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log TSH conc. and plasma TH (thyroid hormone) conc. curve:
- factors that shift curve to the right: TRH, increased leptin, adrenergic (cold), psychosis (CART)
- to the left: glucocorticoids, dopamine, somatostatin, reduced leptin, cytokines (TNF-a), NFkB-induced D2 expression
for every 1 fold change in TH there's a 100 fold change in TSH.
There are signal from arcuate nucleus and dopaminergic/somatostatin neurosn to PVN's TRH neurons.
staining on brain tissues show:
- TH can directly inhibit TRH production, as shown by adding T3 , there's a sharp decrease in TRH mRNA hybridization.
- The TRH secreting PVN neurons have NPY, GRP, and a-MSH staining
  - all those are neuropeptins that have to do with appetite. Makes sense cuz TH increases metabolic

In situ hybridization shows that
- Fed rodents have high TRH in PVN.
- Fasted rodents have low TRH in PVN
  - but when leptin is added in fasted state, TRH level is high.
Therefore, leptin modulates hypothalamic endocrine axes.
- because we don't want breakdown of proteins (a function of TH) in a fasted state.
- this regulation is done via leptin: fasting --> low leptin --> low TRH.
experiment on ob/ob mice (mice that are leptin deficient)
- indirect effect of leptin on PVN: adding leptin increases POMC and aMSH level in arcuate nucleus and thereby decrease orexigenic hormones (AgRP, NPY), this act on PVN and increase TRH
- (AgRP and NPY would inhibit TRH neurons)
- direct effect of leptin: leptin act on periphery level and may also have direct effect in stimulating PVN's TRH neurons.
CART stimulate TRH neurons
Cytokines, event of fasting, T3 from D2, all inhibit PVN.

Major regulatory interactions in thyrotrophs:
- somatostatin and dopamine inhibits TRH's stimulatory effects on TSH. Whereas NE(aR) does the opposite.
- glucocorticoid, act less on downregulating TSH gene and mRNA and more on acting at the level of hypothalamus to downregulate TH eventually.
- T3 downregulates TSH gene, mRNA, post-translational process.
Dopamine is shown to decrease TSH level in the pituitary.
- obese women's basal TSH level is higher than usual probably due to constant high leptin (made by adipose tissue) and also low dopamine.
- experiment on obese women showed that bromocriptine (a dopamine agonist) decrease TSH level.

Regulation of TRH receptor:
- downregulated by T3 and upregulated by estrogen
- glucocorticoid: global inhibitor by directly acting at hypothalamic level and indirectly on the pituitary (as mentioned earlier).
- cytokines are catabolic. TNFa, IL-1,6 are released during infected state.
  - shift the log[TSH]/TH curve to the left to compensate for their catabolic effect.

ex: heart attack
- T3 goes down, followed by T4 and TSH
- this is due to some cytokines
- result: concentrate on healing instead of metabolism
Mechanisms of regulation
- Altered thyroid hormone turnover:
  - preserved TH synthesis
  - heightened TH metabolism and/or secretion by upregulating D1/D3
- mediators include: cytokines, glucocorticoids, reduce leptin, other factors acting via somatostatin and dopamine

TH's some functions:
- protein turnover esp in muscle
- stimulate lipogenesis and lipolysis
  - liver FA(fatty acid) and TG (triglyceride) synthesis
  - cholesterol synthesis
  - lipid mobilization
  - increase LDL-receptor concentration
- stimulate glycolysis, glycogenolysis and glucogenesis (by upregulating PEPCK (Phosphoenolpyruvate carboxykinase (PEPCK)).
- preferentially stimulate usage of fat as substrate for metabolic activity.
BMI (body mass index) depends on balance between food intake and energy consumption, which increases over the years. -> weight gain

exposure to cold:
- below 23*C, heat losing > heat produced
- so on top of BMR (basal metabolic rate) and OT (obligatory thermogenesis), faciliated / adaptive thermogenesis are induced. (shivering, etc)
Mechanism in brown adipocyte
- UCP1 (uncoupling protein) sits on mitochondria and it basically uncouple oxidated phosphorylation of ATP and converts them to heat.
- bile acid and sympathetic system act via adenylyl cyclase and g protein to upregulate heat released via UCP1 by upregulating conversion of TG to fatty acids (increase input)
- intracellular D2 converts T4 to T3, which dimerizes and upregulates gene transcription of UCP1.
adults seem to have very little brown adipocyte, but experiment shows that upon cold exposure, brown adipose tissue shows up.
fat people have difficulty losing weight cuz their sympathetic nervous system is less active (less turning on of Brown adipose tissue)

Monday, March 19, 2012
Neuroendocrine Regulation of Thyroid Function II