Monday, March 19, 2012 CC-BY-NC
Neuroendocrine Regulation of Thyroid Function II

Maintainer: admin

1thryoid hormone regulation

  • 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

2Leptin and TRH#

  • 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.

4other factors#

  • 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.

5Non-specific response to stress

  • 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

6TH and thermogenesis

  • 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

7TH and facultative/adaptive thermogenesis

  • 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)