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Research article - Peer-reviewed, 2022

Circulating insulin-like growth factor system adaptations in hibernating brown bears indicate increased tissue IGF availability

Frobert, Anne Mette; Brohus, Malene; Roesen, Tinna S.; Kindberg, Jonas; Frobert, Ole; Conover, Cheryl A.; Overgaard, Michael T.


Brown bears conserve muscle and bone mass during 6 mo of inactive hibernation. The molecular mechanisms underlying hiber-nation physiology may have translational relevance for human therapeutics. We hypothesize that protective mechanisms involve increased tissue availability of insulin-like growth factors (IGFs). In subadult Scandinavian brown bears, we observed that mean plasma IGF-1 and IGF-2 levels during hibernation were reduced to 36 +/- 10% and 56 +/- 15%, respectively, compared with the active state (n = 12). Western ligand blotting identified IGF-binding protein (IGFBP)-3 as the major IGFBP in the active state, whereas IGFBP-2 was codominant during hibernation. Acid labile subunit (ALS) levels in hibernation were reduced to 41 & PLUSMN;16% compared with the active state (n = 6). Analysis of available grizzly bear RNA sequencing data revealed unaltered liver mRNA IGF-1, IGFBP-2, and IGFBP-3 levels, whereas ALS levels were significantly reduced during hibernation (n = 6). Reduced ALS synthesis and cir-culating levels during hibernation should prompt a shift from ternary IGF/IGFBP/ALS to smaller binary IGF/IGFBP complexes, thereby increasing IGF tissue availability. Indeed, size-exclusion chromatography of bear plasma demonstrated a shift to lower molecular weight IGF-containing complexes in the hibernating versus the active state. Furthermore, we note that the major IGF-2 mRNA isoform expressed in livers in both Scandinavian brown bears and grizzly bears was an alternative splice variant in which Ser29 is replaced with a tetrapeptide possessing a positively charged Arg residue. Homology modeling of the bear IGF-2/ IGFBP-2 complex showed the tetrapeptide in proximity to the heparin-binding domain involved in bone-specific targeting of this complex. In conclusion, this study provides data which suggest that increased IGF tissue availability combined with tissue -spe-cific targeting contribute to tissue preservation in hibernating bears. NEW & NOTEWORTHY Brown bears shift from circulating ternary IGF/IGFBP/ALS complexes in the active state to binary IGF/IGFBP complexes during hibernation, indicating increased tissue IGF-bioactivity. Furthermore, brown bears use a splice variant of IGF-2, suggesting increased bone-specific targeting of IGF anabolic signaling.


acid labile subunit (ALS); hibernation; IGF-binding protein (IGFBP); insulin-like growth factor (IGF); Ursus arctos

Published in

AJP - Endocrinology and Metabolism
2022, volume: 323, number: 3, pages: E307-E318

Authors' information

Frobert, Anne Mette
Aalborg University
Brohus, Malene
Aalborg University
Roesen, Tinna S.
Aalborg University
Norwegian Institute for Nature Research (NINA)
Swedish University of Agricultural Sciences, Department of Wildlife, Fish and Environmental Studies
Frobert, Ole
Orebro University
Frobert, Ole
Aarhus University
Conover, Cheryl A.
Mayo Clinic
Overgaard, Michael T.
Aalborg University

UKÄ Subject classification

Biochemistry and Molecular Biology

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