Leptin "gates" thermogenic action of thyrotropin-releasing hormone in the hindbrain

Brain Res. 2009 Oct 27;1295:135-41. doi: 10.1016/j.brainres.2009.07.063. Epub 2009 Jul 28.


Leptin, acting as a measure of metabolic fuel availability, exerts a powerful permissive influence on neurogenic thermogenesis. During starvation and an absence of leptin, animals cannot produce thermogenic reactions to cold stress. However, thermogenesis is rescued by restoring leptin. We have previously observed (Hermann, G.E., Barnes, M.J., Rogers, R.C., 2006. Leptin and thyrotropin-releasing hormone: cooperative action in the hindbrain to activate brown adipose thermogenesis. Brain Res. 1117, 118-124.) a highly cooperative interaction between leptin and thyrotropin-releasing hormone [TRH] to activate hindbrain generated thermogenic responses. Specifically, exposure to both leptin and TRH elicited a 3.5 degrees C increase in brown adipose tissue [BAT] thermogenesis, while leptin alone did not evoke any change, and TRH alone caused only approximately 1 degrees C increase. The present study shows that the leptin-TRH synergy in controlling brown adipose [BAT] thermogenesis is order-specific and dependent on the feeding status of the animal. That is, fourth ventricular [4V] application of leptin to the food-deprived animal, before TRH injection, yields a substantial increase in BAT; while the reverse order yields a significantly smaller effect. If the animal were fed within minutes of anesthesia, then exogenous leptin was not necessary for TRH to yield a large increase in BAT temperature. The leptin-TRH synergy was uncoupled by pretreatment with the phosphoinositol-tris phosphate kinase [PI3K] inhibitor, wortmannin and the Src-SH2 antagonist, PP2. The TRH transduction mechanism utilizes phospholipase C [PLC] potently regulated by the SH2 site. Previous work in culture systems suggests that the product of PI3K activity [PIP3] potently upregulates PLC by activating the SH2 domain of the PLC complex. Perhaps leptin "gates" the thermogenic action of TRH in the hindbrain by invoking this same mechanism.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adipose Tissue, Brown / metabolism
  • Analysis of Variance
  • Animals
  • Body Temperature Regulation / drug effects
  • Body Temperature Regulation / physiology*
  • Drug Interactions / physiology*
  • Female
  • Injections, Intraventricular
  • Leptin / administration & dosage
  • Leptin / metabolism*
  • Male
  • Rats
  • Rats, Long-Evans
  • Rhombencephalon / drug effects
  • Rhombencephalon / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Thermogenesis / drug effects*
  • Thermogenesis / physiology
  • Thyrotropin-Releasing Hormone / administration & dosage
  • Thyrotropin-Releasing Hormone / metabolism*
  • Time Factors


  • Leptin
  • Thyrotropin-Releasing Hormone