title: Grizzly bears exhibit augmented insulin sensitivity while obese prior to a reversible insulin resistance during hibernation.
abstract: The confluence of obesity and diabetes as a worldwide epidemic necessitates the discovery of new therapies. Success in this endeavor requires translatable preclinical studies, which traditionally employ rodent models. As an alternative approach, we explored hibernation where obesity is a natural adaptation to survive months of fasting. Here we report that grizzly bears exhibit seasonal tripartite insulin responsiveness such that obese animals augment insulin sensitivity but only weeks later enter hibernation-specific insulin resistance (IR) and subsequently reinitiate responsiveness upon awakening. Preparation for hibernation is characterized by adiposity coupled to increased insulin sensitivity via modified PTEN/AKT signaling specifically in adipose tissue, suggesting a state of "healthy" obesity analogous to humans with PTEN haploinsufficiency. Collectively, we show that bears reversibly cope with homeostatic perturbations considered detrimental to humans and describe a mechanism whereby IR functions not as a late-stage metabolic adaptation to obesity, but rather a gatekeeper of the fed-fasting transition.
authors.affiliation: College of Veterinary Medicine and Department of Veterinary Clinical Sciences, Washington State University, Pullman, WA 99164, USA.
authors.forename: O Lynne
authors.initials: OL
authors.lastname: Nelson
authors.affiliation: Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, WA 99164, USA.
authors.forename: Heiko T
authors.initials: HT
authors.lastname: Jansen
authors.affiliation: Department of Pathology, Amgen, Inc., Thousand Oaks, CA 91360, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Galbreath
authors.affiliation: Molecular Structure and Characterization, Amgen, Inc., Thousand Oaks, CA 91360, USA.
authors.forename: Kurt
authors.initials: K
authors.lastname: Morgenstern
authors.affiliation: School of the Environment and School of Biological Sciences, Washington State University, Pullman, WA 99164, USA.
authors.forename: Jamie Lauren
authors.initials: JL
authors.lastname: Gehring
authors.affiliation: School of the Environment and School of Biological Sciences, Washington State University, Pullman, WA 99164, USA.
authors.forename: Kimberly Scott
authors.initials: KS
authors.lastname: Rigano
authors.affiliation: Department of Metabolic Disorders, Amgen, Inc., Thousand Oaks, CA 91360, USA.
authors.forename: Jae
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Metabolic Disorders, Amgen, Inc., Thousand Oaks, CA 91360, USA.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Gong
authors.affiliation: Division of Medical Sciences, Amgen, Inc., Thousand Oaks, CA 91360, USA.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Shaywitz
authors.affiliation: Department of Movement Sciences, University of Idaho, Moscow, ID 83844, USA.
authors.forename: Chantal A
authors.initials: CA
authors.lastname: Vella
authors.affiliation: School of the Environment and School of Biological Sciences, Washington State University, Pullman, WA 99164, USA.
authors.forename: Charles T
authors.initials: CT
authors.lastname: Robbins
authors.affiliation: Department of Metabolic Disorders, Amgen, Inc., Thousand Oaks, CA 91360, USA. Electronic address: kcorbit@amgen.com.
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Corbit
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight; D005260:Female; D057895:Haploinsufficiency; D006605:Hibernation; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D007333:Insulin Resistance; D008297:Male; D009765:Obesity / Q000378:metabolism / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012621:Seasons; D015398:Signal Transduction; D001503:Ursidae
chemical_list: D001786:Blood Glucose; D007328:Insulin; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase