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J Physiol. 2016 Dec 15;594(24):7455-7464. doi: 10.1113/JP272971. Epub 2016 Nov 13.

The complementary and divergent roles of uncoupling proteins 1 and 3 in thermoregulation.

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Department of Molecular Biosciences, College of Natural Sciences, The University of Texas at Austin, Austin, TX, 78712, USA.
Division of Pharmacy and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX, 78712, USA.
Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Cosenza, Italy.
Department of Biochemistry, The University of Utah, Salt Lake City, UT, 84112, USA.
National Heart, Lung, and Blood Institute, Laboratory of Mitochondrial Biology and Metabolism, NIH, Bethesda, MD, 20892, USA.
Cardiovascular and Pulmonary Branch and the Department of Biochemistry and Molecular Medicine, George Washington University, and the Veterans Affairs Medical Center, Washington, DC, 20422, 20052, USA.
Department of Biosciences, Biotechnologies, and Biopharmaceutics and Center of Excellence in Comparative Genomics, University of Bari, 70125, Bari, Italy.
The Ohio Attorney General's Center for the Future of Forensic Science, Bowling Green State University, Bowling Green, OH, 43403, USA.



Both uncoupling protein 1 (UCP1) and UCP3 are important for mammalian thermoregulation. UCP1 and UCP3 in brown adipose tissue mediate early and late phases of sympathomimetic thermogenesis, respectively. Lipopolysaccharide thermogenesis requires skeletal muscle UCP3 but not UCP1. Acute noradrenaline-induced hyperthermia requires UCP1 but not UCP3. Loss of both UCP1 and UCP3 accelerate the loss of body temperature compared to UCP1KO alone during acute cold exposure.


Uncoupling protein 1 (UCP1) is the established mediator of brown adipose tissue-dependent thermogenesis. In contrast, the role of UCP3, expressed in both skeletal muscle and brown adipose tissue, in thermoregulatory physiology is less well understood. Here, we show that mice lacking UCP3 (UCP3KO) have impaired sympathomimetic (methamphetamine) and completely abrogated lipopolysaccharide (LPS) thermogenesis, but a normal response to noradrenaline. By comparison, UCP1 knockout (UCP1KO) mice exhibit blunted methamphetamine and fully inhibited noradrenaline thermogenesis, but an increased febrile response to LPS. We further establish that mice lacking both UCP1 and 3 (UCPDK) fail to show methamphetamine-induced hyperthermia, and have a markedly accelerated loss of body temperature and survival after cold exposure compared to UCP1KO mice. Finally, we show that skeletal muscle-specific human UCP3 expression is able to significantly rescue LPS, but not sympathomimetic thermogenesis blunted in UCP3KO mice. These studies identify UCP3 as an important mediator of physiological thermogenesis and support a renewed focus on targeting UCP3 in metabolic physiology.


LPS; brown adipose tissue; methamphetamine; skeletal muscle; sympathomimetic; thermogenesis; uncoupling protein

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