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Life in the fat lane: seasonal regulation of insulin sensitivity, food intake, and adipose biology in brown bears

Abstract

Grizzly bears (Ursus arctos horribilis) have evolved remarkable metabolic adaptations including enormous fat accumulation during the active season followed by fasting during hibernation. However, these fluctuations in body mass do not cause the same harmful effects associated with obesity in humans. To better understand these seasonal transitions, we performed insulin and glucose tolerance tests in captive grizzly bears, characterized the annual profiles of circulating adipokines, and tested the anorectic effects of centrally administered leptin at different times of the year. We also used bear gluteal adipocyte cultures to test insulin and beta-adrenergic sensitivity in vitro. Bears were insulin resistant during hibernation but were sensitive during the spring and fall active periods. Hibernating bears remained euglycemic, possibly due to hyperinsulinemia and hyperglucagonemia. Adipokine concentrations were relatively low throughout the active season but peaked in mid-October prior to hibernation when fat content was greatest. Serum glycerol was highest during hibernation, indicating ongoing lipolysis. Centrally administered leptin reduced food intake in October, but not in August, revealing seasonal variation in the brain’s sensitivity to its anorectic effects. This was supported by strong phosphorylated signal transducer and activator of transcription 3 labeling within the hypothalamus of hibernating bears; labeling virtually disappeared in active bears. Adipocytes collected during hibernation were insulin resistant when cultured with hibernation serum but became sensitive when cultured with active season serum. Heat treatment of active serum blocked much of this action. Clarifying the cellular mechanisms responsible for the physiology of hibernating bears may inform new treatments for metabolic disorders.

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Abbreviations

T b :

Body temperature

T2DM:

Type 2 diabetes mellitus

WAT:

White adipose tissue

pSTAT3:

Phosphorylated signal transducer and activator of transcription 3

ivITT:

Intravenous insulin tolerance tests

oGTT:

Oral glucose tolerance tests

NP40:

Tergitol-type NP-40

PMSF:

Phenylmethylsulfonyl fluoride

AKT1:

Protein kinase B

GSK3α, GSK3β:

Glycogen synthase kinase-3

IGF1R:

Insulin-like growth factor 1 receptor

IR:

Insulin receptor

IRS1:

Insulin receptor substrate-1

mTOR:

Mammalian target of rapamycin

70S6K:

Ribosomal protein S6 kinase

PTEN:

Phosphatase and tensin homolog

RPS6:

Ribosomal protein S6

TSC2:

Tuberous sclerosis complex-2

rh-leptin:

Recombinant human leptin

aCSF:

Artificial cerebrospinal fluid

BSA:

Bovine serum albumin

2-DG:

2-Deoxyglucose

RT qPCR:

Real time quantitative PCR

ADRB2:

β2-Adrenergic receptor

LEP:

Leptin

LEPR:

Leptin receptor

ATGL:

Adipose triglyceride lipase

ADRB1:

β1-Adrenergic receptor

ADRB3:

β3-Adrenergic receptor

CNS:

Central nervous system

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Acknowledgements

Funding was provided by Amgen Inc., the Interagency Grizzly Bear Committee, the Raili Korkka Brown Bear Endowment, the Bear Research and Conservation Endowment, and a National Science Foundation Graduate Research Fellowship (KSR, 1347943). We thank Danielle Rivet, Joy Erlenbach, Dr. Monica Bando and the other dedicated researchers at WSU’s Bear Research, Education, and Conservation Center for their assistance in data collection and captive bear care. We would also like to thank Jamie Gaber and Marina Savenkova for technical assistance.

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Correspondence to K. S. Rigano or H. T. Jansen.

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Specified raw data files used for analysis have been uploaded to Dryad Digital Repository for public access (doi:10.5061/dryad.sc38b).

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Communicated by G. Heldmaier.

K. S. Rigano and J. L. Gehring contributed equally.

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Rigano, K.S., Gehring, J.L., Evans Hutzenbiler, B.D. et al. Life in the fat lane: seasonal regulation of insulin sensitivity, food intake, and adipose biology in brown bears. J Comp Physiol B 187, 649–676 (2017). https://doi.org/10.1007/s00360-016-1050-9

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Keywords

  • Grizzly bear
  • Hibernation
  • Adipose
  • Glucose
  • Insulin
  • Leptin
  • Adiponectin
  • Food intake