Polyunsaturated fatty acids (PUFA) have a multitude of health effects. Their incorporation into membrane phospholipids (PL) is generally believed to depend directly on dietary influx. PL influence transmembrane protein activity and thus can compensate temperature effects; e.g. PL n-6 PUFA are thought to stabilize heart function at low body temperature (Tb), whereas long chain (>C18) n-3 PUFA may boost oxidative capacity. We found substantial remodeling of membranes in free-living alpine marmots which was largely independent of direct dietary supply. Organ PL n-6 PUFA and n-6 to n-3 ratios were highest at onset and end of hibernation after rapid increases during a brief transitional period prior to hibernation. In contrast, longer chain PL n-3 PUFA content was low at end of summer but maximal at end of hibernation. After termination of hibernation in spring, these changes in PL composition were rapidly reversed. Our results demonstrate selective trafficking of PUFA within the body, probably governed by a circannual endogenous rhythm, as hibernating marmots were in winter burrows isolated for seven months from food and external cues signaling the approaching spring. High concentrations of PL n-6 PUFA throughout hibernation are in line with their hypothesized function of boosting SERCA 2a activity at low Tb. Furthermore, we found increasing rate of rewarming from torpor during winter indicating increasing oxidative capacity that could be explained by the accumulation of long-chain PL n-3 PUFA. It may serve to minimize the time necessary for rewarming despite the increasing temperature range to be covered, because rewarming is a period of highest metabolic rate and hence production of reactive oxygen species. Considering the importance of PUFA for health our results may have important biomedical implications, as seasonal changes of Tb and associated remodeling of membranes are not restricted to hibernators but presumably common among endothermic organisms.

We have recently reported that tyrosine kinase 2 (Tyk2)-deficient mice have a selective defect in the in vivo defense against certain viruses. In our current study we show that Tyk2 is essential for the defense against murine CMV (MCMV). In vivo challenges with MCMV revealed impaired clearance of virus from organs and decreased survival of mice in the absence of Tyk2. Our in vitro studies demonstrate that MCMV replicates to dramatically higher titers in Tyk2-deficient macrophages compared with wild-type cells. We show an essential role of type I IFN (IFN-αβ) in the control of MCMV replication, with a prominent role of IFN-β. MCMV infection leads to the activation of STAT1 and STAT2 in an IFN-αβ receptor 1-dependent manner. Consistent with the role of Tyk2 in IFN-αβ signaling, activation of STAT1 and STAT2 is reduced in Tyk2-deficient cells. However, lack of Tyk2 results in impaired MCMV-mediated gene induction of only a subset of MCMV-induced IFN-αβ-responsive genes. Taken together, our data demonstrate a requirement for Tyk2 in the in vitro and in vivo antiviral defense against MCMV infection. In addition to the established role of Tyk2 as an amplifier of Jak/Stat signaling upon IFN-αβ stimulation, we provide evidence for a novel role of Tyk2 as a modifier of host responses.

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The gastrointestinal tracts of 76 free-living alpine marmots ( Marmota marmota) shot during a population control program in Switzerland were collected and analysed for patterns of change in morphology and function over the period from emergence from hibernation in April to just before re-entry into hibernation in September. Between first emergence and mid-summer (July) the fresh tissue mass of the stomach increased by 105%, the small intestine by 259% (among the largest recorded for a mammal), caecum by 185%, proximal colon by 138%, and distal colon by 144%. Mitotic activity was greatest in the small intestine; the mitotic index was high (40%) compared with indexes in the stomach and hindgut (approximately 4%) even at emergence, and increased to approximately 60% by mid-summer. Microbial activity in the caecum was also significant at emergence. The stomach (length) and caecum (length and fresh mass) increased in response to ingested food earlier than did the small intestine. Between mid-summer and September there were decreases in small intestinal tissue mass and mitotic activity. It is concluded that the gastrointestinal tract of alpine marmots probably continues to function throughout hibernation at a low level, with a mid-winter trough as part of an endogenous circannual rhythm. However, after emergence in spring, increases in size and activity of the tract appear to be a response to ingested food rather than to an endogenous signal. The early signs of down-regulation of the small intestine before re-entry into hibernation, together with its delayed up-regulation in response to food in spring, are consistent with the high costs of maintaining this section of the digestive system.