OVERWEIGHT AND OBESITY

Dharma Lindarto

Div. Endokrin-Metabolik

Departemen Penyakit Dalam FK USU/RSUP H Adam Malik Medan.

Defining obesity

• Obesity - an excessive accumulation of body

fat sufficient to impair health

WHO 894 Obesity Report

Obesity is a Growing Problem

• 127 million adults in the U.S. are overweight, 60 million obese,

and 9 million severely obese.

• 64.5 percent of U.S. adults are overweight (BMI≥25)

• 30.5 percent are obese (BMI≥30)• 30.5 percent are obese (BMI≥30)

• 4.7 percent are severely obese (BM≥40)

• Obesity is the No. 2 preventable cause of death and disability

(smoking is #1)

Media coverage of obesity

Adipose Tissue

White adipose tissue

• Stored under the skin, in mesenteries and omentum, behind the peritoneum

• Primarily fat, also small amounts of protein and water

• Stores triglycerides,

Brown adipose tissue

• Large amounts in infants, small amounts in adults

• Found primarily in scapular, sub-scapular areas

• Heat production, cold adaptation, dissipation of excess energy

Dysfunctionaladipocyte

Adipose Tissue Mass vs. Function

Dysfunctional adipose tissue

without increase in mass

Dysfunctional adipose tissue with increase in

mass

Increased number of

enlargedadipocytes

Normaladipose tissue

Abnormal cytokine productionInflammation���� NEFA

Systemic Insulin Resistance

Abnormal production of hormones

(Adipocytokines ) in fat

���� Lactate���� Angiotensinogen

���� Fat ���� Fat

���� Lipoprotein Lipase

���� IL - 6

Hypertension

InflammationDyslipidemia

Type 2 DM

���� Leptin

���� Adipsin (Complement D)

���� TNF- αααα

���� FFA���� Fat

Stores���� Fat

Stores

���� Plasminogen Activator Inhibitor 1

(PAI-1)

����Resistin

����AdiponectinAdiponectinDM=diabetes mellitus; FFA=free fatty acid; PAI-1=plasminogen activator inhibitor-1; TNFα=tumor necrosis factor alpha; IL-6=interleukin 6.

Slide: After Dr. G Bray

���� Insulin

����Estrogen Thrombosis

Type 2 DM

Arthritis

ASCVD

Asthma

Adipocytokines

• The term ‘adipocytokines’: adipocyte-derived biologically active molecules which may influence the function as well as the structural integrity of other tissues

• Some examples of these substances are:

- leptin,

- acylation-stimulating protein (ASP),

- tumor necrosis factor-a (TNF-a),

- plasminogen activator inhibitor-1 (PAI-1)

- interleukin-6

Adipocytokines

• Leptin is considered to be a fundamental signal of satiety to the brain and has a variety of actions, ranging from interference with sympathetic activity to hematopoiesis and reproductive function

• ASP increases triglyceride synthesis by increasing adipocyte • ASP increases triglyceride synthesis by increasing adipocyte glucose uptake, activating diacylglycerol acyltransferase, and inhibiting hormone-sensitive lipase

• TNF: is involved in insulin resistance in obesity

• PAI-1: is a well-recognized causative factor for vascular

thrombosis

• Resistin; adipose-specific cysteine-rich protein with a • Resistin; adipose-specific cysteine-rich protein with a

capacity to impair insulin sensitivity and glucose

tolerance in murine models

• Adiponectin ; have anti-atherogenic and anti-inflammatory

properties

AutonomicNervousSystem

Hypothalamus, etc

External Factors

Weight is controlled by a feedback system.

GhrelinGhrelin

PYYPYY

CCKCCK*

EfferentAfferent EC-CB1

Vagus Nerve

Food IntakeGut and Liver

Pancreas

System

Energy Expenditure

Adipose Tissue

Aronne LJ. Adapted from Campfield LA, et al. Science. 1998;280:1383-1387; and Porte D, et al. Diabetologia. 1998;41:863-881.

Adrenal Cortex

Energy Balance

and Adipose Stores

Meal Size

Adrenal Steroids

Leptin

Insulin

External Factors

food availability,

palatability

Adiponectin

CCKCCK*

The paraventricular &arcuate nuclei contain neurons capable of stimulating/inhibiting food intake.

Y1R/Y2R denote subtypes of the neuropeptide Y (NPY) rec

MC4R melanocortin 4 rec

Korner J and R Leibel NEJM 349;10

2003

Sugars please Sugars please our brain, our brain, promote promote insulin insulin

secretionsecretion

MC4R melanocortin 4 rec

PYY peptide YY 3–36,

GHsR GH hormone secretagogue rec

AgRP agouti-related protein,

POMC propio o melanocortin

a-MSH a -melanocyte–stimulating protein

LEPR leptin rec, and INSR insulin rec.

Estimation of Body Fat

• Bioelectrical impedance

– Low-energy current to the body that measures the resistance of electrical flow

– Fat is resistant to electrical flow; the more the resistance, the more body fat you have

• DEXA (dual x-ray photon absorptiometry)

– An X-ray body scan that allows for the determination of body fat

• Infrared light

– Assess the interaction of fat and protein in the arm muscle

Body Mass Index (kg/m2)

Dose - Response Risk Relationship

Underweight < 18.5

Normal 18.5 - 25Normal 18.5 - 25

Overweight 25 - 30

Obese > 30

– Class I 30 - 34.9

– Class II 35 - 39.9

– Class III >40

Kategori BMI (kg/m2) BMI Asia

Underweight < 18.5 < 18.5

Normoweight 18.5 - 24.9 18.5 - 22.9

Overweight: > 25 > 23

BMI Criteria (WHO 2000)

Overweight: > 25 > 23

Pre-obese 25.0 – 29.9 23.0 – 24.9

Obese I 30.0 - 34.9 25.0 - 29.9

Obese II 5.0 - 39.9 > 30.0

Obese III > 40.0

Waist Circumference

Waist circumference, independent of

BMI / weight, confers additional

health risk with:health risk with:

– Glucose intolerance / Diabetes

mellitus

– Hypertension

– Dyslipidemia

Important - WC in any weight category

confers similar risk

Central AdiposityCentral Adiposity

Regional Distribution

• The regional distribution of body fat affects risk factors

for the heart disease and type 2 diabetes

Body Fat Distribution: Gynecoid

• Lower-body obesity--Pear shape

• Encouraged by estrogen and progesterone

• Less health risk than upper-body obesity

• After menopause, upper-body obesity appears• After menopause, upper-body obesity appears

Body Fat Distribution: Android

• Upper-body obesity--apple shape

• Associated with more heart disease, HTN, Type II Diabetes

• Abdominal fat is released right into the liver• Abdominal fat is released right into the liver

• Encouraged by testosterone and excessive alcohol intake

• Defined as waist measurement of > 40” for men and >35” for

women

Obesity: Causes and ConsequencesConsequences

Etiology:

i) Enzyme deficiency - responsible for alpha-glycerophosphate oxidation.

ii) Differences in thermogenesis - thin people are better able to dissipate excess calories through better able to dissipate excess calories through

heat production.

iii) Reduced ATPase activity - results in decreased ability to burn calories.

iv)"Hibernation response" - relic of human

evolutionary past initiates overeating.

Etiologyv) Genetic

– inheritance of increased # and size of fat cells

– child with one obese parent has 40% chance

– two obese parents has 80% chance

vi) Socioeconomic factors

– Obesity is more common:

• children & adults from lower socioeconomic grps

• black vs white women

• white vs black men

vii) Psychological - psychogenic component in 90% of cases, however, it is NOT primary cause.

Obesity

���� FFA

�TG

���� HDL

���� Blood

pressure ���� Insulin resistance

���� Blood glucose ���� Blood glucose

Type 2 diabetes

Cardiovascular disease

Metabolic syndrome : The role of obesity.

Role of obesity in insulin resistance

Visceral

↑↑↑↑ Caloricintake

Sedentary

↑↑↑↑ Freefatty acids

↑↑↑↑

Oxidative

stress Insulin

Adapted from Wellen KE, Hotamisligil GS. J Clin Invest. 2005;115:1111-9.

VisceralObesity

Sedentary

lifestyle

Genetic

factors

↑↑↑↑ Glucose

↑↑↑↑ Lipids

stress

Inflammation

Insulin

resistance

���� Hepatic

Insulin

Clearance

���� Portal

FFA

���� Plasma

Insulin

����Visceral

Fat Stores

Fat Cell Products and HypertensionFat Cell Products and Hypertension

���� Renal Na+

Reabsorption

Hypertension

Vascular

Constriction

Angiotensin I

Angiotensin IIAngiotensinogen

Bray GA. Contemp Diagn Obes. 1998.

Medical Complications of Obesity: Almost

every organ system is affected

Coronary heart disease

Pulmonary diseaseabnormal function

obstructive sleep apnea

hypoventilation syndrome

Stroke

Diabetes

Nonalcoholic fatty liver diseasesteatosis

steatohepatitisDyslipidemia

Cataracts

Idiopathic intracranial hypertension

Phlebitisvenous stasis

Gall bladder disease

Gynecologic abnormalitiesabnormal menses

infertility

polycystic ovarian syndrome

Gout

Osteoarthritis

Cancerbreast, uterus, cervix

colon, esophagus, pancreas

kidney, prostate

steatohepatitis

cirrhosisHypertension

Skin

Severe pancreatitis

Obesity Preventionand

ManagementManagement

1. Non pharamcological1. Non pharamcological

Therapy of weight loss:Therapy of weight loss:

2. Pharmacological 2. Pharmacological

Non pharmacological therapy

of Weight loss

Non pharmacological therapy

of Weight loss

Diet Diet i.e. Life style Diet

Exercise

Diet

Exercise

i.e. Life style

modifications

Food Guide Pyramid

Health Benefits of Weight LossHealth Benefits of Weight Loss

Decreased risk for cardiovascular disease.

Decrease glucose and insulin levels.

Decreased blood pressure.

Decreased risk for cardiovascular disease.

Decrease glucose and insulin levels.

Decreased blood pressure.Decreased blood pressure.

Decreased LDL and triglycerides

Increased HDL.

Decrease in severity of sleep apnea.

Reduced symptoms of degenerative joint disease.

Decreased blood pressure.

Decreased LDL and triglycerides

Increased HDL.

Decrease in severity of sleep apnea.

Reduced symptoms of degenerative joint disease.

Treatment of Obesity

• Goal of treatment: 10% weight loss

• Caloric restriction: -500 kcal/day

• Moderate physical activity

– 30 minutes daily

• Behavioral modification

• Drug therapy

National Institutes of Health. Obes Res. 1998; 6 (suppl 2): 51S–209S.

Impact of Weight Loss on Risk Factors

~5%Weight Loss

5%-10%Weight Loss

HbA1c

Blood Pressure

1

2

3

1

2

3Total Cholesterol

HDL Cholesterol

Triglycerides

1. Wing RR et al. Arch Intern Med. 1987;147:1749-1753.

2. Mertens IL, Van Gaal LF. Obes Res. 2000;8:270-278.

3. Blackburn G. Obes Res. 1995;3 (Suppl 2):211S-216S.

4. Ditschunheit HH et al. Eur J Clin Nutr. 2002;56:264-270.

3

3

3

3

4

Pharmacological therapy

of obesity

Pharmacological therapy

of obesity of obesity of obesity

A Guide to Selecting Treatment

BMI Category•Treatment < 24.9 25-26.9 27-29.9 30-35 35-39.9 >40

•Diet, exercise, With co- With co- + + +behavior therapy morbidities morbidities

•Pharmacotherapy With co- + + + morbidities

•Surgery With co- +morbidities

Source:Source: The Practical Guide to the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults.The Practical Guide to the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults.

SystemSystem MechanismMechanism ExamplesExamples

DigestiveDigestive Inhibition of lipaseInhibition of lipase Orlistat(Xenical)Orlistat(Xenical)

CNSCNS Inhibit norepinephrine, Sibutramine(Meridia) Inhibit norepinephrine, Sibutramine(Meridia)

Approved for LongApproved for Long--Term UseTerm Use

Obesity Pharmacotherapy

CNSCNS Inhibit norepinephrine, Sibutramine(Meridia) Inhibit norepinephrine, Sibutramine(Meridia) serotonin and serotonin and

dopamine reuptakedopamine reuptake

Approved for shortApproved for short--term use term use

CNSCNS Norepinephrine release Phentermine, othersNorepinephrine release Phentermine, others

Anorexic drugs Anorexic drugs

“Sibutramine”“Sibutramine”

↑↑↑↑↑↑↑↑ energy energy

expenditure by expenditure by

“Sibutramine”“Sibutramine”

↓↓ absorption absorption

of fat of fat

“Xenical”“Xenical”

“Chitosan”“Chitosan”

↓↓↓↓↓↓↓↓ gastric gastric

emptying by emptying by

“Acarbose”“Acarbose”

“Sibutramine”“Sibutramine”

↓↓ absorption of absorption of

CHO CHO

“Acarbose”“Acarbose”

“Gymenemic “Gymenemic

acid”acid”

Conclusion

Overweight and obese individuals are more likely to

develop type 2 diabetes than their normal-weight

counterparts.

In addition, the incidence of insulin resistance,

hyperinsulinemia, and the insulin resistance syndrome is

greater as BMI increases.

This is the “at

risk”patient

I’m talking about

Chronic kidney disease

Metabolic syndrome as

predictor of CVD

•MS increases risk of CHD

•MS predicts 25% of all new-onset CVD

•10-year risk of MS in men is between 10-20%

•Women with MS

Approaches to the Treatment of the Metabolic Syndrome

Behavioral

Weight loss

Increased physical activity

Pharmacological (treat underlying conditions)

Lipid disordersLipid disorders

Hypertension

Diabetes

Should treatment of these underlying disorders be intensified because the subject has the metabolic syndrome?

Should underlying insulin resistance be treated in nondiabetic subjects?

No clinical trial data to date support the use of pharmacological agents to improve insulin sensitivity in nondiabetic subjects, although this is an area of active interest

It’s everywhereSome 56 percent of South African women are now either

obese or overweight, compared to fewer than 10 percent who

are underweight. More than 17 percent of adolescents here

are overweight—for teenage girls, it's 25 percent, according

to the Medical Research Council. According to the same

report only 2% of South Africans are diabetic. Why?

World Total Cost of diabetes: $153,000,412-$286,844,446 World Total Cost of diabetes: $153,000,412-$286,844,446

depending on the degree of optimism