5 - Obesity & Metabolic Syndrome

Question 1

BMI

Answer 1

Body Weight (kg)

————-

Height (m²)

Classifies OBESITY

Question 2

Metabolic Abnormalities that make up Obesity

Answer 2

• Insulin Resistance
• Beta-Cell Failure
• Dyslipidemia
  
  • ​High TG’s / low HDL / dense LDL
• Non-alcoholic Fatty-Liver Disease
• NOT SYNONYMOUS
  
  • ​You can be obese even though you have normal metabolism
  • Obesity is simply BMI>30 (kg/m²)

Question 3

Obesity & Genetics

Answer 3

Obesity is MULTIFACTORAL

• Some evidence of genetic contribution
  
  • Numerous genese assoiated w/ :
    
    • weight gain / BMI changes
• Epigenetic risk factors also important

Question 4

Enlarged Adipocytes produce:

Answer 4

• Obese patient’s large adipocytes
  
  • produce larger amounts of ​Adipokines
  • promote inflammation
  • increase insulin resistance​

Question 5

What factors impact weight?

Answer 5

Insulin Resistance

Inflammation

GUT MICROBIOME

Question 6

Leptin & Obesity

Answer 6

• Leptin is the key regulator of the brain-gut axis
• Activation of the hypothalmic leptin receptors:
  
  • ​Blocks food intake
  • Increases expenditures
• ​Leptin decreases with weight reduction

Question 7

Genes that encode for what underlie Obesity?

Answer 7

• Leptin
• Leptin Receptor (LEPR-B)
• Insulin

Question 8

Obesity Physiology Pathway

Answer 8

• Imbalance in Caloric Intake & Energy expenditure
  
  • ​-> Positive energy Balance
    
    • -> Inflammed Adipose Tissue
      
      • ​-> Increased FFA release to:
        
        • ​Liver
        • Pancreas
        • Muscle
        • Epicardium__​​​

Question 9

Obesity effects on the LIVER

Answer 9

• Accumalation of intrahepatic TG’s
  
  • -> reduced sensitivity to Insulin
    
    • ​​​in muscle / liver / adipose tissue
• _​​_Excess FFA​ from adipose tissue
  
  • -> hepatic & skeletal Insulin resistance​

Question 10

Metabolic consequences of more circulating FFA from adipocytes

Answer 10

1. Less Glucose uptake in muscles
2. More Glucose uptake by Liver
3. Change in Gut microbiome

Question 11

How does obesity drive Insulin Resistance?

Answer 11

• Liver
  
  • _​_Making too much Glucose
    
    • ​gluconeogenesis + lipotoxcity
• ​Skeletal Muscle
  
  • ​Reduced Glucose Uptake
    
    • ​due to it taking in more Lipids
    • insulin action is reduced
• Chronic Hyperinsulinemia
  
  • Desensitizes Insulin receptors
• ​Low level inflammation -> cytokine release

Question 12

How does inflammation lead to insulin resistance?

Answer 12

• Chronic low-grade inflammation in obesity
  
  • -> increase in Cytokines ( TNF-alpha )
    
    • ​activates JNK + NF-KB
      
      • -> dephosphorylation of Insulin Receptors
        
        • also IRS inhibition by JNK

Question 13

VMN

Ventro-medial hypothalamic nucleus

Signaling in the Hypothalamus

Answer 13

• VMN Stimulation
  
  • -> Supression of food intake
• ​Lesions in VMN -> induce Obesity
• Regulated by Leptin & Insulin
  
  • • NPY
  • + Ghrelin

Question 14

Obese Individuals produce more ____ than normal people

Answer 14

• Leptin
  
  • ​block food uptake
• TNF-alpha
• IL-6
• PAI1
• less Adiponectin
  
  • ​healthy individuals produce more adiponectin

Question 15

ARH

Arcuate Hypothalmus Nucleus

Signaling in the Hypothalamus

Answer 15

• Stimulation of ARH
  
  • ​-> INCREASED food intake
• Damage of ARH -> reverses it
• NPY / AgRP Neurons
  
  • ​+ Ghrelin
    
    • ​stimulates appetite
  • - Leptin
    
    • ​inhibits it

Question 16

NPY

Neuropeptide Y

Signaling in the Hypothalamus

Answer 16

• Stimulates hypothalmic regulation of food intake
• Increases Obesity
• Decreases total energy expenditure
• NPY gene expression is inhibited by Leptin

Question 17

Leptin

Signaling in the Hypothalamus

ARH

Answer 17

• Inhibits ARH NPY Gene Expression
  
  • ​**–> Reduction in **Obesity
  • reduced Hunger / weight
• ​Leptin Resistance

Question 18

Ghrelin

Signaling in the Hypothalamus

ARH

Answer 18

• Peptide hormone produced by the STOMACH
  
  • ​Physically senses when stomach is empty
• ​​STIMULATES APPETITE
  
  • ​–> causes weight gain
• Regulates NPY & AgRP in hypothalmus

Question 19

How does Obesity affect Metabolism?

Answer 19

• Impairment of Glucose Transport into muscle / adipose tissue
  
  • _​_downregulation of GLUT4
• ​​​Increase in Basal Lipolysis
  
  • ​–> increase in FFA
• ​protein metabolism is still controversial

Question 20

Obesity on inflammation

Answer 20

• Obese Adipose -> Increase in Macrophages
  
  • ​-> Increase in pro-inflammatory cytokines
• ​TNF-Alpha
  
  • ​contribute to insulin resistance
    
    • ​Anti-TNF therapy in animals increase insulin sensitivity
  • Reduce GLUT4 expression

Question 21

Why is there more LEPTIN in Obese tissue?

Answer 21

LEPTIN RESISTANCE

there is also less ADIPONECTIN in obese tissue

Question 22

Possible treatments to ​REDUCE OBESITY

Answer 22

• Leptin​
  
  • ​also inhibits NPY
  • but there is leptin resistance
• ​GLP-1 Receptor Agonist
  
  • -> stimulate insulin release
• Anti-TNF
• Anti-Ghrelin

Question 23

Pharmacotherapies for Obesity

Answer 23

• Appetite-Supressants
  
  • ​Phentermine / topiramate
• Lorcaserin
• Naltrexone / Bupropion
• Liraglutide = GLP-1 Receptor Agonist
• ​Serotonergic drugs / Cannabinoid receptor antagonist
  
  • ​no longer approved

Question 24

Metabolic Syndrome’s associated risk factors:

Answer 24

• impaired Fasting Glucose
• Abdominal Obesity
• Hypertension
• Dyslipidemia

Question 25

**Viceral Fat**

Answer 25

**Increases chance for Metabolic Disease** * Fat that surrounds your organs * linked to : * **heart disease** * **T2DM** * **Strokes**

Question 26

**Hip to Waist vs BMI** **H2W**

Answer 26

* **Waist / Hips = H2W Ratio** * ​**More Indicative** since it shows WHERE the fat is stored * more viceral fat is in the stomach * BMI is just weight / height

Question 27

**Insulin Action in MS (metabolic syndrome)**

Answer 27

* _Pancreas_ * _​_**Insulin Resistance** * **​**-\> contribute to MS * Accumalation of **FA's** * **​-\> *Diminished insulin production*** * Viceral Obesity -\> Insulin resistance * -\> **Blood Clots & CVD****​**

Question 28

**Leptin Functions**

Answer 28

* Control peripheral energy status * *Reduce **Appetite*** * Improve **Insulin Sensitivity** * Increase **ENergy Expenditures**

Question 29

**3 Main Causes of Insulin Resitance**

Answer 29

* **Leptinemia** * increased synthesis * *Reduction of **leptin's access to the CNS*** * ***​***due to BBB * **Disruption of signaling** * Impaired ObRB downstream signal transduction * *reduction in OrRB expression @ plasma* * *reduction in Positive regulators* * INCREASE in NEGATIVE receptors

Question 30

**ObRB**

Answer 30

**Leptin Receptor in the Brain**

Question 31

**Adiponectin & MS**

Answer 31

* *levels are reduced in Obesity* * Adiponectin functions: * **May increase insulin sensitivity** * *Suppresses **Glucose** _in the liver_* * Enhances **FA Oxidation** in the _muscle__​​​_

Question 32

**Lipid Metabolism & MS**

Answer 32

* **Dyslipidemia** is associated w/ MS * high **TG's + FFA's** * *decreased **HDL***

Question 33

**HDL** in MS

Answer 33

* **​HDL particles are smaller** in visceral obesity & MS * due to lipoprotein binding more TG vs cholesterol * **Enhances HDL delivery of lipid** to _LIVER_ * _​_forms small dense particles that **Stimulate macrophages & trigger inflammation** * **Promotes ARTERIOSCLEROSIS**

Question 34

**What increases risk for CVD & Artherosclerosis?**

Answer 34

* **Metabolic Syndrome** * **​**Dyslipidemia / HT / Insulin Resistance * **Diabetes** * **Non-Alcoholic Faty Liver Disease (NAFLD)**