BIOC 462B: Dr' Tischler

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BIOC 462B Dr. Tischler
OBESITY-DIABETES
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• Objectives
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• Describe the leptin signaling system, including
  the signal transduction mechanism and factors
  that mediate effects of this receptor in the
  hypothalamus and/or periphery.
• Discuss how activation of the Peroxisome
  Proliferator Activated Receptor gamma (PPAR?)?
  affects expression of resistin and thereby
  serves as a target for therapy in resensitizing
  type 2 diabetes patients to insulin.
• Discuss the effects of insulin, thyroid hormone
  (T3), ?3-adrenergic receptor activation, and
  ?-melanocyte stimulating hormone on uncoupling
  protein, hormone-sensitive lipase (mobilizes
  fatty acids from stored triacylglycerol) and/or
  lipoprotein lipase (releases fatty acids from
  triacylglycerol carried by lipoproteins).

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• Objectives (cont)
•  
• 4. Describe how increased circulating fatty
  acids in obesity leads to development of the
  metabolic syndrome and the insulin resistance
  associated with type 2 diabetes.
• 5. Discuss the roles of amylin, tumor necrosis
  factor (TNF)-?, , resistin, and
  hypoadiponectinemia in the development of
  metabolic syndrome and progression to type 2
  diabetes.
• 6. Describe the association between type 2
  diabetes and a) hypertriglyceridemia (excess
  blood triacylglycerol), b) hyperglycemia (excess
  blood gluose), and c) ketoacidosis.

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SET POINT HYPOTHESIS

• blood-borne factors mediate control of body
  weight at a "set point
• factors interact with the hypothalamus
• factors regulate
• food intake (appetite)
• energy expenditure (level of activity and body
  temperature)
• deficiency or defect in factors may disrupt
  normal weight control leading ? weight gain ?
  type 2 diabetes
• 80 of type 2 diabetes due to obesity
• model of food intake lipostat concept
  signals proportional to size of fat stores
  integrate with other regulators of food intake
• depletion of energy in adipose cells increases
  food consumption
• food intake is regulated within a lipostatic
  system for energy homeostasis

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LEPTIN RECEPTOR
?-MSH4 RECEPTOR (MC4-R)
Hunger AGRP Galanin NPY Orexin A Orexin B
Satiety CART CCK-PZ GLP-I ?-MSH Serotonin
Integrated Signalling Network
Adipose
Leptin ?MSH 1,2,3,5-receptors ?3-Adrenergic
receptor Resistin/Resistin receptor PPAR? RXR
ligands Uncoupling Protein (UCP)
Figure 1. Biochemical factors that play a role
in control of weight. AGRP, agouti-related
peptide CART, Cocaine-Amphetamine Regulated
Transcript ?-MSH, ?-Melanocyte Stimulating
Hormone melanocortin (MC) NPY, Neuropeptide-Y
PPAR, Peroxisome Proliferator Activated Receptor
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Hypothalamus arcuate nucleus
JAK-STAT
Leptin receptor
Adipose
Adipose stores are HIGH
Figure 2. The leptin signaling system and its
effects when adipose stores are "high"
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Hypothalamus
? AGRP from hunger neurons Block ?MSH binding
? ?MSH
Adipose
Adipose stores are low
Figure 2. The leptin signaling system and its
effects when adipose stores are low"
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LEPTIN

• Secreted by white adipose tissue
• Leptin receptors
• mostly in hypothalamus
• same receptor family as GH and PRL operate
  via JAK-STAT
• Restrictions as anti-obesity agent
• peptide hormone must penetrate blood-brain
  barrier synthetic analogues difficult to make
• leptin rarely defective in obese patients
• human obesity associated with elevated leptin
  resistance
• defects in receptor are rare

LEPTIN RECEPTOR DEFECT Shows leptin needed for
sexual maturation MC4 receptor in hypothalamus
affects sexual function leptin influences
functioning of hypothalamus/pituitary
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Table 1 Neural control of appetite
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Lose hunger signal
HYPOTHALAMUS
Leptin Receptor (via JAK-STAT)
SATIETY
?-MSH
Catecholamines
Satiety signal
PANCREAS ?-cells
ANTERIOR PITUITARY
THYROID
?-MSH
Leptin
Altered Gene Transcription
Gs/cAMP
MC1,2,3,5-R
ADIPOSE
PKA activates HSL
PPAR?
?-oxidation TCA cycle
Represses resistin
TAG ? FFA
15-deoxy-?12,14-PGJ2 (ligand)
UCP
Heat
ENERGY EXPENDITURE
Figure 3. Integrated model of human weight
control.
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4A. FAT BURNING CYCLE IN ADIPOSE
HYPOTHALAMUS
PANCREAS ?-cells
?-MSH
Leptin
Insulin
catecholamines (from SNS)
Resisitin
X
?3-AR
Altered Gene Transcription
autocrine
Gs/cAMP
PKA activates HSL
MC1,2,3,5-R
ADIPOSE CELL
LIVER
TAG ? FFA
FFA
UCP
Heat
ENERGY EXPENDITURE
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FFA from adipose
4B. FAT BURNING CYCLE IN MUSCLE
HYPOTHALAMUS
Leptin
Anterior Pituitary
THYROID
TSH
ADIPOSE
T3
FFA
Altered Gene Transcription
MUSCLE CELL
FFA
ENERGY EXPENDITURE
UCP
Heat
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METABOLIC SYNDROME

• Also called syndrome X or insulin resistance
  syndrome
• Assortment of metabolic perturbations
• Potential risk to develop type 2 diabetes
• Essential factors
• glucose intolerance
• obesity
• hypertension
• dyslipidemia (too much lipid)
• Obesity precedes metabolic changes associated
  with syndrome

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METABOLIC SUSCEPTIBILITY

• Metabolic syndrome requires one or more
  susceptibility factors
• defective insulin signaling
• adipose tissue disorders
• sedentary lifestyle
• mitochondrial defects
• aging
• drugs
• ? Insulin sensitivity (insulin resistance) is
  common
• ? Excess fat decreases likelihood of syndrome
  despite susceptibility

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FACTORS AFFECTING INSULIN SENSITIVITY
Role of Fatty Acids Circulating fats major
causal factor for insulin resistance Induce
resistance by replacing glucose as key fuel
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The Scenario Worsens A formula for metabolic
disaster
Insulin resistance ? Failure to inhibit
hormonesensitive lipase ? Increased lipolysis
? Increased fatty acids in the blood ? Fatty acids
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FACTORS AFFECTING INSULIN SENSITIVITY
Role of Pro-Inflammatory Cytokines Tumor Necrosis
Factor (TNF-?) causes hypertriglyceridemia in
obesity ? elevated Fas Resistin prevents
adipocytes from becoming larger causes insulin
resistance lowers glucose tolerance Activation
of PPAR? (by prostaglandin J2) counteracts
resistin
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FACTORS AFFECTING INSULIN SENSITIVITY
Role of Anti-Inflammatory Cytokine Adiponectin
decreases in circulation in metabolic
syndrome Hypoadiponectinemia associated
with insulin resistance metabolic syndrome type
2 diabetes dyslipidemia cardiovascular
disease hypertension
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DEVELOPMENT OF DYSLIPIDEMIA (hypertriglyceridemia)
Obesity favors increased triglyceride
formation Insulin resistance favors
lipolysis Insulin (elevated) still promotes
hepatic lipogenesis d ? Adiponectin prevents
inactivation of lipogenesis Circulating fats
incorporated into triglycerides by liver for
VLDL Fats generate cholesterol for VLDL ?VLDL
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FACTORS AFFECTING GLUCOSE HOMEOSTASIS (hyperglycem
ia)
Insulin resistance issue compounded by the fed
state Glucagon-like peptide secreted in
response to nutrients activates liver
gluconeogenesis promotes insulin
secretion insulin resistance elevated glucose
? hyperinsulinemia The Bottomline glucose use
diminished (? muscle/fat cell glucose
transport liver glycolysis) glucose production
enhanced (? liver glycogenolysis and
gluconeogenesis)
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FATS FURTHER FOSTER FRUSTRATING FIASCO
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PROGRESSION OF TYPE 2 DIABETES INADEQUATE INSULIN
SECRETION
Insulin resistance ? Hyperglycemia
? Hyperinsulinemia ? Increased demands on the
pancreatic ß-cells ? Mild decreased response of
insulin secretion to glucose ? Hyperglycemia
worsens ? Demand increases ? Ultimately response
to glucose becomes inadequate Early stage ?
treatable with sulfonylureas (facilitate Ca2
entry) Late stage ? mixed diabetes a type 2 with
defective insulin secretion
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WHY DOES INSULIN SECRETION BECOME
INADEQUATE? Glucose Toxicity Theory
?
Hyperglycemia ? glucose toxicity Mechanism
beta cells over-taxed
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WHY DOES INSULIN SECRETION BECOME
INADEQUATE? Lipotoxicity Theory
Excess circulating fatty acids ? lipotoxicity
Possible mechanisms in beta cells obesity
blunting response to glucose altered
mitochondrial metabolism of pyruvate ? ATP
induction of an uncoupling protein ? oxidative
phosphorylation
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WHY DOES INSULIN SECRETION BECOME
INADEQUATE? Lipotoxicity and the Amylin Theory
? FA linked to islet amyloid polypeptide
(amylin) Amylin reduces postprandial glucagon
secretion ? diminish hepatic glucose output ?
reduce risk of hyperglycemia. High fat diet ?
of cells with amylin and density per
cell amylin lesions ? replace cell mass
? barrier to diffusion? Deposits ? reduce
cell function ? impair insulin secretion
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KETOACIDOSIS Excessive build-up of ketone bodies
(organic acids) results in acidosis causing a
fall in blood pH
In type 2 diabetic patients the events that can
lead to ketosis are
Relative (or absolute) lack of insulin
BUT
Figure 6. Development of an ketoacidosis
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METABOLIC ISSUES LEADING TO CORONARY ARTERY
DISEASE
Lipoprotein Abnormalities ? VLDL overcomes ?
lipoprotein lipase (due to resistance) leads to ?
LDL ? LDL increases risk of CAD/atherosclerosis ?
LDL provides more substrate for oxidation to
oxidized LDL
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METABOLIC ISSUES LEADING TO CORONARY ARTERY
DISEASE

• Lipoprotein Abnormalities what else can go
  wrong?
• LDL becomes smaller/denser in metabolic syndrome
• Modified particles more atherogenic
• more toxic to endothelium
• more easily pass through basement membrane
• greater susceptibility to oxidation
• bind selectively to macrophage scavenger
  receptors

Macrophages loaded with CE release cytokines ?
inflammation ? cell proliferation ? cell
aggregation And then there is plaque formation
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HEALTHY ENDOTHELIUM
DAMAGED ENDOTHELIUM
Figure 7. Development of an atheroma
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Another Scenario Worsens
Chronic hyperglycemia ? non-specific protein
glycosylation (Advanced Glycation
Endproducts) collagen is glycosylated BUT is
replaced slowly ? traps modified LDL in smooth
muscle layer
Metabolic syndrome/diabetes lowers HDL ?
worsens the pathogenesis Hypertriglyceridemia
decreases HDL size and density ? cleared more
easily ? lowers scavenging capacity ? ?
intracellular cholesterol ? ? lowers LDL
receptors ? ? LDL cholesterol in the circulation
? ? risk of CAD/atherosclerosis
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METABOLIC ISSUES LEADING TO CORONARY ARTERY
DISEASE
The Clot-forming State in Metabolic
Syndrome/Diabetes Metabolic syndrome ? diabetes
? CAD linked to inflammatory response ? TNF?
resistin plus ? adiponectin ? pro-inflammatory
condition Pro-inflammatory condition ? favors
clot formation