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Regulated hypothermia in mouse is caused by AMP, adenosine A1 and A3 receptor agonists via three distinct mechanisms

Thursday, September 15, 2016 — Poster Session II

12:00 p.m. – 1:30 p.m.
FAES Terrace
NIDDK
SYSBIO-7

Authors

  • JL Carlin
  • DK Tosh
  • S Jain
  • O Gavrilova
  • KA Jacobson
  • ML Reitman

Abstract

Adenosine and AMP have been implicated in triggering the torpor response seen in small mammals during hibernation or fasting. Adenosine is thought to act through A1AR in the nucleus of the solitary tract or pre-optic area to elicit hypothermia in rodents. AMP is also proposed to be a natural regulator of torpor. However, AMP-induced torpor was intact in mice lacking any one of the adenosine receptors (A1AR, A2AAR, A2BAR, or A3AR). Our lab has characterized a third mechanism to achieve hypothermia through A3AR mast cell degranulation and central histamine H1 receptors. We found that putative A1AR agonists at commonly used doses are non-selective and work via both A1AR and A3AR to cause hypothermia. Cl-ENBA (15ug/mouse, i.c.v) caused hypothermia in WT mice that is lost in Adora1-/- mice. Cl-ENBA (3mg/kg) elicited hypothermia in Adora3-/- mice and was associated with reduced energy expenditure, reduced activity, and behavior in a temperature gradient test. AMP (100mg/kg) caused hypothermia and reduced activity. AMP (100ug/mouse, i.c.v) caused hypothermia in WT mice that remains intact in Adora1-/- mice. AMP also caused reduced energy expenditure, reduced activity, and behavior in a temperature gradient test. Cl-ENBA and AMP hypothermia remained intact in KitW-sh/W-sh mice and after pretreatment with pyrilamine. Finally, we show the torpor response after a 24 hour fast occurs in mice lacking A1AR, A3AR, or both, demonstrating that these receptors are not required for this effect. These data demonstrate at least three distinct mechanisms (A1AR, A3AR, AMP) that cause a centrally mediated hypothermia response in mice.

Category: Systems Biology