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Seasonal oscillation of liver-derived hibernation protein complex in the central nervous system of non-hibernating mammals
Marcus M. Seldin, Mardi S. Byerly, Pia S. Petersen, Roy Swanson, Anne Balkema-Buschmann, Martin H. Groschup, G. William Wong


Mammalian hibernation elicits profound changes in whole-body physiology. The liver-derived hibernation protein (HP) complex, consisting of HP-20, HP-25 and HP-27, was shown to oscillate circannually, and this oscillation in the central nervous system (CNS) was suggested to play a role in hibernation. The HP complex has been found in hibernating chipmunks but not in related non-hibernating tree squirrels, leading to the suggestion that hibernation-specific genes may underlie the origin of hibernation. Here, we show that non-hibernating mammals express and regulate the conserved homologous HP complex in a seasonal manner, independent of hibernation. Comparative analyses of cow and chipmunk HPs revealed extensive biochemical and structural conservations. These include liver-specific expression, assembly of distinct heteromeric complexes that circulate in the blood and cerebrospinal fluid, and the striking seasonal oscillation of the HP levels in the blood and CNS. Central administration of recombinant HPs affected food intake in mice, without altering body temperature, physical activity levels or energy expenditure. Our results demonstrate that HP complex is not unique to the hibernators and suggest that the HP-regulated liver–brain circuit may couple seasonal changes in the environment to alterations in physiology.


  • * These authors contributed equally to this work

  • Author contributions

    G.W.W. conceived the project; M.M.S., M.S.B., P.S.P., R.S. and G.W.W. designed and executed the experiments; A.B.-B. and M.H.G. provided critical reagents; M.M.S., M.S.B., P.S.P. and G.W.W. drafted and revised the manuscript.

  • Competing interests

    The authors declare no competing financial interests.

  • Funding

    This work was supported by the National Institutes of Health [DK084171 to G.W.W.]. P.S.P. is supported by a travel fellowship from the Carlsberg Foundation. Deposited in PMC for release after 12 months.

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