5 - Obesity & Metabolic Syndrome Flashcards
BMI
Body Weight (kg)
————-
Height (m2)
Classifies OBESITY
Metabolic Abnormalities that make up Obesity
- 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)
Obesity & Genetics
Obesity is MULTIFACTORAL
- Some evidence of genetic contribution
- Numerous genese assoiated w/ :
- weight gain / BMI changes
- Numerous genese assoiated w/ :
- Epigenetic risk factors also important
Enlarged Adipocytes produce:
- Obese patient’s large adipocytes
- produce larger amounts of Adipokines
- promote inflammation
- increase insulin resistance
What factors impact weight?
Insulin Resistance
Inflammation
GUT MICROBIOME
Leptin & Obesity
- 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
Genes that encode for what underlie Obesity?
- Leptin
- Leptin Receptor (LEPR-B)
- Insulin
Obesity Physiology Pathway
- Imbalance in Caloric Intake & Energy expenditure
-
-> Positive energy Balance
-
-> Inflammed Adipose Tissue
-
-> Increased FFA release to:
- Liver
- Pancreas
- Muscle
- Epicardium__
-
-> Increased FFA release to:
-
-> Inflammed Adipose Tissue
-
-> Positive energy Balance
Obesity effects on the LIVER
- Accumalation of intrahepatic TG’s
- -> reduced sensitivity to Insulin
- in muscle / liver / adipose tissue
- -> reduced sensitivity to Insulin
- __Excess FFA from adipose tissue
- -> hepatic & skeletal Insulin resistance
Metabolic consequences of more circulating FFA from adipocytes
- Less Glucose uptake in muscles
- More Glucose uptake by Liver
- Change in Gut microbiome
How does obesity drive Insulin Resistance?
-
Liver
- __Making too much Glucose
- gluconeogenesis + lipotoxcity
- __Making too much Glucose
-
Skeletal Muscle
-
Reduced Glucose Uptake
- due to it taking in more Lipids
- insulin action is reduced
-
Reduced Glucose Uptake
- Chronic Hyperinsulinemia
- Desensitizes Insulin receptors
- Low level inflammation -> cytokine release
How does inflammation lead to insulin resistance?
-
Chronic low-grade inflammation in obesity
- -> increase in Cytokines ( TNF-alpha )
- activates JNK + NF-KB
- -> dephosphorylation of Insulin Receptors
- also IRS inhibition by JNK
- -> dephosphorylation of Insulin Receptors
- activates JNK + NF-KB
- -> increase in Cytokines ( TNF-alpha )
VMN
Ventro-medial hypothalamic nucleus
Signaling in the Hypothalamus
-
VMN Stimulation
- -> Supression of food intake
- Lesions in VMN -> induce Obesity
- Regulated by Leptin & Insulin
- NPY
- + Ghrelin
Obese Individuals produce more ____ than normal people
-
Leptin
- block food uptake
- TNF-alpha
- IL-6
- PAI1
-
less Adiponectin
- healthy individuals produce more adiponectin
ARH
Arcuate Hypothalmus Nucleus
Signaling in the Hypothalamus
-
Stimulation of ARH
- -> INCREASED food intake
- Damage of ARH -> reverses it
-
NPY / AgRP Neurons
- + Ghrelin
- stimulates appetite
-
- Leptin
- inhibits it
- + Ghrelin
NPY
Neuropeptide Y
Signaling in the Hypothalamus
- Stimulates hypothalmic regulation of food intake
- Increases Obesity
- Decreases total energy expenditure
- NPY gene expression is inhibited by Leptin
Leptin
Signaling in the Hypothalamus
ARH
-
Inhibits ARH NPY Gene Expression
- **–> Reduction in **Obesity
- reduced Hunger / weight
- Leptin Resistance
Ghrelin
Signaling in the Hypothalamus
ARH
- Peptide hormone produced by the STOMACH
- Physically senses when stomach is empty
-
STIMULATES APPETITE
- –> causes weight gain
- Regulates NPY & AgRP in hypothalmus
How does Obesity affect Metabolism?
-
Impairment of Glucose Transport into muscle / adipose tissue
- __downregulation of GLUT4
-
Increase in Basal Lipolysis
- –> increase in FFA
- protein metabolism is still controversial
Obesity on inflammation
- 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
-
contribute to insulin resistance
Why is there more LEPTIN in Obese tissue?
LEPTIN RESISTANCE
there is also less ADIPONECTIN in obese tissue
Possible treatments to REDUCE OBESITY
-
Leptin
- also inhibits NPY
- but there is leptin resistance
-
GLP-1 Receptor Agonist
- -> stimulate insulin release
- Anti-TNF
- Anti-Ghrelin
Pharmacotherapies for Obesity
-
Appetite-Supressants
- Phentermine / topiramate
- Lorcaserin
- Naltrexone / Bupropion
- Liraglutide = GLP-1 Receptor Agonist
-
Serotonergic drugs / Cannabinoid receptor antagonist
- no longer approved
Metabolic Syndrome’s associated risk factors:
- impaired Fasting Glucose
- Abdominal Obesity
- Hypertension
- Dyslipidemia
Viceral Fat
Increases chance for Metabolic Disease
- Fat that surrounds your organs
- linked to :
- heart disease
- T2DM
- Strokes
Hip to Waist vs BMI
H2W
-
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
Insulin Action in MS (metabolic syndrome)
-
Pancreas
-
Insulin Resistance
- -> contribute to MS
- Accumalation of FA’s
- -> Diminished insulin production
-
Insulin Resistance
- Viceral Obesity -> Insulin resistance
- -> Blood Clots & CVD
Leptin Functions
- Control peripheral energy status
- Reduce Appetite
- Improve Insulin Sensitivity
- Increase ENergy Expenditures
3 Main Causes of Insulin Resitance
-
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
ObRB
Leptin Receptor in the Brain
Adiponectin & MS
- levels are reduced in Obesity
- Adiponectin functions:
- May increase insulin sensitivity
- Suppresses Glucose in the liver
- Enhances FA Oxidation in the muscle__
Lipid Metabolism & MS
-
Dyslipidemia is associated w/ MS
- high TG’s + FFA’s
- decreased HDL
HDL in MS
-
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
- __forms small dense particles that Stimulate macrophages & trigger inflammation
What increases risk for CVD & Artherosclerosis?
-
Metabolic Syndrome
- Dyslipidemia / HT / Insulin Resistance
- Diabetes
- Non-Alcoholic Faty Liver Disease (NAFLD)
