Leptin and central control of energy homeostasis Flashcards
Name the 5 circuits that control energy homeostasis
- Homeostatic feeding
- Anorexia circuits
- Hedonic feeding
- Energy expenditure
- Glucose homeostasis
In which 2 ways does NPY neurons suppress the actiopn of POMC neurons - 2 neuron model of ARC circuitry
Directly through neurotransmitters - GABA
Competitive means contending over same 2nd order neuones
What is ghrelin?
28 aa peptide produced and secreted by endocrine cells lining the stomach and small intestine.
Ghrelin plays a physiological role in hunger and meal initiation. Levels are high in states of energy deficit, fasting, diabetics.
Becomes biologically active after acylation of serine-3 by octanoic acid, catalysed by GOAT (ghrelin-O-acyltransferase).
Is an endogenous ligands for growth hormone secretagogue receptor (GHS-R), which is expressed in the brain with high concentrations in hypothalmic nuclei (ARC, VMH, PVN). Ghrelin is a potent stimulant to GH secretion.
Why is ghrelin not the direct cause of human obesity?
Systemic and icv administration of ghrelin stimulates food intake, reduces energy expenditure and leads to increased body weight. Block of GHS-R also causes decreased adiposity and food intake in normal adults.
BUT
Does not appear to cause most forms of human obesity as obese humans have levels of ghrelin lower than lean individuals. - negative correlation of ghrelin and BMI.
Describe ghrelins effects on hypothalamic neurones
Ghrelin admininstered icv increases NPY & AgRP mRNA levels but has no effect on POMC mRNA. Increases number of excitatory inputs and decreases number of inhibitory inputs to NPY/AgRP neurons and vice versa for POMC/CART neurons.
Recordings from NPY-GFP and POMC-GFP neurons show that ghrelin depolarises NPY neurones directyl and hyperpolarisaes POMC neurons indirectly via GABAA and Y1 Receptors - See pic
Important to switch on feeding response when fasting.
How does ghrelin modify energy usage?
Chronic ghrelin infusion to CNS results in increased lipogenesis and decreased lipid oxidation. Increases expression of fat storing enxymes in WAT and decreases expression of uncoupling Proteins (UCPs) in BAT - reflects decreased use of fat for energy generation. Increased levels of ghrelin act to trigger CNS pathways to prepare body to process incoming nutients appropriately for storage as fat.
CNS ghrelin increases blood glucose and decreased insulin secretion - stops you becoming hypoglycamic during fasting.
What is the difference bwteen anorexia nervosa and cachexia?
AN - Reduced dietary intake leading to weight loss
Cachexia - Increased energy expenditure, often despite reduced energy intake. Associated with pathology.
What can induce cachexia?
LPS - Lipopolysaccharide
Tumour growth
MC4R knock out mice are resistant to what?
LPS or tumour related anorexia.
What is the relationship of ghrelin and tumour bearing rats?
Potency of ghrelin is reduced - ghrelin resistance.
Ghrelin/GSH-R agonists are in clinical trials for treatment of cancer induced cachexia
Summarise the relatioship of ghrelin resistance and diet induced obesity (DIO)
DIO reduces ghrelin secretion, plamsa ghrelin, GOAT mRNA and transport across BBB.
Fasting fails to increases ghrelin in DIO mice
Peripheral or central administratiuon of ghrelin fails to increase feeding in DIO mice
central ghrelin administration faisl to increase ARC NPY/AgRP mRNA expression and secretion oif DIO mice
Therefore
The hypothalamic circuitry (ARC: NPY/AgRP neurons) controlling food intake (and energy balance) become resistant to ghrelin levels during obesity. Direct effect of ghrelin is blocked on feeding but its effects on increased fat deposition and glucose homeostasis is not.
Outline ghrelin resistance mechanism and functions
Hyperleptinaemia may cause ghrelin resistance, as ob/ob retain ghrelin resistance until given leptin centrally.
Come bsck to this
What is LEAP2 and how does it contribute to ghrelin resistance?
Liver-Enriched Antimicrobial Peptide 2 is a 40 aa peptide primarily expressed in the liver. It blovks the actions of ghrelin on food intake, CH secretion and glucose. Acts as an inverse agonist to GHSR - has the opposite effect to ghrelin.
Fasting reduces and refeeding increases plasma LEAP2.
In DIO: raised LEAP2 therefore low ghrelin, suggesting that LEAP2 contributes to ghrelin resistance in obese states.
In periods of weight loss, the decrease of LEAP2 may contributeto rebound weight gain.
How does JAK STAT work in a leptin receptor ?
JAK STAT to melt the fat
- Leptin binds to LEP-Rb extracellularly, a dimer, which allows association of JAK2.
- LEP-Rb does not have an intrinsic kinase components and therefore employs JAK2 in its JAK2 docking sites.
- JAK 2 elicits autophosphorylation and transactivation of kinase
- JAK2 rapidly phosphylates intracellular tyrosine residues.
- Phospho-tyrosine residues on LEP-Rb provide binding sites for signalling molecules.
- STAT3 (signal transduction and transcription family of proteins) docks with Y1138-p phosphotyrosin molecule.
- JAK2 phosphorylates STAT3 which then dissociates from LEP-Rb.
- Phosphorylated STAT3 dimerises and translocates to nucleus and binds to DNA elements in promotor regions of targeted genes to alter transciption (eg. POMC)
