Obesity lecture/chapter in book

Question 1

What kind of receptor is the Insulin receptor?

Answer 1

A tyrosine kinase receptor, it directly phosphorylates its insulin receptor substrates, IRSs.

Question 2

What pathways does the Insulin receptor activate?

Answer 2

via SH2 domains, it binds GRB2 which couples it to the Ras/MAPK growth factor pathway, and PI3K which activates most of its metabolic effects.

PI3K
activates AKT, also called Protein kinase B,
Inhibits GSK3, which disinhibits glycogen synthase, and glycogen synthesis increases.

activates FOxO transcription factors, inhibiting gluconeogenesis

activates mTOR signaling, increasing protein synthesis.

activates SREBP (sterol regulator element binding proteins) transcription factors, increasing lipid synthesis.

GRB2, activates SOS, a

Question 3

What are the major pathways that inhibit insulin receptor substrates?

Answer 3

JNK : c-jun N terminal kinases
and
IKKbeta : I-kappa-B kinase beta.

Both are serine kinases that phosphoinhibit IRS at serine residues, while the activating insulin receptor phosphorylates tyrosines.

SOCS3, Suppressor of cytokine signaling, binds and inhibits the insulin receptor on its cytosolic side.

All of these pathways are induced by IL-6 and TNFalpha.

Question 4

What are the two major insulin sensitising adipokines?

Answer 4

Leptin and adiponectin

Question 5

What are the effects of leptin in the liver

Answer 5

Stimulates gluconeogenesis by activating PEPCK
Increases glycogen consumption.

Increases beta oxidation by activating PPAR alpha

inhibits lipogenesis, and inhibits expression of SREBPs

Question 6

Leptins actions in muscle

Answer 6

Stimulates AMPK

Stimulates fatty acid oxidation. via PPARalpha activation.

Question 7

What doe levels of leptin correlate best with.

Answer 7

The amount of adipose tissue in a person. Obese people have higher leptin levels, and also can develop leptin resistance much like insulin resistance.

Leptin does not increase during acute overfeeding.

Leptin levels drop during starvation.

Question 8

Where is adiponectin synthesized?

What are its main targets?

Answer 8

Adipose tissue.

Its receptors are in the liver and muscles.

Its essential function is to enhance liver and muscle responses to insulin.

Question 9

What are the effects of adiponectin on skeletal muscle

Answer 9

The activation (tyrosine phosphorylation of) the insulin receptor is enhances.

Enhances FA oxidation
Increases glucose uptake
Increases lactate production
Phosphoinhibits acetyl-CoA carboxylase (inhibiting FA syntehsis)

Question 10

Effects of adiponectin on liver

Answer 10

Inhibits FFA uptake and VLDL production. 
Increases FA oxidation
Increases aerobic glucose utilization 
Increases glycogen synthesis
Inhibits gluconeogenesis.

Question 11

What are the major inhibitors of the adipokines?

Answer 11

Inflammatory cytokines TNFalpha and IL-6

Their levels are increased in obesity, and they decreases the level of adiponectin specifically.

Levels of TNF-alpha are correlated with BMI increases.

Question 12

What signaling pathways do inflammatory cytokines activate that can cause insulin resistance?

Answer 12

JNK and IKKbeta serine kinase pathways.

Question 13

What are major factors in insulin resistance?

Answer 13

TNFalpha, IL-6 proinflammatory signaling.

ER stress of beta cells, inhibiting insulin synthesis.

ER stress in adipocytes, decreasing adiponectin synthesis.

TKR2 and TLR4 expression are also increased on adipocytes in obesity, and can be activated at low levels by saturated fatty acids, causing a loop or pro-inflammatory signaling.

The Unfolded Protein Response, also induces pro-inflammatory signaling, insulin resistance.

Question 14

What transcription factor is the major regulator of adipocyte differentiation/function

Answer 14

PPARgamma. and its receptor RXR, retinoid X receptor.

Question 15

How is BMI calculated

Answer 15

Kg body weight / height in meters squared

Question 16

Normal BMI?

Answer 16

18.5-25 kg/m2

Question 17

Overweight BMI

Answer 17

25-29.9 kg/m2

Question 18

Obese BMI’s

mild, moderate, severe

Answer 18

30-35 kg/m2
35-40
Above 40

Question 19

What is the threshold for abdominal obesity?

Answer 19

men above 94 centimeters

women above 80 centimeters.

Question 20

What is the percentage of obesity in the US?

In Europe?

Answer 20

above 25% in the US

about 20% in europe.

Question 21

Which glucose transporter is insulin sensitive?

Answer 21

GLUT4

Question 22

Which glucose transporter is expressed on beta cells?

Where else is it expressed?

Answer 22

GLUT-2

Hepatocytes
Kidney
Enterocytes

It is low affinity

Question 23

Which glucose transporter(s) is involved in basal glucose uptake and is not insulin sensitive?

Where is it express

Answer 23

GLUT-1 expressed throughout body, is saturated at normal glucose levels for continual glucose uptake.
In brain, RBCs, encothelial cells, many body tissues.

GLUT-3 high affinity, neurons and other neural cells specifically.

Question 24

Basic differences between
Hormone sensitive lipase
and
Lipoprotein Lipase

Answer 24

Hormone sensitive lipase breaks down triglyceride into fatty acid and glycerol during fasting under influence of increased epinephrine/cortisol or decreased insulin.

Lipoprotein lipase breaks down chylomicron/VLDL and is involved in uptake of triglyceride into adipose tissues It needs Apo-CII cofactor.

Question 25

How does insulin affect HSL How does glucagon affect HSL

Answer 25

Insulin causes phosphoprotein phosphatase to dephosphorylate and inactivate HSL. Glucagon causes PKA to activate HSL by phosphorylation.

Question 26

What reaction does HSL catalyze?

Answer 26

It converts TAGs to DAGs and DAGs to MAGs. It cannot remove the final FA from a MAG. That requires MAG lipase.

Question 27

What other lipases can degrade TAGS besides HSL?

Answer 27

TAG lipase found in lysosomes, in liver and adipose. Esterase, High affinity to short chain fatty acids.

Question 28

High yield facts about leptin and ghrelin.

Answer 28

High yield facts about Satiety regulation : - Leptin is secreted from Adipose tissue, and it induces satiety through its action on the hypothalamic ARCUATE nucleus, exerting its effect through 2 main actions : 1) Decreases Neuropeptide Y (NPY) and Agoutin-Related Peptide(AgRP) ( an appetite stimulant ) 2) Increases ProOpioMelanoCortin( POMP) and Cocaine Amphetamine Regulated Transcript (CART) ( Appetite suppressants) - Ghrelin is secreted from the stomach FUNDUS and the pancreatic Epsilon cells. It is the hunger hormone, and it counteracts Leptin's actions. - Obese patient usually has high Leptin levels due to high adipose tissue --> leads to Leptin desensitization --> Loss of Leptin action ( much like DM2 ) - Sleep deprivation increases Ghrelin and decreases Leptin.

Question 29

How does leptin affect appetite?

Answer 29

Decreases appetite, induces satiety. In the hypothalamic arcuate nucleus: Decreasing Neuropeptide Y (NPY) Decreasing Agoutin-Related Peptide(AgRP) Increasing POMC Increasing Cocain amphetamine regulated transcript (CART) Increases CRH, TRH

Question 30

How does leptin affect carbohydrate metabolism

Answer 30

decreases insulin secretion Increases liver gluconeogenesis activates Glucose 6 phosphatase Activates PEPCK Increases muscle GLUT4 expression.

Question 31

How does leptin affect lipid metabolism

Answer 31

increases beta oxidation, by inducing carnitine palmitoyltransferase, increasing FA transport into the mitochondria Decreases lipid synthesis, by lowering expression of SREBP.

Question 32

How does leptin affect body temperature?

Answer 32

It increases temperature, by increasing UCP2 expression, uncoupler.

Question 33

How does leptin inhibit insulin signal transduction?

Answer 33

Activates JAK2, then STAT3, then SOCS. the Suppressor of Cytokine Signalling. It can bind and inhibit the activity of BOTH the Insulin Receptor and/or the Leptin receptor It is induced by IL-6 and TNF-alpha as well.

Question 34

What enzymes of fatty acid metabolism are affected by insulin?

Answer 34

Insulin activates Acetyl-CoA Carboxylase ACC. First step in cytosolic FA synthesis. Increases glucose uptake GLUT4 activity Insulin increases PFK-2 activity (by dephosphorylating it with, which generates Fructose 2,6 bisphosphate F26BP, which potently activates PFK-1, the committed, rate limiting step of glycolysis. F26BP also inhibits Fructose 1,6 bisphosphatase, inhibiting gluconeogenesis.

Question 35

What is are some genetic cause of obesity

Answer 35

MC4R mutations are the most frequent genetic cause of obesity. Melanocortin receptor which is found to also have a strong role in satiety. Responsible for some of the satiating effercts of POMC and the stress response. Null mutations of Leptin or the Leptin Receptor.

Question 36

Effect of AgRP

Answer 36

Agouti-related peptide. An inverse agonist (inhibitor/silencer) of MC3R and MC4Rs. Causes increased food intake

Question 37

Effect of NPY

Answer 37

Synthesized by arcuate nucleus acts on paraventricular nucleus and ventromedial nucleus to increase food intake Weight loss increases NPY.

Question 38

Effect of Tyrosine-Tyrosine Protein (PYY)

Answer 38

decreases intestinal motility, emptying of stomach, decreases appetite PYY defects can cause obesity.

Question 39

What is metabolic syndrome

Answer 39

having at least 3 of these 5 symptoms ``` Hypertension >130mmHg High blood TAGs High fasting glucose Above 5.6mmol/L Low HDL Central obesity above 102cm males above 88cm females. ```

Question 40

What are the consequences of obesity for this exam?

Answer 40

Metabolic syndrome T2DM, insulin resistance Non-alcoholic fatty liver Ischemic heart disease Stroke Hyperuricemia, Gout Breast cancer, Endometrial cancer Colorectal cancer Polycystic ovarian syndrome ``` Sleep apnea Asthma Depressed respiration, lung infections Depression Fatigue ``` Vertebral compression, Hernia

Question 41

Obesity therapy

Answer 41

lifestyle change. lose 5-10% of current body mass over 6 months. Goal is for heart to be at aerobic range, 220bpm minus the age. 150 minutes of exercise a week, walking or running. no more than 2 consecutive days off. Psychiatric support to gain motivation. Medicine only recommended if BMI is above 30, or if it is above 27 and there is notable comorbidities. Orlistat, inhibits intestinal lipases, preventing absorption of intestinal fats. Surgical gastrectomy, only with severe comorbidity if BMI is above 35 kg/m2