Abstract
Bombesin receptor subtype-3 (BRS-3) regulates energy homeostasis, with Brs3 knockout (Brs3(-/y)) mice being hypometabolic, hypothermic, and hyperphagic and developing obesity. We now report that the reduced body temperature is more readily detected if body temperature is analyzed as a function of physical activity level and light/dark phase. Physical activity level correlated best with body temperature 4 min later. The Brs3(-/y) metabolic phenotype is not due to intrinsically impaired brown adipose tissue function or in the communication of sympathetic signals from the brain to brown adipose tissue, since Brs3(-/y) mice have intact thermogenic responses to stress, acute cold exposure, and β3-adrenergic activation, and Brs3(-/y) mice prefer a cooler environment. Treatment with the BRS-3 agonist MK-5046 increased brown adipose tissue temperature and body temperature in wild-type but not Brs3(-/y) mice. Intrahypothalamic infusion of MK-5046 increased body temperature. These data indicate that the BRS-3 regulation of body temperature is via a central mechanism, upstream of sympathetic efferents. The reduced body temperature in Brs3(-/y) mice is due to altered regulation of energy homeostasis affecting higher center regulation of body temperature, rather than an intrinsic defect in brown adipose tissue.
Keywords:
CL316243; MK-5046; bombesin receptor subtype-3; brown adipose tissue; obesity; sympathetic nervous system; thermoregulation.
Publication types
-
Comparative Study
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adipose Tissue, Brown / cytology
-
Adipose Tissue, Brown / drug effects
-
Adipose Tissue, Brown / innervation
-
Adipose Tissue, Brown / metabolism*
-
Adrenergic beta-3 Receptor Agonists / administration & dosage
-
Adrenergic beta-3 Receptor Agonists / pharmacology
-
Animals
-
Body Temperature Regulation* / drug effects
-
Cold-Shock Response / drug effects
-
Crosses, Genetic
-
Dioxoles / administration & dosage
-
Dioxoles / pharmacology
-
Efferent Pathways / drug effects
-
Efferent Pathways / metabolism
-
Energy Metabolism / drug effects
-
Hypothalamus / drug effects
-
Hypothalamus / metabolism*
-
Imidazoles / administration & dosage
-
Imidazoles / pharmacology
-
Infusions, Intravenous
-
Infusions, Intraventricular
-
Mice
-
Mice, Inbred C57BL
-
Mice, Knockout
-
Motor Activity
-
Nerve Tissue Proteins / agonists
-
Nerve Tissue Proteins / genetics
-
Nerve Tissue Proteins / metabolism
-
Neurons / drug effects
-
Neurons / metabolism*
-
Pyrazoles / administration & dosage
-
Pyrazoles / pharmacology
-
Receptors, Bombesin / agonists
-
Receptors, Bombesin / genetics
-
Receptors, Bombesin / metabolism*
-
Sympathetic Nervous System / drug effects
-
Sympathetic Nervous System / metabolism*
-
Thermogenesis* / drug effects
Substances
-
1,1,1-trifluoro-2-(4-(1H-pyrazol-1-yl)phenyl)-3-(4-((1-(trifluoromethyl)cyclopropyl)methyl)-1H-imidazol-2-yl)propan-2-ol
-
Adrenergic beta-3 Receptor Agonists
-
Dioxoles
-
Imidazoles
-
Nerve Tissue Proteins
-
Pyrazoles
-
Receptors, Bombesin
-
bombesin receptor subtype 3
-
disodium (R,R)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)-amino)propyl)-1,3-benzodioxole-2,3-dicarboxylate