16 - Receptors that are linked to Enzymes

• BMI = weight (kg)/height (m) x height^2 (m^2)
• BMI

  Obese >30

  Overweight 25-30

  Normal <25
• Mechanisms of dealing with excess calorific intake:

  1. Conversion of excess to glycogen to fat which is stored in adipose tissue.
  2. Increased locomotor activity: excess burnt by extra exercise
  3. Thermogenesis: conversion of excess to heat
• The Lipostat Theory, 1953 postulates that eating behaviour is inhibited when body weight exceeds a certain value ('the set point'). It also postulates that energy consumption increases above the set point.

  Inhibition of eating behaviour and increased energy use should therefore reduce body mass back to the set point.

  When adipose tissue increases: feedback inhibits feeding behaviour and feedforward signals stimulate oxidation of fatty acids

  When adipose tissue decreases, the reverse happens:  feedback stimulates feeding behaviour (I’m hungry) and reduced fatty acid oxidation (let’s store it).
• Evidence for Lipostat model:

  A soluble factor called LEPTIN (from Gk:  leptos, thin) is released into the bloodstream by adipose tissue.

  Leptin binds leptin receptors in the hypothalamus, and changes feeding behaviour.

  Action at a distance:  therefore, ENDOCRINE signalling.
• First identified in mice

  The product of the LepOB (obese) gene

  The number and size of adipocytes is increased in Lepob/Lepob mice
• Lepob/Lepob mice display the physiology and behaviour of starvation.

  •raised cortisol levels (stress response)

  •hypothermic (have difficulty staying warm)

  •low fertility

  •impaired wound healing

  •unrestrained appetite
• Lepob/Lepob mice display some similarities to Type II diabetes.

  •metabolic disturbances:  hyperglycaemic

  •insulin resistant
• defects in leptins lead to a diabetic phenotype
• Long-term correction of obesity and diabetes in genetically obese mice by a single intramuscular injection of recombinant adeno-associated virus (rAAV) encoding mouse leptin.

  (rAAV fixed leptin deficiency in mice)
• recombinant human leptin treatment works in a patient with congenital leptin deficiency
• The leptin receptor is the product of the LeprDB gene.  Expressed in the hypothalamus.
• Leprdb/ Leprdb mice:

  •obese

  •insulin resistant

  •elevated plasma insulin levels

  •elevated blood glucose levels

  •polyuric

  •severe depletion of the insulin-producing β-cells of the pancreatic islets

  •dead by 10 months of age.

  •poor wound healingdo not respond to leptin injection

  Effectively, these mice have a genetically caused Type II diabetes
• Leptin is released by adipose tissue. It carries a message that fat reserves are sufficient.

  It binds receptors in specific neurons (the anorexigenic or appetite-reducing neurons) in the hypothalamus, and stimulates a signalling cascade that results in release of a hormone (α-MSH, alpha-melanocyte stimulating hormone)  that modulates nervous transmission.

  The effects are:

  •suppression of appetite (eat less)

  •stimulation of the sympathetic nervous system (do more)

  •increased blood pressure

  •increased heart rateincreased thermogenesis
• 2 leptins bind to Lep-R, dimerising it generating sites for the recruitment of JAK.

  JAK phosphorylates Lep-R which recruits STATs. JAK phosphorylates the fat STATs.

  The phosphorylated STATs dimerise, exposing thier nuclear localisation signal.

  The dimerised STATs enter the nucleus and are active transcription factors.

  alpha-MSH is produced and signals the brain to stop eating
• JAK is a soluable kinase
• Janus kinases (JAKs) are cytosolic, non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway.

  One domain is a kinase, while the other negatively regulates the kinase activity of the first.
• STAT proteins (Signal Transducer and Activator of Transcription) are latent transcription factors that are activated by JAKs.
• STATs 3, 5 and 6 are the ‘fat STATs’
• Leptin also signals in liver and muscle cells, making them more sensitive to insulin.
• Erythropoietin (EPO) is a hormone cytokine that controls the development of erythrocytes (red blood cells) from precursor cells in the bone marrow.
• Erythropoietin is unusual among the hematopoietic growth factors because it is produced primarily in the kidneys rather than the bone marrow.
• The kidney measures haematocrit (the volume of blood occupied by red blood cells) and sets it at a normal value of 45%.

  Under hypoxic conditions, erythropoietin is secreted from the kidneys to increase the production of red blood cells.
• Altitude training: increases volume of haematocrit which increases rbc count
• EPO is dangerous and rarely medically used: severe anaemia with no option of blood transfusion or complicated ovarian cancer
• EPO signalling:

  via JAK-STAT pathway using STAT5 causes STAT dimerization and activation and modulation of gene expression

  OR

  via JAK autophosphorylation, EPO signalling can access a Ras-dependant pathway causing the Ras, Raf MAPK cascade

  Together growth and development can be coordinated.