Obesity lecture/chapter in book Flashcards
What kind of receptor is the Insulin receptor?
A tyrosine kinase receptor, it directly phosphorylates its insulin receptor substrates, IRSs.
What pathways does the Insulin receptor activate?
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
What are the major pathways that inhibit insulin receptor substrates?
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.
What are the two major insulin sensitising adipokines?
Leptin and adiponectin
What are the effects of leptin in the liver
Stimulates gluconeogenesis by activating PEPCK
Increases glycogen consumption.
Increases beta oxidation by activating PPAR alpha
inhibits lipogenesis, and inhibits expression of SREBPs
Leptins actions in muscle
Stimulates AMPK
Stimulates fatty acid oxidation. via PPARalpha activation.
What doe levels of leptin correlate best with.
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.
Where is adiponectin synthesized?
What are its main targets?
Adipose tissue.
Its receptors are in the liver and muscles.
Its essential function is to enhance liver and muscle responses to insulin.
What are the effects of adiponectin on skeletal muscle
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)
Effects of adiponectin on liver
Inhibits FFA uptake and VLDL production. Increases FA oxidation Increases aerobic glucose utilization Increases glycogen synthesis Inhibits gluconeogenesis.
What are the major inhibitors of the adipokines?
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.
What signaling pathways do inflammatory cytokines activate that can cause insulin resistance?
JNK and IKKbeta serine kinase pathways.
What are major factors in insulin resistance?
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.
What transcription factor is the major regulator of adipocyte differentiation/function
PPARgamma. and its receptor RXR, retinoid X receptor.
How is BMI calculated
Kg body weight / height in meters squared
Normal BMI?
18.5-25 kg/m2
Overweight BMI
25-29.9 kg/m2
Obese BMI’s
mild, moderate, severe
30-35 kg/m2
35-40
Above 40
What is the threshold for abdominal obesity?
men above 94 centimeters
women above 80 centimeters.
What is the percentage of obesity in the US?
In Europe?
above 25% in the US
about 20% in europe.
Which glucose transporter is insulin sensitive?
GLUT4
Which glucose transporter is expressed on beta cells?
Where else is it expressed?
GLUT-2
Hepatocytes
Kidney
Enterocytes
It is low affinity
Which glucose transporter(s) is involved in basal glucose uptake and is not insulin sensitive?
Where is it express
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.
Basic differences between
Hormone sensitive lipase
and
Lipoprotein Lipase
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.
How does insulin affect HSL
How does glucagon affect HSL
Insulin causes phosphoprotein phosphatase to dephosphorylate and inactivate HSL.
Glucagon causes PKA to activate HSL by phosphorylation.
What reaction does HSL catalyze?
It converts TAGs to DAGs and DAGs to MAGs.
It cannot remove the final FA from a MAG.
That requires MAG lipase.
What other lipases can degrade TAGS besides HSL?
TAG lipase found in lysosomes, in liver and adipose.
Esterase, High affinity to short chain fatty acids.
High yield facts about leptin and ghrelin.
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.
How does leptin affect appetite?
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
How does leptin affect carbohydrate metabolism
decreases insulin secretion
Increases liver gluconeogenesis
activates Glucose 6 phosphatase
Activates PEPCK
Increases muscle GLUT4 expression.
How does leptin affect lipid metabolism
increases beta oxidation,
by inducing carnitine palmitoyltransferase, increasing FA transport into the mitochondria
Decreases lipid synthesis, by lowering expression of SREBP.
How does leptin affect body temperature?
It increases temperature, by increasing UCP2 expression, uncoupler.
How does leptin inhibit insulin signal transduction?
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.
What enzymes of fatty acid metabolism are affected by insulin?
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.
What is are some genetic cause of obesity
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.
Effect of AgRP
Agouti-related peptide.
An inverse agonist (inhibitor/silencer) of MC3R and MC4Rs.
Causes increased food intake
Effect of NPY
Synthesized by arcuate nucleus acts on paraventricular nucleus and ventromedial nucleus to increase food intake
Weight loss increases NPY.
Effect of Tyrosine-Tyrosine Protein (PYY)
decreases intestinal motility, emptying of stomach,
decreases appetite
PYY defects can cause obesity.
What is metabolic syndrome
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.
What are the consequences of obesity for this exam?
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
Obesity therapy
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
