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.
- 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
- Altered thyroid hormone turnover:
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)