4. Metabolic Disease 2: Genetic Approaches Flashcards
What model organism is used for majority of studies on metabolic disease and why?
- Mouse
- Easiest to perform conditional KO in
What suggests the brain fundamentally regulates glucose homeostasis?
The brain centrally regulates all homeostatic processes
What is a highly likely primary cause of T2D?
How could this occur?
- Primary cause likely lies in the interaction between the brain and peripheral tissues leading to a major disruption in core homeostatic processes
- Abnormal signalling from peripheral tissues to brain (e.g. indicating insufficient fat is present leading brain to stimulate increased food intake and body fat)
- Abnormal signalling from brain to peripheral tissues (e.g. reduced signalling to pancreas and liver)
What is leptin and what is its function?
Leptin is a hormone secreted by adipocytes that signals to brain the status of the body’s energy content
How can we prove leptin’s importance in governing normal metabolism?
What did this show?
- Make a genetically-null animal
- Mice lacking leptin are obese, diabetic, hypoactive and infertile
How did Cohen et al (2001) resolve the relative importance of leptin’s effects on central and peripheral sites?
Generated mice with neuron-specific or hepatocyte-specific KO of leptin receptor
What did the results of Cohen et al (2001) study on tissue-specific leptin receptor knockout show?
Neuron-specifc leptin receptor KO
- Level of obesity negatively correlated with level of leptin receptor in hypothalamus - mice with lowest levels were obese
- Showed elevated plasma levels of leptin, insulin and glucose
- Showed increased levels of NPY RNA
Hepatocyte-specific leptin receptor KO
- Mice weighed the same as WT with no alterations in body composition
What did the results of Cohen et al (2001) study on tissue-specific leptin receptor knockout suggest?
The brain is a direct target for the weight-reducing and neuroendocrine effects of leptin
What animal model studies show the brain mediates the majority of leptin effects on energy homeostasis?
- Mice lacking leptin receptor signalling (leptin receptor KO) are obese, diabetic, hypoactive and infertile
- Conditional KO of leptin receptors in neurons induces obesity
- We know leptin receptor KO causes this phenotype because a reconstitution study showed that overexpression of leptin receptors in neurons in a neutron-specific leptin receptor KO rescued the WT phenotype - Intracerebroventricular injection of leptin in leptin-null mice causes weight loss and reduced food intake
- As majority of leptin is in CSF suggests primary effect is on brain
Where are neurons expressing leptin receptors located in the brain?
In the hypothalamus, specifically the Arcuate Nucleus
What are the 2 types of neurons in the arcuate nucleus?
- Neurons expressing the neurohormone NPY
- Neurons expressing the pro-protein Pomc
What is the effects of NPY and Pomc neurons?
NPY and Pomc neurons have antagonistic effects on a common downstream neuron:
- NPY neurons stimulate hunger and increase food intake
- Pomc neurons stimulate fullness and reduce food intake
What effect do leptin receptors have on NPY and Pomc neurons?
- Leptin stimulates Pomc neurons
- Leptin represses NPY neurons
How might abnormal leptin signalling cause obesity and T2D?
Results in abnormal balance of NPY and Pomc neurons which causes abnormal signalling from brain to peripheral tissues
What is the current model for hypothalamic regulation of hepatic glucose production?
- Adipocytes release leptin
- Leptin signals to NPY and Pomc neurons in arcuate nucleus
- By an unknown neural circuit there is signalling to the brainstem
- Brainstem signals to Vagus nerve which signals to liver to decrease hepatic glucose production
