Thermoregulatory and metabolic phenotypes of mice lacking noradrenaline and adrenaline.
Adrenaline and noradrenaline, the main effectors of the sympathetic nervous system and adrenal medulla, respectively, are thought to control adiposity and energy balance through several mechanisms. They promote catabolism of triglycerides and glycogen, stimulate food intake when injected into the central nervous system, activate thermogenesis in brown adipose tissue, and regulate heat loss through modulation of peripheral vasoconstriction and piloerection. Thermogenesis in brown adipose tissue occurs in response to cold and overeating (diet induced), and there is an inverse relationship between diet-induced thermogenesis and obesity both in humans and in animal models. As a potential model for obesity, we generated mice that cannot synthesize noradrenaline or adrenaline by inactivating the gene that encodes dopamine beta-hydroxylase. These mice are cold intolerant because they have impaired peripheral vasoconstriction and are unable to induce thermogenesis in brown adipose tissue through uncoupling protein (UCP1). The mutants have increased food intake but do not become obese because their basal metabolic rate is also elevated. The unexpected increase in basal metabolic rate is not due to hyperthyroidism, compensation by the widely expressed uncoupling protein UCP2, or shivering.
Thomas
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Howard Hughes Medical Institute, Department of Biochemistry, University of Washington, Seattle 98195-7370, USA.
Palmiter
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D000273:Adipose Tissue / Q000187:drug effects / Q000502:physiology; D002001:Adipose Tissue, Brown / Q000033:anatomy & histology / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001481:Basal Metabolism / Q000502:physiology*; D001833:Body Temperature Regulation / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology; D004299:Dopamine beta-Hydroxylase / Q000235:genetics / Q000378:metabolism; D015103:Droxidopa / Q000494:pharmacology; D004837:Epinephrine / Q000172:deficiency* / Q000502:physiology; D007473:Ion Channels; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D024101:Mitochondrial Proteins; D009638:Norepinephrine / Q000172:deficiency* / Q000502:physiology; D009765:Obesity / Q000209:etiology*; D010101:Oxygen Consumption / Q000502:physiology; D010641:Phenotype; D011506:Proteins / Q000235:genetics / Q000502:physiology; D014475:Uncoupling Agents; D000071256:Uncoupling Protein 1; D000071246:Uncoupling Protein 2
D002352:Carrier Proteins; D007473:Ion Channels; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D011506:Proteins; C000604371:UCP1 protein, human; C000604389:UCP2 protein, human; C000604372:Ucp1 protein, mouse; C000604390:Ucp2 protein, mouse; D014475:Uncoupling Agents; D000071256:Uncoupling Protein 1; D000071246:Uncoupling Protein 2; D004299:Dopamine beta-Hydroxylase; D015103:Droxidopa; D009638:Norepinephrine; D004837:Epinephrine