title: Hypothermia in mouse is caused by adenosine A1and A3receptor agonists and AMP via three distinct mechanisms.
abstract: Small mammals have the ability to enter torpor, a hypothermic, hypometabolic state, allowing impressive energy conservation. Administration of adenosine or adenosine 5'-monophosphate (AMP) can trigger a hypothermic, torpor-like state. We investigated the mechanisms for hypothermia using telemetric monitoring of body temperature in wild type and receptor knock out (Adora1-/-, Adora3-/-) mice. Confirming prior data, stimulation of the A3adenosine receptor (AR) induced hypothermia via peripheral mast cell degranulation, histamine release, and activation of central histamine H1receptors. In contrast, A1AR agonists and AMP both acted centrally to cause hypothermia. Commonly used, selective A1AR agonists, including N6-cyclopentyladenosine (CPA), N6-cyclohexyladenosine (CHA), and MRS5474, caused hypothermia via both A1AR and A3AR when given intraperitoneally. Intracerebroventricular dosing, low peripheral doses of Cl-ENBA [(±)-5'-chloro-5'-deoxy-N6-endo-norbornyladenosine], or using Adora3-/-mice allowed selective stimulation of A1AR. AMP-stimulated hypothermia can occur independently of A1AR, A3AR, and mast cells. A1AR and A3AR agonists and AMP cause regulated hypothermia that was characterized by a drop in total energy expenditure, physical inactivity, and preference for cooler environmental temperatures, indicating a reduced body temperature set point. Neither A1AR nor A3AR was required for fasting-induced torpor. A1AR and A3AR agonists and AMP trigger regulated hypothermia via three distinct mechanisms.
authors.affiliation: Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892, USA.
authors.forename: Jesse Lea
authors.initials: JL
authors.lastname: Carlin
authors.affiliation: Mouse Metabolism Core, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892, USA.
authors.forename: Shalini
authors.initials: S
authors.lastname: Jain
authors.affiliation: Department of Pharmacology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Gizewski
authors.affiliation: Department of Pharmacology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
authors.forename: Tina C
authors.initials: TC
authors.lastname: Wan
authors.affiliation: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892, USA.
authors.forename: Dilip K
authors.initials: DK
authors.lastname: Tosh
authors.affiliation: Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892, USA.
authors.forename: Cuiying
authors.initials: C
authors.lastname: Xiao
authors.affiliation: Department of Pharmacology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Auchampach
authors.affiliation: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892, USA.
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
authors.affiliation: Mouse Metabolism Core, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892, USA.
authors.forename: Oksana
authors.initials: O
authors.lastname: Gavrilova
authors.affiliation: Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892, USA. Electronic address: marc.reitman@nih.gov.
authors.forename: Marc L
authors.initials: ML
authors.lastname: Reitman
mesh_terms: D000241:Adenosine / Q000008:administration & dosage / Q000031:analogs & derivatives; D058907:Adenosine A1 Receptor Agonists / Q000008:administration & dosage*; D058909:Adenosine A3 Receptor Agonists / Q000008:administration & dosage*; D000249:Adenosine Monophosphate / Q000502:physiology*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000502:physiology; D005334:Fever / Q000139:chemically induced*; D006632:Histamine / Q000378:metabolism; D007276:Injections, Intraventricular; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D043682:Receptor, Adenosine A1 / Q000235:genetics / Q000502:physiology*; D043684:Receptor, Adenosine A3 / Q000235:genetics / Q000502:physiology*; D011969:Receptors, Histamine H1 / Q000502:physiology; D064348:Torpor
chemical_list: D058907:Adenosine A1 Receptor Agonists; D058909:Adenosine A3 Receptor Agonists; D043682:Receptor, Adenosine A1; D043684:Receptor, Adenosine A3; D011969:Receptors, Histamine H1; C027513:N(6)-cyclohexyladenosine; C048599:N(6)-cyclopentyladenosine; D000249:Adenosine Monophosphate; D006632:Histamine; D000241:Adenosine
keywords: (1R,2R,3S,5S)-4-(2-chloro-6-((dicyclopropylmethyl)amino)-9H-purin-9-yl)bicyclo[3.1.0]hexane-2,3-diol; (±)-5'-chloro-5'-deoxy-N(6)-endo-norbornyladenosine; 2-Chloro-N(6)-cyclopentyladenosine; A(1)AR; A(3)AR; AMP; Adenosine; Adenosine 5'-monophosphate; CCPA; CHA; CPA; Cl-ENBA; Hypothermia; MRS5474; N(6)-(p-sulfo-phenyl)adenosine; N(6)-R-phenylisopropyladenosine; N(6)-cyclohexyladenosine; N(6)-cyclopentyladenosine; R-PIA; SPA; Torpor