MULTI-MORBIDITY from METABOLIC/CV/CANCER and INFLAMM.

Question 1

GLAST/CreER2 mouse - what is it useful for?

Answer 1

Lineage tracing of a-Tanycytes

Question 2

What are a-Tanycytes, where are they found and what can they do?

Answer 2

Hypothalamic stem cell-like cells which can self renew or give rise to Pomc/NpY neurons
Found lining the 3rd venticle of the brain
Potential treatment for diabetes and obesity if we can work out how to stimulate proliferation of these?

Question 3

MICHAEL SCHWARTS ET AL & MICE – what did he do??

used a-Tanycytes and the 3rd ventricle of the brain!!!

Answer 3

• Injected FGF1 into the 3rd ventricle of T2D mice
• Resulted in SUSTAINED REMISSION of HYPERGLYCEMIA
• Increased clearance of glucose in the blood

——> Tanycytes are FGF responsive

Question 4

What is the HSP25 gene (a-Tanycytes)

Answer 4

Increase in expression of HSP25 gene in Tanycytes when stimulated with FGF1 — gene may be involved in the proliferation of T2D neurons

Question 5

Examples of CNCDs?

Answer 5

Chronic non-communicable diseases -
Cancer, CV disease, T2D
Cause 60% of deaths worldwide!!

Question 6

Contribution of poor diet and smoking – how are FFAs involved?

Answer 6

Increased FFAs in bloodstream –> insulin resistance –> Increased conc HEPATIC LIPASE and APOLIPOPROTEIN B –> Increased concs LDLs and decreased concs HDLs

Question 7

What can insulin resistance cause?

Answer 7

Hypertension, T2D, Visceral obesity, Atherosclerosis (ca lead to stroke or heart attack), systemic inflammation

Question 8

How can insulin resistance cause increased risk of certain types of cancers? examples include – Breast, bowel, pancreatic, oesophageal

Answer 8

INCREASED OESTROGEN LEVELS - oestrogen levels increase after menopause causing cell proliferation

INCREASED INSULIN/GFS - excess fat = increased insulin levels due to hyperglycemia which causes cell proliferation

INFLAMMATION - macrophages in fatty tissue release cytokines as part of the inflammatory response - this causes cell division

Question 9

Why are these so heavily linked regarding control of insulin levels?

Answer 9

Insulin pathway is HIGHLY CONSERVED, ANCIENT PATHWAY which is fundamental to AGEING

Question 10

There is a potent glucose-lowering response seen which is elicited by activation of brain fibroblast growth factor (FGF).

What was shown upon intracerebroventricular injection of FGF1? (mouse and rat models)

Answer 10

a single intracerebroventricular injection of FGF1 at a dose one-tenth of that needed for antidiabetic efficacy following peripheral injection induces sustained diabetes remission in both mouse and rat models of T2D