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BIOKIMIA OBESITAS

ANNISA HANIFWATI

Referensi : - Clinical Biochemistry review Vol 25, Aug 2004 - Textbook of Biochemistry Illustrated Review Fifth edition, Lippincotts 2010 - Biochemistry of Leptin, Shaliana, National Dairy Research India - The Biochemistry of Obesity, Rick Voake MD - Medical Biochemistry 4th ed,2002,NV Bhagavan

THE CLINICAL BIOCHEMISTRY OF OBESITY

ABSTRACT OBESITY: RESULT OF EXCESSIVE ENERGY INTAKE COMPARE TO ENERGY USAGE ( DECREASED PHYSICAL ACTIVITY) PHYSICAL CONSEQUENCES OF OBESITY : ARTHRITIS, INSULIN RESISTANCE, DIABETES, FATTY LIVER, CAD, HYPERTENSION, PCOS PATOPHYSIOLOGICAL MECHANISME : COMBINATION OF TOXIC METABOLIC EFFECTS OF FFA & ADIPOKINES

INTRODUCTION OBESITY : INCREASED ADIPOSE TISSUE MASS ADIPOSE TISSUE : - STORAGE TISSUE FOR TRIACYLGLICEROL - AN ENDOKRIN ORGAN, RELEASING ADIPOKINES . DEFINITION OBESITAS WHO GUIDELINE 1985: BMI>25 : OVERWEIGHT >28,5 : OBESE (WOMEN) >30 : OBESE (MEN) BMI: calculated as weight (kg) divided by height squared (m2)

ACQUIRES CAUSE OF OBESITY - CHILDREN : INCREASED ENERGY INTAKE (SUGAR), DECREASED PHYSICAL ACTIVITY - CUSHING SYNDROME : TRUNCAL / VISCERAL OBESITY - HYPOTHYROIDISME : RARE CASE OF OBESITY, WEIGHT GAIN IS DUE TO WATER RETTENTION, WHICH IS REVERSIBLE AFTER THYROID HORMON THERAPY NORMALLY : SIGNAL FROM THE GUT & ADIPOSE TISSUE ARE INTEGRATED IN HTE CNS TO AFFECTS APPETITE & ENERGY HOMEOSTASIS & LIMIT WEIGHT GAIN PATHOLOGICAL OBESITY: FAILURE OF HOEMOSTATIC MECHANISME

GENETIC CAUSE OF OBESITY - THRIFTY GENE HYPOTHESIS : CERTAIN POPULATIONS MAY HAVE GENES THAT DETERMINE INCREASED FAT STORAGE, IN A MODERN ENVIRONMENT RESULT IN OBESITY & DM TYPE 2 - SINDROMA PRADER-WILLI, SINDROM ANGELMAN, SINDROM WILSONTURNER . LEPTIN ASSOCIATED GENES LEPTIN SECRETED FROM ADIPOCYTES INTO THE CIRCULATION TRANVERSE INTO THE CNS BINDS TO LEPTIN RECEPTOR IN HIPOTALAMUS LEPTIN STIMULATES PRODUCTION OF ALFA MSH & ACTH. MSH BIND TO MELANOCORTIN RESEPTOR IN HIPOTALAMUS, CAUSE DECREASE FOOD INTAKE

MUTATION OF SISTEM ( LEPTIN, RESEPTOR, MSH), CAUSE OBESITY (RARE/ UNCOMMON) OBESITY : USUALLY HIGH LEPTIN, BUT LEPTIN RESISTEN, CAUSE DEFICIENCY LEPTIN OBESITY & INSULIN RESISTANCE : OBESITY & DM TYPE 2: INSULIN RESISTEN DM TYPE 2 : OVERWEIGHT, OBESE > 90% PREECED THE ONSET DM TYPE 2: WEIGHT GAIN & INSULIN RESISTEDM CURRENT THEORIES : DM TYPE 2 DEVELOP WHEN PANCREATIC BETA CELL OUTPUT CAN NO LONGER SATISFY THE DEMAND, IMPOSED BY INCREASED INSULIN RESISTEN

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FFA PARADIGMA LINKING OBESITY TO INSULIN RESISTANCE - ELEVATED CELLULER LEVEL OF FFA : PRODUCE INSULIN, RESISTANCE IN SKELETAL MUSCLE&LIVER, REDUCE BETA CELL FUNCTION, CAUSE LIPOTOXICITY . . CAUSATIVE FACTOR INVOLVED IN HEPATIC INSULIN RESISTANCE : HEPATIC FFA TRIGLYCERIDE ACCUMULATION INSULIN RESISTENT MUSCLE CHARACTERISED BY : LOWERED ABILITY TO OXIDISE FFA

IMBALANCE BETWEEN FFA UPTAKE- OXIDASI - PROMOTING ACCUMULATION OF LIPID & TRIACYLGLYCEROL IN SKELETAL MUSCLE, CAUSE INSULIN RESISTANCE . FFA : - BLOCK INSULIN SIGNALLING PATHWAY - LEAD INSULIN RESISTEN ADIPOKINE PARADIGMA LINGKING OBESITY TO INSULIN RESISTAN ADIPOSE TISSUE : AN ENDOKRINE ORGAN ADIPOKINES : ADIPOSE TISSUE-DERIVED HORMONES&INFLAMMATORY CYTOKIN DYSFUNCTION OF ADIPOSE TISSUE CAUSING SYSTEMIC INSULIN RESISTEN

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LEPTIN - DISCOVERD IN 1994 - LEPTIN : DECREASE NEUROPEPTIDE Y IN HIPOTALAMUS, SHOULD SUPPRESS APPETITE - LEPTIN PRODUCE BY ADIPOSE TISSUE, PLACENTA, BONE MARROW, SOMACH, MUSCLE, BRAIN

Leptin: encoded by the OB (obese gene) protein is 167 amino acid residues long generated mainly in adipose tissue messenger reduce fuel intake increases heart rate, blood pressure, thermogenesis acts on leptin receptors Leptin receptor encoded by the DB (diabetic gene) in mice located mainly in the hypothalamus also expressed in cells of the adrenal cortex & betacells Hanekamp 2003 Theodor binding of hormone to receptor reduces appetite 14

Leptin

Leptin deficient mice


Leptin deficient homozygous mice (ob gene) behave like mice that are constantly starving are 3 times bigger than normal cant stay warm resemble diabetic mice(DB) are insulin-resistant db/db mice are obese and diabetic
ob/ob

OB/ob
Theodor Hanekamp 2003

or OB/OB
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Leptin cascade
Appetite suppressing neuropeptides
(a -MSH) a-melanocyte-stimulating hormone (POMC)Proopiomelanocortin (CRH) Corticotropin releasing hormone (CART) Hypothalamic peptide

Appetite stimluating neuropeptides


(NPY) Neuropeptide Y

Theodor Hanekamp 2003

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BIOCHEMICAL MEDIATOR OF OBESITY

BIOCHEMICAL MEDIATOR OF OBESITY

The regulation of intake & expenditure is achieved by coordinating the effect of endocrine mediators & neural signal that arise from adipose tissue, endocrine gland, neurological & gastrointestin system. All of the information finally is integrated by the CNS

One of the most significant mediator of the energy store in the adipose tissue is leptin (from the Greek), leptin meaning thin. Leptin is a protein of 167 amino acid residues that is synthesized in adipocytes. Its syntesis is increased by insulin, glucocorticoid, &estrogen & is decreased by beta adrenergic agent. The role of leptin in obesity comes from studies in rodent.

In genetically obese mice (ob/ob) the observed gross obesity is due to abscense of leptin production in adipocytes. Leptin action on energy metabolisme is mediated by receptor in many cells and it bind spesifically to a receptor in the hypotalamus. The action of leptin involves at least 2 pathways.

During starvation &weight loss, adipose tissue is decreased, low level of leptin. Low leptin leads to production of neuropeptide Y, which is syntesized in the arcuate nuclues of hypotalamus & transported axonally to the paraventricular nucleus. Neuropeptide Y binds to its reseptor & functions as a potent appetite stimulant.The effect is increased appetite, decrease energy expenditure, increase parasympathetic activity

An opposite, when the leptin level rise, mediated by melanocyte-stimulating hormon (MSH), that bind melanocortin 4 receptor (MC4R). MSH binding to MCR4 initiates biological response: decrease appetite, increase energy expenditure & increase symphatetic activity

Most obese human, plasma level of leptin are high due to excess adipose tissue. Inspite of abundant leptin, there is continued overeating Inheritage obese disorder : hyperphagia lead obesity, hypogonadisme, mental retardation (Willi Prader syndrom, 1 of 10.000-20.000 birth). Delete in chromosom 15

THE BIOCHEMISTRY OF OBESITY

The Hypothalamic-Leptin Axis


Feedback system Allows the fat cells to tell the brain to quit seeking more food when too much fat is present. Allows the brain to adjust the metabolic rate to control energy use.

Lustig, Ped Annals, 35:12 Dec 2006

Physiological effects of Leptin


Regulation of food intake ,energy expenditure and body weight . Thermogenesis . Reproductive function . Supressed bone formation . Directly act on the cells of liver and muscles . Related to inflammatory response . Contribute to early hematopoiesis.

When excess fat builds up in the fat cell, leptin is produced and enters the bloodstream. Leptin receptors in the hypothalamus are triggered. This shifts the hypothalamus into Spend Energy mode. Leptin changes SLOWLY (days to weeks)
Lustig, Ped Annals, 35:12 Dec 2006

The Hypothalamic-Leptin Axis How it works:

Spend Energy Mode


Increase TSH to increase Appetite reduction (Dont thyroid output and increase need to waste time looking for more food) baseline energy expenditure Increase sympathetic tone to Beta-adrenergic stimulus to skeletal muscle increasing fat cells increases lypolysis ATP and mitochondrial (Break out stored energy for proteins (Muscles are immediate use) prepared to function optimally)
Lustig, Ped Annals, 35:12 Dec 2006

Conserve Energy Mode


Appetite increases (Need to seek more food for energy) Decrease sympathetic and increase vagal tone to slow down muscle function Increase fat absorption by fat cells
Lustig, Ped Annals, 35:12 Dec 2006

Vagus increases peristalsis and insulin production (for food processing) Vagus nerve also slows heart rate and myocardial oxygen consumption

What if leptin feedback is blocked?


Hypothalamus is tricked into thinking that there is no leptin being released from fat cells. It then sends Orexin-A all over your brain, making you think you are starving. The hypothalamus is stuck in conserve energy mode, increasing appetite, slowing down metabolic rate, increasing fat storage. Your brain is constantly starving even though the fat cells are busting at the seams!

Orexin-A (hypocretin-1)
Small peptide hormone released by the hypothalamus to act on the rest of the brain. It signals hunger, after the hypothalmus is stimulated by ghrelin from the stomach It also signals wakefulness, so that your brain stays awake long enough to seek food, and not to hibernate! Another reason obese children dont sleep well

Energy in = Energy out ???


Obese children are leptin resistant (leptin receptors are blocked) They are stuck in Conserve Energy mode Their brains are starving, so they are constantly seeking more food Yet very little of that energy is available for activity, since it is routed away into the fat cells.

What blocks leptin?


Brain damage to the leptin receptor area: hypothalamic obesity syndrome Insulin excess blocks leptin receptors (Fructose is what leads to insulin excess)

What blocks leptin?


Brain damage to the leptin receptor area: hypothalamic obesity syndrome Insulin excess blocks leptin receptors (Fructose is what leads to insulin excess)

Insulin excess blocks leptin

Lustig, Ped Annals, 35:12 Dec 2006

Insulin excess blocks leptin


Insulin receptors in the brain share the same substrate as leptin receptors When there is excess insulin, it hogs all the substrate, leaving none for leptin to use. Leptin attaches to the receptor, but nothing happens.

In the hyperinsulin state


Even high levels of leptin have no effect on the hypothalamus Known as leptin resistance Occurs in a large percentage of overweight children and adults

CAUSA HYPERINSULINEMIA : HIGH FAT DIET LOW FIBER DIET SLEEP DEPRIVATION HIGH FRUCTOSA

Fructose: A major cause of hyperinsulinemia


Fructose is absorbed from the intestine and enters the liver without insulin regulation, AND it does not suppress ghrelin (hunger hormone). It is then converted into acetyl-CoA, which floods the Kreb cycle, forcing excess production of FFA, triglycerides and VLDL lipoproteins.

Review:
What fructose becomes in your liver
FFA (free fatty acids, the building blocks of all lipids) VLDL lipoproteins and triglycerides (the nasty lipids most associated with cardio- vascular disease) Uric acid (oxidative stress, vascular inflammation)

Fiber is also a factor


Fiber adds bulk to foods, so the stomach turns off ghrelin sooner Fiber slows absorption of sugar in the gut Fiber binds to bile acids, reducing fat absorption from the gut Fruits and veggies are a good source

Fructose: A major cause of hyperinsulinemia


All this excess fat production leads to fatty liver which causes hepatic insulin resistance Fructose also activates the enzyme jnk-1 which causes hepatic inflammation, and more insulin resistance Faulty feedback to the liver results in massive insulin production, leptin resistance, and obesity

Fiber is also a factor


Fiber adds bulk to foods, so the stomach turns off ghrelin sooner Fiber slows absorption of sugar in the gut Fiber binds to bile acids, reducing fat absorption from the gut Fruits and veggies are a good source

Other symptoms of fructose poisoning


Diabetes (hyperinsulin state, insulin resistance) Cardiovascular disease Hypertension (renovascular damage) Fatty liver Hyperlipidemia Increased BMI from excess lipid stored in fat cells Sound familiar?

Metabolic Syndrome = Fructose Poisoning

With higher BMI, other symptoms can evolve PCOS (polycystic ovary syndrome) Acanthosis nigricans Diabetic complications Elevated CRP, endothelial damage

BIOCHEMISTRY OF LEPTIN

How leptin works ?

Role of leptin in regulation of food intake and body weight


Decrease hunger and food consumption inhibition of neuropeptide Y synthesis .
Food intake linked to its ability to regulate the neuroendocrine system .

Neuropeptide Y
36 a.a residue produce in the arcuate nucleus of the hypothalamus . Rich in tyrosine residues . Appetite stimulating hypothalamic peptide

Contd.
Found in many organ, high level of NPY are found in brainstem and hypothalamus . Stimulates leptin production in adipose tissue by increasing food intake and insulin secretion. Action through the parasympathetic nervous system.

Role of leptin in lipid metabolism


Inhibits intracellular lipid concentration Activate 5 AMP-activated protein kinase (AMPK) Inhibits acetyl coenzyme-A carboxylase (ACC) Increase in fatty acid oxidation and reducing the fat tissue in muscles and liver

.
Increase insulin sensitivity .

Inducers and suppressers of leptin expression


Inducers Feeding Glucocorticoids Effect + + Species Rodent + man Rodent + man

Insulin
Cytokines Obesity Fasting Pertussis toxin -receptor antagonists Thiazolidinediones

+
C or + + + -

Rodent
Man Rodent Rodent + man Rodent + man Rodent Rodent Rodent

cAMP

Rodent

Feedback loop
Food intake trigger the output of glucocorticoids and insulin Favour fat accumulation & increase leptin Leptin travels to hypothalamus Regulate body mass & control body energy intake , energy expenditure

NPY also regulate body fat mass

Obesity
Main focus of leptin research. Dramatic effects on obesity in mice.

In human a body mass index over 27.3 for man & 27.8 for women.
Hypothalamic insensitivity to leptin fundamental mechanism of obesity.

Leptin resistance
Mutation of the gene for leptin receptors in the brain Post receptor abnormalities in leptin signal transduction Impaired leptin transport across blood- brain barrier

What about humans:


Human fat cells also manufacture leptin protein (167 a.a ) Mutation in gene for leptin or its receptor are rarely found in obese people High blood conc. leptin indicates leptin resistance

Extreme obesity in 5 members of two families that are homozygous for mutation in their leptin gene like ob/ob mice.

Contd.
Extreme obesity among three members of a family homozygous for mutation in leptin receptor gene-like db/db mice. Only moderate obesity in people heterozygous for leptin gene. Recombinant human leptin available. The 16 september 1999 issue the New England Journal of Medicine reports- 9 year old girl homozygous for frame shift mutation leptin gene.

Contd.

Factor in obesity - -3 adrenoreceptor


Defect contribute leptin resistance/leptin expression

A paradox exists-comparison between mouse & human research cannot be made

Future prospects
More focus on leptin receptor & involvement in leptin resistance Relation to reproduction Mechanisms involved in regulation of leptin