesterol (1/5 of TG)- Ugly
60
B. Triglycerides
300
Hyper triglyceridemia ↑TG, HDL, LDL, Lp(a) - N
 INTERPRET THIS LIPID
PROFILE REPORT
A. Total Cholesterol 160
HDL Cholesterol (Soldiers) - Good
25
Non HDL Cholesterol(Culprits) 135
LDL Cholesterol – Bad fellows
85
Lipoprotein(a) – Deadly fellows
20
VLDL Cholesterol (1/5 of TG)- Ugly
30
B. Triglycerides
150
Low HDL : ↓HDL, LDL, TG, Lp(a) - N
 INTERPRET THIS LIPID
PROFILE REPORT
A. Total Cholesterol 200
HDL Cholesterol (Soldiers) - Good
45
Non HDL Cholesterol(Culprits) 155
LDL Cholesterol – Bad fellows
75
Lipoprotein(a) – Deadly fellows
50
VLDL Cholesterol (1/5 of TG)- Ugly
30
B. Triglycerides
150
High Lipoprotein(a) : ↑Lp(a) , HDL, LDL, TG - N
 INTERPRET THIS LIPID
PROFILE REPORT
A. Total Cholesterol 200
HDL Cholesterol (Soldiers) - Good
25
Non HDL Cholesterol(Culprits) 175
LDL Cholesterol – Bad fellows
95
Lipoprotein(a) – Deadly fellows
20
VLDL Cholesterol (1/5 of TG)- Ugly
60
B. Triglycerides
300
High Lipoprotein(a) : ↓HDL, ↑TG, LDL, Lp(a) - N
 INTERPRET THIS LIPID
PROFILE REPORT
A. Total Cholesterol 260
HDL Cholesterol (Soldiers) - Good 50
Non HDL Cholesterol(Culprits) 210
LDL Cholesterol – Bad fellows 120
Lipoprotein(a) – Deadly fellows
40
VLDL Cholesterol (1/5 of TG)- Ugly
50
B. Triglycerides
250
Combined Dyslipidemia : ↑ TC↑LDL↑TG ↑Lp(a)
APA AKIBAT DARI DISLIPIDEMIA ?
 Macrophages and Foam Cells Express Growth
Factors and Proteinases

Monocyte Vessel Lumen

LDL

Adhesion Endothelium
MCP-1
Molecules LDL
Intima
Modified
Cytokines LDL Growth Factors
Metalloproteinases

Cell Proliferation
Macrophage
Foam Cell Matrix Degradation
Ross R. N Engl J Med 1999;340:115-126.
ATHEROSCLEROSIS: A PROGRESSIVE DISEASE
Plaque rupture

Adhesion Macrophage
Oxidized
Monocyte LDL-C molecule
LDL-C
Foam cell
CRP

Smooth muscle
cells

Endothelial Plaque instability

Inflammation Oxidation
dysfunction and thrombus

Libby P. Circulation. 2001;104:365-372; Ross R. N Engl J Med. 1999;340:115-126.

 APAKAH ADA BUKTI BAHWA
LIPID BERBAHAYA DAN DAPAT
MENYEBABKAN ADANYA
PENYAKIT KARDIOVASKULER ?
 ATP III Lipid and
Lipoprotein Classification

LDL Cholesterol (mg/dL)

<100 Optimal
100–129 Near optimal/above optimal
130–159 Borderline high
160–189 High
≥190 Very high

HDL Cholesterol (mg/dL)

<40 Low
≥60 High

Total Cholesterol (mg/dL)

<200 Desirable
200–239 Borderline high
≥240High
Therapeutic Lifestyle Changes in
LDL-Lowering Therapy
Major Features
• TLC Diet
– Reduced intake of cholesterol-raising nutrients
(same as previous Step II Diet)
• Saturated fats <7% of total calories
• Dietary cholesterol <200 mg per day
– LDL-lowering therapeutic options
• Plant stanols/sterols (2 g per day)
• Viscous (soluble) fiber (10–25 g per day)
• Weight reduction
• Increased physical activity
Therapeutic Lifestyle Changes
Nutrient Composition of TLC Diet

Nutrient Recommended Intake

• Saturated fat Less than 7% of total calories
• Polyunsaturated fat Up to 10% of total calories
• Monounsaturated fat Up to 20% of total calories
• Total fat 25–35% of total calories
• Carbohydrate 50–60% of total calories
• Fiber 20–30 grams per day
• Protein Approximately 15% of total calories
• Cholesterol Less than 200 mg/day
• Total calories (energy) Balance energy intake and expenditure
to maintain desirable body weight/
prevent weight gain
 A Model of Steps in
Therapeutic Lifestyle Changes (TLC)

Visit 2 Visit 3
Evaluate LDL Evaluate LDL
Visit I 6 response 6 response Q 4-6 Visit N
Begin wks If LDL goal not wks If LDL goal not mo Monitor
Lifestyle achieved, intensify achieved, consider Adherenc
Therapies LDL-Lowering Tx adding drug Tx e
to TLC
• Emphasize
reduction in
saturated fat & • Reinforce reduction
cholesterol in saturated fat and
cholesterol • Initiate Tx for
• Encourage Metabolic
moderate physical • Consider adding
plant stanols/sterols Syndrome
activity
• Increase fiber • Intensify weight
• Consider referral management &
intake
to physical activity
a dietitian • Consider referral to
a dietitian • Consider referral
to a dietitian