Neuropeptide Y (NPY)
One of the most abundant in the human brain.
High in the NPY-containing neurones in the ARC.
Stimulates food intake and reduced energy expenditure.
What does a NPY receptor antagonist do to feeding?
What are the names of the 5 NPY receptor subtypes?
Lacking any one of these leads to obesity
alpha melanocyte-stimulating hormone.
Encoded by the POMC gene.
When the POMC gene expression reduced?
On fasting and increased following positive energy balance.
aMSH levels are high where and what does it do to food intake?
Levels are high in the hypothalamus
inhibits food intake.
Name the 2 melanocortin receptor subtypes?
MC3 & MC4.
Mainly expressed in brain.
Deletion of these receptors can cause obesity.
It is a gene
Encodes a small protein AGOUTI.
Antagonist of the MC1 receptor (responsible for hair colour)
Mutations in Ay expression?
Causing ubiquitous ectopic expression.
Agouti is antagonist of what 2 receptors?
MC4- cause obesity.
What are the similaries to NPY?
Similaries to Agouti?
What does it do to food intake
AgRP is co-expressed with NPY in ARC neurones.
Both are antagonist to MC3 and MC4.
AgRP causes long-lasting increased food intake.
What other genes spontaneously mutate can result in obesity?
fa gene: results in leptin insensitivity.
fat mutation: responsible for cleavage of POMC.
tubby: Produces a truncated protein.
Signalling pathway from adipose to second-order neurones for long-term food intake?
How common are monogenic causes of human obesity?
Ob mutations are extremely rare.
Leptin receptor (db) mutation has been reported.
What is the more common gene cause of obesity?
Mutation in MC4-R
Single mutant allele resulting in reduced signalling
Name the 4 gene deficiencies that cause obesity?
MC4-R (encodes for MSH receptor)
How to treat Ob patients?
Daily injections of leptin.
Why isn't leptin used in common obesity?
Obesity characterised by high leptin levels (correlates with high fat level)
Use of leptin therapeutically is limited by sever leptin resistance present in most obese individuals.
Diet-induced obesity results in leptin resistance.
What are the 2 theories?
1) Defective leptin transport into brain.
2) Altered signal transduction following leptin binding to its receptor.
Diet induced obesity displays resistance to?
peripheral administration of recominant leptin and insulin.
Associated with increased hepatic glucose output and peripheral insulin resistance
Leptin and insulin dsplay convergent signalling?
Both activate P13-kinase in hypothalamic neurones.
Displays neuronal resistance to leptin and insulin
Resistant to diet induced obesity.
The signalling pathway from letpin and insulin receptor?
Suppressor of cytokine signalling
Inhibits JAK-STAT signalling
Binds to Ob-Rb and prevents leptin-mediated signalling.
Levels increase with obesity.
Regulates insulin signalling through reduced IRS-mediated signalling.
The 4 contributors to hypothalamic resistance?
SHP2: knockout-obesity and leptin resistance
Hyperleptinemia: need to reduced leptin conc circulation.
ER Stress: loss of leptin sensitivity.
Inflammation: promotes chronic inflammation of tissues
Appetite suppressants drugs
Acting to inhibit noradrenaline uptake.
No longer used.
Appetite suppressant drugs
Acting on 5-HT system.
No longer used
Selectively inhibits re-uptake of noradrenaline, 5-HT and dopamine.
Major concerns over side-effects.
Present illegally in many weight loss products
Inhibits pancreatic lipase decreasing triglyceride absorption.
Side effects includ cramping and severe diarrhea.
Need to take vitamin supplements.
delta9- tetrahydrocannabinol (delta9-THC)
Receptors for this agonist exist CB1 and CB2.
Endocannabinoids present in high conc in hypothalamus- stimulate food intake.
Effective at reducing food intake in DIO mice.
Agonist of 5-HT2c receptors
Approved in June 2012
Combination of bupropion (dopamine re-uptake inhibitor and naltrexone).
Further studies on the safety.
Gastric by-pass surgery.
Induces high level of complete resolution of type 2 diabetes.