Obesity

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• Obesity
• It has been clear for several decades that
  maintenance of body weight is under genetic
  control, largely due to identification of
  mutations in mice that result in obesity.
  Recently, amid great excitement, several such
  genes have been cloned from mice and humans, and
  it's very likely that additional genetic
  determinants will soon be identified.
• The incentive to understand genetic control over
  body weight can largely be attributed to two
  factors
• Obesity is a monumental problem in the developed
  world and the allure of finding a drug to cure
  this problem is strong.
• There is a strong association between development
  of obesity in adulthood and development of other
  important diseases, including diabetes,
  hypertension and heart disease.

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Sources and Control of Lipid Synthesis

• Sources
• a. From ingested triacylglycerols
• b. From ingested glucose
• Control of Lipid Synthesis
• Nutritional-high carbohydrate diet
• Hormonal
• high plasma insulin
• Leptin-leptin receptor interactions

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Fate of Ingested lipids
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General Structure of Lipoproteins
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Nascent Chylomicrons
TGs of VLDL are also hydrolyzed by the same
mechanism
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Overall Reaction of Fatty Acid Synthesis

• Catalyzed by FAS complex consists of seven
  different enzymes and a small protein called ACP
  (acyl carrier protein)
• Acetyl CoA 7 Malonyl CoA 14 NADPH 14 H
• CH3- CO-SCoA 7 CO2-CH2- CO-SCoA
• Palmitic Acid 14 NADP 8 CoA 7 CO2 7 H2O
• (C16 Fatty acid)

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Sources of NADPH for FA Synthesis

• From Hexose Monophosphate Shunt Pathway
• Glucose-6-P NADP 6-Phospho
  gluconate NADPH
• 6-Phosphogluconate NADP
  Ribulose-5-phosphate NADPH
• 2. Malate NADP Pyruvate
  NADPH

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Formation of Malonyl CoA
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Subunit Composition of Acetyl CoA Carboxylase
(ACC)

• ACC is the rate-limiting enzyme of FA Synthesis
• BCCP-biotin carboxyl carrier protein-10,000 mol.
  wt no enzymatic function.
• Biotin Carboxylase (BC)
• BCCP HCO3- ATP? BCCP-CO2 ADP P
• 3. Transcarboxylase (TC)
• BCCP-CO2 Acetyl CoA? Malonyl CoA BCCP
• CH3-C-SCoA
  CO2-CH2-C-SCoA

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Steps of Fatty Acid Synthesis by FAS
complex(seven enzymes and an ACP)

• Acetyl CoA ACP Malonyl CoA
  ACP
• Acyl Transacylase
  Malonyl Transacylase
• Acetyl-ACP
  Malonyl ACP
• (CH3-CO-SACP)
  (CO2-CH2-CO-SACP)
• CH3-CO-CH2-CO-SACP CO2
• 
  ß-ketoacylACP Reductase
• CH3-CHOH-CH2-CO-SACP NADP
• (ß-hydroxybutyryl-SACP)

Beta-Ketoacyl-ACP Synthase
Ketoacyl-ACP synthase
(Acetoacetyl-ACP)
NADPH H
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Continue FAS

• CH3-CHOH-CH2-CO-SACP
• 
  (ß-Hydroxybutyryl-SACP)
• 
  ß-hydroxyacylACP dehydratase
• CH3-CHCH-CO-SACP H2O
• (Crotonyl
  -SACP)
• 
  aß-enoylACP reductase
• CH3-CH2-CH2-CO-SACP NADP
• (Butyryl-SACP)

NADPH H
From malonyl CoA
From acetyl CoA
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Additional Steps

• Butyryl- S-ACP Malonyl-CoA
• CH3-CH2-CH2-CH2-CH2-CO-SACP
• (Hexanoyl-SACP) (C6) Malonyl CoA
• Octanoyl-SACP (C8) Malonyl CoA
• Decanoyl-SACP (C10) Malonyl CoA
• Dodecanoyl-SACP (C12) Malonyl CoA
• Tetradecanoyl-SACP (C14) Malonyl CoA
• Hexadecanoyl-SACP (C16)
• Palmityl
  thioesterase
• Hexadecanoic Acid ((Palmitic Acid)
• CH3-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-C
  H2-CH2-CH2-COOH

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Regulation of FASynthesis

• Citrate FAS
• Insulin Glucagon
• ACC (dimer) ACC
  (polymer)
• (400,000)
  (4-8 x106)
• (inactive)
  (active)

Citrate
(-)Palmitoyl CoA (-)Malonyl CoA
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Insulin and Glucagon Effects

• Glucagon, epinephrine adenylate cyclase
  cAMP
• 
  
• ACC (polymer)
  Phospho-ACC(polymer)
• Active
  Inactive
• Protein Phosphatase
• 
  
• () up regulates
• Insulin

cAMP dependent Protein Kinase
ATP ADP
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Nutritional and Hormonal control

• High glucose
• High sucrose
• High fructose
• Insulin
• High Fat diet
• Caloric restriction
• Diabetes

Increased transcription and translation of mRNA
for ACC and FAS
Decreased transcription and translation of mRNA
for ACC and FAS
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Mechanism of Plaque formation
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Ob gene-Leptin(OMIM164160) db gene-Leptin
receptor(OMIM 601007)
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C16 to ?9C161 or C18 to ?9C181
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Learning Objectives

• Learn about sources of acetyl CoA, Malonyl CoA
  and NADPH
• Understand the role of HCO3-1_in the formation of
  malonyl CoA and of ACP in fatty acid synthesis
• Be knowledgeable about the rate limiting step for
  overall fatty acid synthesis.
• Know the complexity of fatty acid synthesizing
  enzymes
• Understand how insulin, glucagon and high
  carbohydrate and fat diets control fatty acid
  synthesis.
• Understand the role of leptin and leptin receptor
  in obesity