Peptidomic Analysis Reveals Seasonal Neuropeptide and Peptide Hormone Changes in the Hypothalamus and Pituitary of a Hibernating Mammal

During the winter, hibernating mammalsundergo extremechangesin physiology, which allow them to survive several months withoutaccess to food. These animals enter a state of torpor, which is characterizedby decreased metabolism, near-freezing body temperatures, and a dramaticallyreduced heart rate. The neurochemical basis of this regulation islargely unknown. Based on prior evidence suggesting that the peptide-richhypothalamus plays critical roles in hibernation, we hypothesizedthat changes in specific cell-cell signaling peptides (neuropeptidesand peptide hormones) underlie physiological changes during torpor/arousalcycles. To test this hypothesis, we used a mass spectrometry-basedpeptidomics approach to examine seasonal changes of endogenous peptidesthat occur in the hypothalamus and pituitary of a model hibernatingmammal, the thirteen-lined ground squirrel (Ictidomystridecemlineatus). In the pituitary, we observed changesin several distinct peptide hormones as animals prepared for torporin October, exited torpor in March, and progressed from spring (March)to fall (August). In the hypothalamus, we observed an overall increasein neuropeptides in October (pre-torpor), a decrease as the animalentered torpor, and an increase in a subset of neuropeptides duringnormothermic interbout arousals. Notable changes were observed forfeeding regulatory peptides, opioid peptides, and several peptideswithout well-established functions. Overall, our study provides criticalinsight into changes in endogenous peptides in the hypothalamus andpituitary during mammalian hibernation that were not available fromtranscriptomic measurements. Understanding the molecular basis ofthe hibernation phenotype may pave the way for future efforts to employhibernation-like strategies for organ preservation, combating obesity,and treatment of stroke.