Journal of Comparative Physiology B

, Volume 187, Issue 4, pp 649–676 | Cite as

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

  • K. S. RiganoEmail author
  • J. L. Gehring
  • B. D. Evans Hutzenbiler
  • A. V. Chen
  • O. L. Nelson
  • C. A. Vella
  • C. T. Robbins
  • H. T. JansenEmail author
Original Paper


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.


Grizzly bear Hibernation Adipose Glucose Insulin Leptin Adiponectin Food intake 



Body temperature


Type 2 diabetes mellitus


White adipose tissue


Phosphorylated signal transducer and activator of transcription 3


Intravenous insulin tolerance tests


Oral glucose tolerance tests


Tergitol-type NP-40


Phenylmethylsulfonyl fluoride


Protein kinase B

GSK3α, GSK3β

Glycogen synthase kinase-3


Insulin-like growth factor 1 receptor


Insulin receptor


Insulin receptor substrate-1


Mammalian target of rapamycin


Ribosomal protein S6 kinase


Phosphatase and tensin homolog


Ribosomal protein S6


Tuberous sclerosis complex-2


Recombinant human leptin


Artificial cerebrospinal fluid


Bovine serum albumin




Real time quantitative PCR


β2-Adrenergic receptor




Leptin receptor


Adipose triglyceride lipase


β1-Adrenergic receptor


β3-Adrenergic receptor


Central nervous system



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.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts.

Data sharing statement

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

Supplementary material

360_2016_1050_MOESM1_ESM.tiff (5.9 mb)
Supplementary material 1 (TIFF 6078 kb)
360_2016_1050_MOESM2_ESM.tiff (5.9 mb)
Supplementary material 2 (TIFF 6078 kb)
360_2016_1050_MOESM3_ESM.tiff (5.9 mb)
Supplementary material 3 (TIFF 6078 kb)
360_2016_1050_MOESM4_ESM.docx (18 kb)
Supplementary material 4 (DOCX 17 kb)


  1. Ahima RS, Flier JS (2000) Adipose tissue as an endocrine organ. Trends Endocrinol Metab 11(8):327–332. doi: 10.1016/s1043-2760(00)00301-5 PubMedCrossRefGoogle Scholar
  2. Ahima RS, Prabakaran D, Flier JS (1998) Postnatal leptin surge and regulation of circadian rhythm of leptin by feeding. Implications for energy homeostasis and neuroendocrine function. J Clin Invest 101(5):1020–1027. doi: 10.1172/jci1176 PubMedPubMedCentralCrossRefGoogle Scholar
  3. Anderson KD, Lambert PD, Corcoran TL, Murray JD, Thabet KE, Yancopoulos GD, Wiegand SJ (2003) Activation of the hypothalamic arcuate nucleus predicts the anorectic actions of ciliary neurotrophic factor and leptin in intact and gold thioglucose-lesioned mice. J Neuroendocrinol 15(7):649–660. doi: 10.1046/j.1365-2826.2003.01043.x PubMedCrossRefGoogle Scholar
  4. Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, Hotta K, Shimomura I, Nakamura T, Miyaoka K, Kuriyama H, Nishida M, Yamashita S, Okubo K, Matsubara K, Muraguchi M, Ohmoto Y, Funahashi T, Matsuzawa Y (1999) Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun 257(1):79–83. doi: 10.1006/bbrc.1999.0255 PubMedCrossRefGoogle Scholar
  5. Atcha Z, Cagampang FR, Stirland JA, Morris ID, Brooks AN, Ebling FJ, Klingenspor M, Loudon AS (2000) Leptin acts on metabolism in a photoperiod-dependent manner, but has no effect on reproductive function in the seasonally breeding Siberian hamster (Phodopus sungorus). Endocrinology 141(11):4128–4135. doi: 10.1210/endo.141.11.7769 Google Scholar
  6. Atkinson SN, Ramsay MA (1995) The effects of prolonged fasting of the body composition and reproductive success of female polar bears (Ursus maritimus). Funct Ecol 9(4):559–567. doi: 10.2307/2390145 CrossRefGoogle Scholar
  7. Barboza PS, Farley SD, Robbins CT (1997) Whole-body urea cycling and protein turnover during hyperphagia and dormancy in growing bears (Ursus americanus and U. arctos). Can J Zool 75(12):2129–2136. doi: 10.1139/z97-848 CrossRefGoogle Scholar
  8. Barnes BM (1989) Freeze avoidance in a mammal: body temperatures below 0 degree C in an Arctic hibernator. Science 244(4912):1593–1595PubMedCrossRefGoogle Scholar
  9. Baron AD, Brechtel G, Wallace P, Edelman SV (1988a) Fasting decreases rates of noninsulin-mediated glucose uptake in man. J Clin Endocrinol Metab 67(3):532–540. doi: 10.1210/jcem-67-3-532 PubMedCrossRefGoogle Scholar
  10. Baron AD, Brechtel G, Wallace P, Edelman SV (1988b) Rates and tissue sites of non-insulin- and insulin-mediated glucose uptake in humans. Am J Physiol 255(6 Pt 1):E769–774PubMedGoogle Scholar
  11. Bates SH, Myers MG (2003) The role of leptin receptor signaling in feeding and neuroendocrine function. Trends Endocrin Met 14(10):447–452. doi: 10.1016/j.tem.2003.10.003 CrossRefGoogle Scholar
  12. Bauer VW, Squire TL, Lowe ME, Andrews MT (2001) Expression of a chimeric retroviral-lipase mRNA confers enhanced lipolysis in a hibernating mammal. Am J Physiol Regul I 281(4):R1186–R1192Google Scholar
  13. Bauman WA, Meryn S, Florant GL (1987) Pancreatic hormones in the nonhibernating and hibernating golden mantled ground squirrel. Comp Biochem Physiol A Comp Physiol 86(2):241–244PubMedCrossRefGoogle Scholar
  14. Belant JL, Kielland K, Follmann EH, Adams LG (2006) Interspecific resource partitioning in sympatric ursids. Ecol Appl 16(6):2333–2343. doi:10.1890/1051-0761(2006)016[2333:IRPISU]2.0.CO;2Google Scholar
  15. Blüher M (2012) Clinical relevance of adipokines. Diabetes Metab J 36(5):317–327. doi: 10.4093/dmj.2012.36.5.317 PubMedPubMedCentralCrossRefGoogle Scholar
  16. Boyer BB, Barnes BM (1999) Molecular and metabolic aspects of mammalian hibernation—expression of the hibernation phenotype results from the coordinated regulation of multiple physiological and molecular events during preparation for and entry into torpor. Bioscience 49(9):713–724. doi: 10.2307/1313595 CrossRefGoogle Scholar
  17. Boyer BB, Ormseth OA, Buck L, Nicolson M, Pelleymounter MA, Barnes BM (1997) Leptin prevents posthibernation weight gain but does not reduce energy expenditure in Arctic ground squirrels. Comp Biochem Phys C 118(3):405–412Google Scholar
  18. Bratusch-Marrain PR (1983) Insulin-counteracting hormones: their impact on glucose metabolism. Diabetologia 24(2):74–79PubMedCrossRefGoogle Scholar
  19. Bruce DS, Darling NK, Seeland KJ, Oeltgen PR, Nilekani SP, Amstrup SC (1990) Is the polar bear (Ursus maritimus) a hibernator? Continued studies on opioids and hibernation. Pharmacol Biochem Behav 35(3):705–711PubMedCrossRefGoogle Scholar
  20. Carey HV, Andrews MT, Martin SL (2003) Mammalian hibernation: cellular and molecular responses to depressed metabolism and low temperature. Physiol Rev 83(4):1153–1181. doi: 10.1152/physrev.00008.2003 PubMedCrossRefGoogle Scholar
  21. Clarke IJ, Tilbrook AJ, Turner AI, Doughton BW, Goding JW (2001) Sex, fat and the tilt of the earth: effects of sex and season on the feeding response to centrally administered leptin in sheep. Endocrinology 142(6):2725–2728. doi: 10.1210/endo.142.6.8318 PubMedCrossRefGoogle Scholar
  22. Cochet N, Meister R, Florant GL, Barre H (1999) Regional variation of white adipocyte lipolysis during the annual cycle of the alpine marmot. Comp Biochem Phys C 123(3):225–232Google Scholar
  23. Collins S, Surwit RS (2001) The beta-adrenergic receptors and the control of adipose tissue metabolism and thermogenesis. Recent Prog Horm Res 56:309–328. doi: 10.1210/rp.56.1.309 PubMedCrossRefGoogle Scholar
  24. Dahle B, Zedrosser A, Swenson JE (2006) Correlates with body size and mass in yearling brown bears (Ursus arctos). J Zool 269(3):273–283. doi: 10.1111/j.1469-7998.2006.00127.x CrossRefGoogle Scholar
  25. Dark J (2005) Annual lipid cycles in hibernators: integration of physiology and behavior. Annu Rev Nutr 25:469–497. doi: 10.1146/annurev.nutr.25.050304.092514 PubMedCrossRefGoogle Scholar
  26. Dawe AR, Spurrier WA (1969) Hibernation induced in ground squirrels by blood transfusion. Science 163(864):298–299. doi: 10.1126/science.163.3864.298 PubMedCrossRefGoogle Scholar
  27. DeFronzo RA, Jacot E, Jequier E, Maeder E, Wahren J, Felber JP (1981) The effect of insulin on the disposal of intravenous glucose. Results from indirect calorimetry and hepatic and femoral venous catheterization. Diabetes 30(12):1000–1007. doi: 10.2337/diab.30.12.1000 PubMedCrossRefGoogle Scholar
  28. Derocher AE, Stirling I (1996) Aspects of survival in juvenile polar bears. Can J Zool 74(7):1246–1252CrossRefGoogle Scholar
  29. Eddy SF, Storey KB (2003) Differential expression of Akt, PPAR gamma, and PGC-1 during hibernation in bats. Biochem Cell Biol 81(4):269–274. doi: 10.1139/o03-056 PubMedCrossRefGoogle Scholar
  30. Erlenbach JA, Rode KD, Raubenheimer D, Robbins CT (2014) Macronutrient optimization and energy maximization determine diets of brown bears. J Mammal 95(1):160–168. doi: 10.1644/13-MAMM-A-161 CrossRefGoogle Scholar
  31. Evans AL, Singh NJ, Friebe A, Arnemo JM, Laske TG, Frobert O, Swenson JE, Blanc S (2016) Drivers of hibernation in the brown bear. Front Zool 13 (7). doi: 10.1186/s12983-016-0140-6
  32. Exton JH, Park CR (1968) Control of gluconeogenesis in liver. II. Effects of glucagon, catecholamines, and adenosine 3′,5′-monophosphate on gluconeogenesis in the perfused rat liver. J Biol Chem 243(16):4189–4196PubMedGoogle Scholar
  33. Farley SD, Robbins CT (1994) Development of two methods to estimate body composition of bears. Can J Zool 72(2):220–226. doi: 10.1139/z94-029 CrossRefGoogle Scholar
  34. Fedorov VB, Goropashnaya AV, Toien O, Stewart NC, Gracey AY, Chang CL, Qin SZ, Pertea G, Quackenbush J, Showe LC, Showe MK, Boyer BB, Barnes BM (2009) Elevated expression of protein biosynthesis genes in liver and muscle of hibernating black bears (Ursus americanus). Physiol Genom 37(2):108–118. doi: 10.1152/physiolgenomics.90398.2008 CrossRefGoogle Scholar
  35. Florant GL, Lawrence AK, Williams K, Bauman WA (1985) Seasonal changes in pancreatic B-cell function in euthermic yellow-bellied marmots. Am J Physiol 249(2 Pt 2):R159–165PubMedGoogle Scholar
  36. Florant GL, Porst H, Peiffer A, Hudachek SF, Pittman C, Summers SA, Rajala MW, Scherer PE (2004) Fat-cell mass, serum leptin and adiponectin changes during weight gain and loss in yellow-bellied marmots (Marmota flaviventris). J Comp Physiol B 174(8):633–639. doi: 10.1007/s00360-004-0454-0 PubMedCrossRefGoogle Scholar
  37. Folk GE, Folk MA, Minor JJ (1972) Physiological condition of three species of bears in winter dens. Int C Bear 2:107–124Google Scholar
  38. Folk GE, Larson A, Folk MA (1976) Physiology of hibernating bears. In: Third international conference on bear research and management, Binghamton. International Association on Bear Research and Management, pp 373–380Google Scholar
  39. Friedman JM, Halaas JL (1998) Leptin and the regulation of body weight in mammals. Nature 395(6704):763–770. doi: 10.1038/27376 PubMedCrossRefGoogle Scholar
  40. Frühbeck G, Gómez-Ambrosi J, Muruzábal FJ, Burrell MA (2001) The adipocyte: a model for integration of endocrine and metabolic signaling in energy metabolism regulation. Am J Physiol Endocrinol Metab 280(6):E827–847PubMedGoogle Scholar
  41. Frühbeck G, Méndez-Giménez L, Fernández-Formoso J-A, Fernández S, Rodríguez A (2014) Regulation of adipocyte lipolysis. Nutr Res Rev 27(01):63–93. doi: 10.1017/S095442241400002X PubMedCrossRefGoogle Scholar
  42. Galic S, Oakhill JS, Steinberg GR (2010) Adipose tissue as an endocrine organ. Mol Cell Endocrinol 316(2):129–139. doi: 10.1016/j.mce.2009.08.018 PubMedCrossRefGoogle Scholar
  43. Gardi J, Nelson OL, Robbins CT, Szentirmai É, Kapás L, Krueger JM (2011) Energy homeostasis regulatory peptides in hibernating grizzly bears. Gen Comp Endocr 172(1):181–183. doi: 10.1016/j.ygcen.2010.12.015 PubMedCrossRefGoogle Scholar
  44. Gehring JL, Rigano KS, Evans Hutzenbiler BD, Nelson OL, Robbins CT, Jansen HT (2016) A protocol for the isolation and cultivation of brown bear (Ursus arctos) adipocytes. Cytotechnology 68(5):2177–2191. doi: 10.1007/s10616-015-9937-y PubMedCrossRefGoogle Scholar
  45. Geiser F (2004) Metabolic rate and body temperature reduction during hibernation and daily torpor. Annu Rev Physiol 66:239–274. doi: 10.1146/annurev.physiol.66.032102.115105 PubMedCrossRefGoogle Scholar
  46. Geiser F (2013) Hibernation. Curr Biol 23(5):R188–193. doi: 10.1016/j.cub.2013.01.062 PubMedCrossRefGoogle Scholar
  47. Granneman JG, Lahners KN, Chaudhry A (1991) Molecular cloning and expression of the rat beta 3-adrenergic receptor. Mol Pharmacol 40(6):895–899PubMedGoogle Scholar
  48. Gregoire FM, Smas CM, Sul HS (1998) Understanding adipocyte differentiation. Physiol Rev 78(3):783–809PubMedGoogle Scholar
  49. Guven S, El-Bershawi A, Sonnenberg GE, Wilson CR, Hoffmann RG, Krakower GR, Kissebah AH (1999) Plasma leptin and insulin levels in weight-reduced obese women with normal body mass index: relationships with body composition and insulin. Diabetes 48(2):347–352PubMedCrossRefGoogle Scholar
  50. Hajer GR, van Haeften TW, Visseren FLJ (2008) Adipose tissue dysfunction in obesity, diabetes, and vascular diseases. Eur Heart J 29(24):2959–2971. doi: 10.1093/eurheartj/ehn387 PubMedCrossRefGoogle Scholar
  51. Halaas JL, Gajiwala KS, Maffei M, Cohen SL, Chait BT, Rabinowitz D, Lallone RL, Burley SK, Friedman JM (1995) Weight-reducing effects of the plasma protein encoded by the obese gene. Science 269(5223):543–546. doi: 10.1126/science.7624777 PubMedCrossRefGoogle Scholar
  52. Havel PJ (2002) Control of energy homeostasis and insulin action by adipocyte hormones: leptin, acylation stimulating protein, and adiponectin. Curr Opin Lipidol 13(1):51–59. doi: 10.1097/00041433-200202000-00008 PubMedCrossRefGoogle Scholar
  53. Heldmaier G (2011) Physiology. Life on low flame in hibernation. Science 331(6019):866–867. doi: 10.1126/science.1203192
  54. Hellgren EC (1988) Ecology and physiology of a black bear (Ursus americanus) population in Great Dismal Swamp and reproductive physiology in the captive female black bear. Dissertation, Virginia Polytechnic Institute and State University, BlacksburgGoogle Scholar
  55. Hers I, Vincent EE, Tavare JM (2011) Akt signalling in health and disease. Cell Signal 23(10):1515–1527. doi: 10.1016/j.cellsig.2011.05.004 PubMedCrossRefGoogle Scholar
  56. Hilderbrand GV, Jenkins SG, Schwartz CC, Hanley TA, Robbins CT (1999a) Effect of seasonal differences in dietary meat intake on changes in body mass and composition in wild and captive brown bears. Can J Zool 77(10):1623–1630. doi: 10.1139/z99-133 CrossRefGoogle Scholar
  57. Hilderbrand GV, Schwartz CC, Robbins CT, Jacoby ME, Hanley TA, Arthur SM, Servheen C (1999b) The importance of meat, particularly salmon, to body size, population productivity, and conservation of North American brown bears. Can J Zool 77(1):132–138. doi: 10.1139/z98-195 CrossRefGoogle Scholar
  58. Hill EM (2013) Seasonal changes in white adipose tissue in American black bears (Ursus americanus). University of Tennessee, KnoxvilleGoogle Scholar
  59. Hissa R, Siekkinen J, Hohtola E, Saarela S, Hakala A, Pudas J (1994) Seasonal patterns in the physiology of the European brown bear (Ursus arctos arctos) in Finland. Comp Biochem Phys A 109(3):781–791CrossRefGoogle Scholar
  60. Hissa R, Hohtola E, Tuomala-Saramaki T, Laine T, Kallio H (1998) Seasonal changes in fatty acids and leptin contents in the plasma of the European brown bear (Ursus arctos arctos). Ann Zool Fennnici 35:215–224Google Scholar
  61. Hoehn KL, Hudachek SF, Summers SA, Florant GL (2004) Seasonal, tissue-specific regulation of Akt/protein kinase B and glycogen synthase in hibernators. Am J Physiol Regulat I 286(3):R498–504. doi: 10.1152/ajpregu.00509.2003 CrossRefGoogle Scholar
  62. Jansen HT, Hileman SM, Lubbers LS, Jackson GL, Lehman MN (1996) A subset of estrogen receptor-containing neurons project to the median eminence in the ewe. J Neuroendocrinol 8(12):921–927. doi: 10.1111/j.1365-2826.1996.tb00822.x PubMedCrossRefGoogle Scholar
  63. Jansen HT, Hileman SM, Lubbers LS, Kuehl DE, Jackson GL, Lehman MN (1997) Identification and distribution of neuroendocrine gonadotropin-releasing hormone neurons in the ewe. Biol Reprod 56(3):655–662. doi: 10.1095/biolreprod56.3.655 PubMedCrossRefGoogle Scholar
  64. Jansen HT, Leise T, Stenhouse G, Pigeon K, Kasworm W, Teisberg J, Radandt T, Dallmann R, Brown S, Robbins CT (2016) The bear circadian clock doesn’t ‘sleep’ during winter dormancy. Front Zool 13(1):1–16. doi: 10.1186/s12983-016-0173-x CrossRefGoogle Scholar
  65. Jensen MD, Chandramouli V, Schumann WC, Ekberg K, Previs SF, Gupta S, Landau BR (2001) Sources of blood glycerol during fasting. Am J Physiol Endocrinol Metab 281(5):E998–E1004PubMedGoogle Scholar
  66. Jiang G, Zhang BB (2003) Glucagon and regulation of glucose metabolism. Am J Physiol Endocrinol Metab 284(4):E671–678. doi: 10.1152/ajpendo.00492.2002 PubMedCrossRefGoogle Scholar
  67. Jones JD, Burnett P, Zollman P (1999) The glyoxylate cycle: does it function in the dormant or active bear? Comp Biochem Phys B 124(2):177–179. doi: 10.1016/S0305-0491(99)00109-1 CrossRefGoogle Scholar
  68. Joyce-Zuniga NM, Newberry RC, Robbins CT, Ware JV, Jansen HT, Nelson OL (2016) Positive reinforcement training for blood collection in grizzly bears (Ursus arctos horribilis) results in undetectable elevations in serum cortisol levels: a preliminary investigation. J Appl Anim Welf Sci 19(2):210–215. doi: 10.1080/10888705.2015.1126523 PubMedCrossRefGoogle Scholar
  69. Kadowaki T, Yamauchi T, Kubota N, Hara K, Ueki K, Tobe K (2006) Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J Clin Invest 116(7):1784–1792. doi: 10.1172/JCI29126 PubMedPubMedCentralCrossRefGoogle Scholar
  70. Kamine A, Shimozuru M, Shibata H, Tsubota T (2012a) Changes in blood glucose and insulin responses to intravenous glucose tolerance tests and blood biochemical values in adult female Japanese black bears (Ursus thibetanus japonicus). Jpn J Vet Res 60(1):5–13. doi: 10.14943/jjvr.60.1.5 PubMedGoogle Scholar
  71. Kamine A, Shimozuru M, Shibata H, Tsubota T (2012b) Effects of intramuscular administration of tiletamine-zolazepam with and without sedative pretreatment on plasma and serum biochemical values and glucose tolerance test results in Japanese black bears (Ursus thibetanus japonicus). Am J Vet Res 73(8):1282–1289. doi: 10.2460/ajvr.73.8.1282 PubMedCrossRefGoogle Scholar
  72. Karjalainen M, Hohtola E, Hissa R (1994) No metabolic suppression in the Djungarian hamster or rat by injections of plasma from the winter-sleeping brown bear. J Therm Biol 19(5):321–325. doi: 10.1016/0306-4565(94)90068-X CrossRefGoogle Scholar
  73. Keim NL, Stern JS, Havel PJ (1998) Relation between circulating leptin concentrations and appetite during a prolonged, moderate energy deficit in women. Am J Clin Nutr 68(4):794–801PubMedGoogle Scholar
  74. Kershaw EE, Flier JS (2004) Adipose tissue as an endocrine organ. J Clin Endocr Metab 89(6):2548–2556. doi: 10.1210/jc.2004-0395 PubMedCrossRefGoogle Scholar
  75. Kingsley MCS, Nagy JA, Russell RH (1983) Patterns of weight gain and loss for grizzly bears in northern Canada. Int C Bears 5:174–178. doi: 10.2307/3872535 Google Scholar
  76. Koch C, Augustine RA, Steger J, Ganjam GK, Benzler J, Pracht C, Lowe C, Schwartz MW, Shepherd PR, Anderson GM, Grattan DR, Tups A (2010) Leptin rapidly improves glucose homeostasis in obese mice by increasing hypothalamic insulin sensitivity. J Neurosci 30(48):16180–16187. doi: 10.1523/jneurosci.3202-10.2010 PubMedPubMedCentralCrossRefGoogle Scholar
  77. Kronfeld-Schor N, Richardson C, Silvia BA, Kunz TH, Widmaier EP (2000) Dissociation of leptin secretion and adiposity during prehibernatory fattening in little brown bats. Am J Physiol Regul I 279(4):R1277–1281Google Scholar
  78. Laske TG, Garshelis DL, Iaizzo PA (2011) Monitoring the wild black bear’s reaction to human and environmental stressors. BMC Physiol 11:13. doi: 10.1186/1472-6793-11-13 PubMedPubMedCentralCrossRefGoogle Scholar
  79. Lee M, Choi I, Park K (2002) Activation of stress signaling molecules in bat brain during arousal from hibernation. J Neurochem 82(4):867–873. doi: 10.1046/j.1471-4159.2002.01022.x PubMedCrossRefGoogle Scholar
  80. Lee YH, Wang MY, Yu XX, Unger RH (2016) Glucagon is the key factor in the development of diabetes. Diabetologia 59(7):1372–1375. doi: 10.1007/s00125-016-3965-9 PubMedCrossRefGoogle Scholar
  81. Lehman MN, Karsch FJ, Silverman AJ (1988) Potential sites of interaction between catecholamines and LHRH in the sheep brain. Brain Res Bull 20(1):49–58PubMedCrossRefGoogle Scholar
  82. Lewis GF, Carpentier A, Adeli K, Giacca A (2002) Disordered fat storage and mobilization in the pathogenesis of insulin resistance and type 2 diabetes. Endocr Rev 23(2):201–229. doi: 10.1210/edrv.23.2.0461 PubMedCrossRefGoogle Scholar
  83. Li R, Fan W, Tian G, Zhu H, He L, Cai J, Huang Q, Cai Q, Li B, Bai Y, Zhang Z, Zhang Y, Wang W, Li J, Wei F, Li H, Jian M, Li J, Zhang Z, Nielsen R, Li D, Gu W, Yang Z, Xuan Z, Ryder OA, Leung FC, Zhou Y, Cao J, Sun X, Fu Y, Fang X, Guo X, Wang B, Hou R, Shen F, Mu B, Ni P, Lin R, Qian W, Wang G, Yu C, Nie W, Wang J, Wu Z, Liang H, Min J, Wu Q, Cheng S, Ruan J, Wang M, Shi Z, Wen M, Liu B, Ren X, Zheng H, Dong D, Cook K, Shan G, Zhang H, Kosiol C, Xie X, Lu Z, Zheng H, Li Y, Steiner CC, Lam TT, Lin S, Zhang Q, Li G, Tian J, Gong T, Liu H, Zhang D, Fang L, Ye C, Zhang J, Hu W, Xu A, Ren Y, Zhang G, Bruford MW, Li Q, Ma L, Guo Y, An N, Hu Y, Zheng Y, Shi Y, Li Z, Liu Q, Chen Y, Zhao J, Qu N, Zhao S, Tian F, Wang X, Wang H, Xu L, Liu X, Vinar T, Wang Y, Lam TW, Yiu SM, Liu S, Zhang H, Li D, Huang Y, Wang X, Yang G, Jiang Z, Wang J, Qin N, Li L, Li J, Bolund L, Kristiansen K, Wong GK, Olson M, Zhang X, Li S, Yang H, Wang J, Wang J (2010) The sequence and de novo assembly of the giant panda genome. Nature 463(7279):311–317. doi: 10.1038/nature08696 PubMedCrossRefGoogle Scholar
  84. Liao Y, Hung M-C (2010) Physiological regulation of Akt activity and stability. Am J Transl Res 2(1):19–42PubMedPubMedCentralGoogle Scholar
  85. Logie L, Ruiz-Alcaraz AJ, Keane M, Woods YL, Bain J, Marquez R, Alessi DR, Sutherland C (2007) Characterization of a protein kinase B inhibitor in vitro and in insulin-treated liver cells. Diabetes 56(9):2218–2227. doi: 10.2337/db07-0343 PubMedCrossRefGoogle Scholar
  86. Lohuis TD, Beck TDI, Harlow HJ (2005) Hibernating black bears have blood chemistry and plasma amino acid profiles that are indicative of long-term adaptive fasting. Can J Zool 83(9):1257–1263. doi: 10.1139/z05-120 CrossRefGoogle Scholar
  87. Maffei M, Halaas J, Ravussin E, Pratley RE, Lee GH, Zhang Y, Fei H, Kim S, Lallone R, Ranganathan S et al (1995) Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med 1(11):1155–1161. doi: 10.1038/nm1195-1155 PubMedCrossRefGoogle Scholar
  88. Malnick SD, Knobler H (2006) The medical complications of obesity. Q J Med 99(9):565–579. doi: 10.1093/qjmed/hcl085 CrossRefGoogle Scholar
  89. Mantzoros CS, Magkos F, Brinkoetter M, Sienkiewicz E, Dardeno TA, Kim SY, Hamnvik OP, Koniaris A (2011) Leptin in human physiology and pathophysiology. Am J Physiol Endocrinol Metab 301(4):E567–584. doi: 10.1152/ajpendo.00315.2011 PubMedPubMedCentralCrossRefGoogle Scholar
  90. Marbán SL, Roth J (1996) Transgenic hyperinsulinemia: a mouse model of insulin resistance and glucose intolerance without obesity. In: Shafrir E (ed) Lessons from animal diabetes, 6th edn. Birkhauser, Boston, pp 201–224Google Scholar
  91. Mari A, Pacini G, Murphy E, Ludvik B, Nolan JJ (2001) A model-based method for assessing insulin sensitivity from the oral glucose tolerance test. Diabetes Care 24(3):539–548PubMedCrossRefGoogle Scholar
  92. Martin SL (2008) Mammalian hibernation: a naturally reversible model for insulin resistance in man? Diab Vasc Dis Res 5(2):76–81. doi: 10.3132/dvdr.2008.013 PubMedCrossRefGoogle Scholar
  93. McCain S, Ramsay E, Kirk C (2013) The effects of hibernation and captivity on glucose metabolism and thyroid hormones in American black bear (Ursus americanus). J Zoo Wildlife Med 44(2):324–332. doi: 10.1638/2012-0146R1.1 CrossRefGoogle Scholar
  94. McCarthy TJ, Banks WA, Farrell CL, Adamu S, Derdeyn CP, Snyder AZ, Laforest R, Litzinger DC, Martin D, LeBel CP, Welch MJ (2002) Positron emission tomography shows that intrathecal leptin reaches the hypothalamus in baboons. J Pharmacol Exp Ther 301(3):878–883. doi: 10.1124/jpet.301.3.878 PubMedCrossRefGoogle Scholar
  95. McGee-Lawrence M, Buckendahl P, Carpenter C, Henriksen K, Vaughan M, Donahue S (2015) Suppressed bone remodeling in black bears conserves energy and bone mass during hibernation. J Exp Biol 218(13):2067–2074. doi: 10.1242/jeb.120725 PubMedPubMedCentralCrossRefGoogle Scholar
  96. Medina M, Wandosell F (2011) Deconstructing GSK-3: the fine regulation of its activity. Int J Alzheimers Dis 2011:479249. doi: 10.4061/2011/479249 PubMedPubMedCentralGoogle Scholar
  97. Meier U, Gressner AM (2004) Endocrine regulation of energy metabolism: review of pathobiochemical and clinical chemical aspects of leptin, ghrelin, adiponectin, and resistin. Clin Chem 50(9):1511–1525. doi: 10.1373/clinchem.2004.032482 PubMedCrossRefGoogle Scholar
  98. Morrison CD (2008) Leptin resistance and the response to positive energy balance. Physiol Behav 94(5):660–663. doi: 10.1016/j.physbeh.2008.04.009 PubMedPubMedCentralCrossRefGoogle Scholar
  99. Mostafa N, Everett DC, Chou SC, Kong PA, Florant GL, Coleman RA (1993) Seasonal changes in critical enzymes of lipogenesis and triacylglycerol synthesis in the marmot (Marmota flaviventris). J Comp Physiol B 163(6):463–469PubMedGoogle Scholar
  100. Myers MG, Cowley MA, Munzberg H (2008) Mechanisms of leptin action and leptin resistance. Annu Rev Physiol 70:537–556. doi: 10.1146/annurev.physiol.70.113006.100707 PubMedCrossRefGoogle Scholar
  101. Myers MG Jr, Leibel RL, Seeley RJ, Schwartz MW (2010) Obesity and leptin resistance: distinguishing cause from effect. Trends Endocrin Metab 21(11):643–651. doi: 10.1016/j.tem.2010.08.002 CrossRefGoogle Scholar
  102. Nakamura S, Okano T, Shibata H, Saito M, Komatsu T, Asano M, Sugiyama M, Tsubota T, Suzuki M (2008) Relationships among changes of serum leptin concentration, leptin mRNA expression in white adipose tissue (WAT), and WAT fat-cell size in female Japanese black bears (Ursus thibetanus japonicus). Can J Zool 86(9):1042–1049. doi: 10.1139/Z08-080 CrossRefGoogle Scholar
  103. Nelson RA (1973) Winter sleep in the black bear: a physiologic and metabolic marvel. Mayo Clin Proc 48:733–737PubMedGoogle Scholar
  104. Nelson OL, Robbins CT (2010) Cardiac function adaptations in hibernating grizzly bears (Ursus arctos horribilis). J Comp Physiol B 180(3):465–473. doi: 10.1007/s00360-009-0421-x PubMedCrossRefGoogle Scholar
  105. Nelson RA, Folk GE, Pfeiffer EW, Craighead JJ, Jonkel CJ, Steiger DL (1983) Behavior, biochemistry, and hibernation in black, grizzly and polar bears. In: International conference on bear research and management, Madison, pp 284–290Google Scholar
  106. Nelson OL, McEwen MM, Robbins CT, Felicetti L, Christensen WF (2003) Evaluation of cardiac function in active and hibernating grizzly bears. JAVMA J Am Vet Med A 223(8):1170–1175. doi: 10.2460/javma.2003.223.1170 CrossRefGoogle Scholar
  107. Obici S (2009) Molecular targets for obesity therapy in the brain. Endocrinology 150(6):2512–2517. doi: 10.1210/en.2009-0409 PubMedCrossRefGoogle Scholar
  108. O’Brien RM, Granner DK (1991) Regulation of gene expression by insulin. Biochem J 278(Pt 3):609–619PubMedPubMedCentralCrossRefGoogle Scholar
  109. Ormseth OA, Nicolson M, Pelleymounter MA, Boyer BB (1996) Leptin inhibits prehibernation hyperphagia and reduces body weight in arctic ground squirrels. Am J Physiol 271(6 Part 2):R1775–R1779Google Scholar
  110. Palumbo PJ, Wellik DL, Bagley NA, Nelson RA (1983) Insulin and glucagon responses in the hibernating black bear. Int C Bear 5:291–296Google Scholar
  111. Pessin JE, Thurmond DC, Elmendorf JS, Coker KJ, Okada S (1999) Molecular basis of insulin-stimulated GLUT4 vesicle trafficking. Location! Location! Location! J Biol Chem 274(5):2593–2596PubMedCrossRefGoogle Scholar
  112. Pipeleers DG, Schuit FC, Van Schravendijk CF, Van de Winkel M (1985) Interplay of nutrients and hormones in the regulation of glucagon release. Endocrinology 117(3):817–823. doi: 10.1210/endo-117-3-817 PubMedCrossRefGoogle Scholar
  113. Pi-Sunyer FX (2002) The obesity epidemic: pathophysiology and consequences of obesity. Obes Res 10(Suppl 2):97S–104S. doi: 10.1038/oby.2002.202 PubMedCrossRefGoogle Scholar
  114. Proescholdt MG, Hutto B, Brady LS, Herkenham M (2000) Studies of cerebrospinal fluid flow and penetration into brain following lateral ventricle and cisterna magna injections of the tracer [14C]inulin in rat. Neuroscience 95(2):577–592PubMedCrossRefGoogle Scholar
  115. Reaven G (2004) The metabolic syndrome or the insulin resistance syndrome? Different names, different concepts, and different goals. Endocrin Metab Clin 33(2):283–303. doi: 10.1016/j.ecl.2004.03.002 CrossRefGoogle Scholar
  116. Reidy SP, Weber J (2000) Leptin: an essential regulator of lipid metabolism. Comp Biochem Phys A 125(3):285–298. doi: 10.1016/S1095-6433(00)00159-8 CrossRefGoogle Scholar
  117. Robbins CT, Ben-David M, Fortin JK, Nelson OL (2012) Maternal condition determines birth date and growth of newborn bear cubs. J Mammal 93(2):540–546. doi: 10.1644/11-MAMM-A-155 CrossRefGoogle Scholar
  118. Robson AB, Sykes AR, McKinnon AE, Bell ST (2004) A model of magnesium metabolism in young sheep: transactions between plasma, cerebrospinal fluid and bone. Br J Nutr 91(1):73–79. doi: 10.1079/BJN20041005 PubMedCrossRefGoogle Scholar
  119. Rocha DM, Faloona GR, Unger RH (1972) Glucagon-stimulating activity of 20 amino acids in dogs. J Clin Invest 51(9):2346–2351. doi: 10.1172/JCI107046 PubMedPubMedCentralCrossRefGoogle Scholar
  120. Rode KD, Robbins CT, Shipley LA (2001) Constraints on herbivory by grizzly bears. Oecologia 128(1):62–71. doi: 10.1007/s004420100637 CrossRefGoogle Scholar
  121. Rooks CR, Penn DM, Kelso E, Bowers RR, Bartness TJ, Harris RB (2005) Sympathetic denervation does not prevent a reduction in fat pad size of rats or mice treated with peripherally administered leptin. Am J Physiol Regul I 289(1):R92–102. doi: 10.1152/ajpregu.00858.2004 CrossRefGoogle Scholar
  122. Rosset A, Spadola L, Ratib O (2004) OsiriX: an open-source software for navigating in multidimensional DICOM images. J Digit Imaging 17(3):205–216. doi: 10.1007/s10278-004-1014-6 PubMedPubMedCentralCrossRefGoogle Scholar
  123. Rutt KA, Bruce DS, Chiang PP, Oeltgen PR, Welborn JR, Nilekani SP (1987) Summer hibernation in ground squirrels (Citellus tridecemlineatus) induced by injection of whole or fractionated plasma from hibernating black bears (Ursus americanus). J Therm Biol 12(2):135–138. doi: 10.1016/0306-4565(87)90052-0 CrossRefGoogle Scholar
  124. Sacca L, Eigler N, Cryer PE, Sherwin RS (1979) Insulin antagonistic effects of epinephrine and glucagon in the dog. Am J Physiol 237(6):E487–492PubMedGoogle Scholar
  125. Schwartz CC, Fortin JK, Teisberg JE, Haroldson MA, Servheen C, Robbins CT, Van Manen FT (2014) Body and diet composition of sympatric black and grizzly bears in the Greater Yellowstone ecosystem. J Wildlife Manag 78(1):68–78. doi: 10.1002/jwmg.633 CrossRefGoogle Scholar
  126. Seeley RJ, Van Dijk G, Campfield LA, Smith FJ, Burn P, Nelligan JA, Bell SM, Baskin DG, Woods SC, Schwartz MW (1996) Intraventricular leptin reduces food intake and body weight of lean rats but not obese Zucker rats. Horm Metab Res 28(12):664–668. doi: 10.1055/s-2007-979874 PubMedCrossRefGoogle Scholar
  127. Shanik MH, Xu Y, Skrha J, Dankner R, Zick Y, Roth J (2008) Insulin resistance and hyperinsulinemia: is hyperinsulinemia the cart or the horse? Diabetes Care 31(Suppl 2):S262–268. doi: 10.2337/dc08-s264 PubMedCrossRefGoogle Scholar
  128. Sikes RS, Gannon WL, Mammalogists AS (2011) Guidelines of the American Society of Mammalogists for the use of wild mammals in research. J Mammal 92(1):235–253. doi: 10.1644/10-MAMM-F-355.1 CrossRefGoogle Scholar
  129. Sommer F, Backhed F (2013) The gut microbiota—masters of host development and physiology. Nat Rev Microbiol 11(4):227–238. doi: 10.1038/nrmicro2974 PubMedCrossRefGoogle Scholar
  130. Sommer F, Stahlman M, Ilkayeva O, Arnemo JM, Kindberg J, Josefsson J, Newgard CB, Frobert O, Backhed F (2016) The gut microbiota modulates energy metabolism in the hibernating brown bear Ursus arctos. Cell Rep 14(7):1655–1661. doi: 10.1016/j.celrep.2016.01.026 PubMedCrossRefGoogle Scholar
  131. Spady TJ, Harlow HJ, Butterstein G, Durrant B (2009) Leptin as a surrogate indicator of body fat in the American black bear. Ursus 20(2):120–130. doi: 10.2192/08GR025.1 CrossRefGoogle Scholar
  132. Spurrier WA, Folk GE Jr, Dawe AR (1976) Induction of summer hibernation in the 13-lined ground squirrel shown by comparative serum transfusions from arctic mammals. Cryobiology 13(3):368–374PubMedCrossRefGoogle Scholar
  133. Stenvinkel P, Jani AH, Johnson RJ (2013) Hibernating bears (Ursidae): metabolic magicians of definite interest for the nephrologist. Kidney Int 83(2):207–212. doi: 10.1038/ki.2012.396 PubMedCrossRefGoogle Scholar
  134. Stevenson RW, Steiner KE, Davis MA, Hendrick GK, Williams PE, Lacy WW, Brown L, Donahue P, Lacy DB, Cherrington AD (1987) Similar dose responsiveness of hepatic glycogenolysis and gluconeogenesis to glucagon in vivo. Diabetes 36(3):382–389PubMedCrossRefGoogle Scholar
  135. Tashima LS, Adelstein SJ, Lyman CP (1970) Radioglucose utilization by active, hibernating, and arousing ground squirrels. Am J Physiol 218(1):303–309PubMedGoogle Scholar
  136. Toien O, Blake J, Edgar DM, Grahn DA, Heller HC, Barnes BM (2011) Hibernation in black bears: independence of metabolic suppression from body temperature. Science 331(6019):906–909. doi: 10.1126/science.1199435 PubMedCrossRefGoogle Scholar
  137. Tokuyama K, Galantino HL, Green R, Florant GL (1991) Seasonal glucose uptake in marmots (Marmota flaviventris): the role of pancreatic hormones. Comp Biochem Phys A 100(4):925–930CrossRefGoogle Scholar
  138. Trayhurn P, Beattie JH (2001) Physiological role of adipose tissue: white adipose tissue as an endocrine and secretory organ. P Nutr Soc 60(3):329–339. doi: 10.1079/pns200194 CrossRefGoogle Scholar
  139. Trayhurn P, Hoggard N, Mercer JG, Rayner DV (1999) Leptin: fundamental aspects. Int J Obes Relat Metab Disord 23(Suppl 1):22–28. doi: 10.1038/sj.ijo.0800791 PubMedCrossRefGoogle Scholar
  140. Tsubota T, Sato M, Okano T, Nakamura S, Asano M, Komatsu T, Shibata H, Saito M (2008) Annual changes in serum leptin concentration in the adult female Japanese black bear (Ursus thibetanus japonicus). J Vet Med Sci 70(12):1399–1403PubMedCrossRefGoogle Scholar
  141. Wang LC, Belke D, Jourdan ML, Lee TF, Westly J, Nurnberger F (1988) The “hibernation induction trigger”: specificity and validity of bioassay using the 13-lined ground squirrel. Cryobiology 25(4):355–362PubMedCrossRefGoogle Scholar
  142. Wang P, Walter RD, Bhat BG, Florant GL, Coleman RA (1997) Seasonal changes in enzymes of lipogenesis and triacylglycerol synthesis in the golden-mantled ground squirrel (Spermophilus lateralis). Comp Biochem Phys B 118(2):261–267CrossRefGoogle Scholar
  143. Ware JV, Nelson OL, Robbins CT, Jansen HT (2012) Temporal organization of activity in the brown bear (Ursus arctos): roles of circadian rhythms, light, and food entrainment. Am J Physiol Regul I 303(9):R890–R902. doi: 10.1152/ajpregu.00313.2012 CrossRefGoogle Scholar
  144. Weitten M, Robin JP, Oudart H, Pevet P, Habold C (2013) Hormonal changes and energy substrate availability during the hibernation cycle of Syrian hamsters. Horm Behav 64(4):611–617. doi: 10.1016/j.yhbeh.2013.08.015 PubMedCrossRefGoogle Scholar
  145. Welch AJ, Bedoya-Reina OC, Carretero-Paulet L, Miller W, Rode KD, Lindqvist C (2014) Polar bears exhibit genome-wide signatures of bioenergetic adaptation to life in the arctic environment. Genome Biol Evol 6(2):433–450. doi: 10.1093/gbe/evu025 PubMedPubMedCentralCrossRefGoogle Scholar
  146. Wilcox G (2005) Insulin and insulin resistance. Clin Biochem Rev 26(2):19–39PubMedPubMedCentralGoogle Scholar
  147. Wilson BE, Deeb S, Florant GL (1992) Seasonal changes in hormone-sensitive and lipoprotein lipase mRNA concentrations in marmot white adipose tissue. Am J Physiol 262(2 Pt 2):R177–181PubMedGoogle Scholar
  148. Wu J, Bostrom P, Sparks LM, Ye L, Choi JH, Giang AH, Khandekar M, Virtanen KA, Nuutila P, Schaart G, Huang K, Tu H, van Marken Lichtenbelt WD, Hoeks J, Enerback S, Schrauwen P, Spiegelman BM (2012) Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 150(2):366–376. doi: 10.1016/j.cell.2012.05.016 PubMedPubMedCentralCrossRefGoogle Scholar
  149. Wu CW, Biggar KK, Storey KB (2013) Biochemical adaptations of mammalian hibernation: exploring squirrels as a perspective model for naturally induced reversible insulin resistance. Braz J Med Biol Res 46(1):1–13PubMedPubMedCentralCrossRefGoogle Scholar
  150. Yaksh TL, Scott B, LeBel CL (2002) Effects of continuous lumbar intrathecal infusion of leptin in rats on weight regulation. Neuroscience 110(4):703–710. doi: 10.1016/S0306-4522(01)00608-X PubMedCrossRefGoogle Scholar
  151. Zeng W, Pirzgalska RM, Pereira MM, Kubasova N, Barateiro A, Seixas E, Lu YH, Kozlova A, Voss H, Martins GG, Friedman JM, Domingos AI (2015) Sympathetic neuro-adipose connections mediate leptin-driven lipolysis. Cell 163(1):84–94. doi: 10.1016/j.cell.2015.08.055 PubMedCrossRefGoogle Scholar
  152. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372(6505):425–432. doi: 10.1038/372425a0 PubMedCrossRefGoogle Scholar
  153. Ziemke F, Mantzoros CS (2010) Adiponectin in insulin resistance: lessons from translational research. Am J Clin Nutr 91(1):258S–261S. doi: 10.3945/ajcn.2009.28449C PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • K. S. Rigano
    • 1
    Email author
  • J. L. Gehring
    • 1
  • B. D. Evans Hutzenbiler
    • 2
  • A. V. Chen
    • 3
  • O. L. Nelson
    • 3
  • C. A. Vella
    • 4
  • C. T. Robbins
    • 1
    • 5
  • H. T. Jansen
    • 2
    Email author
  1. 1.School of Biological SciencesWashington State UniversityPullmanUSA
  2. 2.Department of Integrative Physiology and NeuroscienceWashington State UniversityPullmanUSA
  3. 3.Department of Veterinary Clinical Sciences, College of Veterinary MedicineWashington State UniversityPullmanUSA
  4. 4.Department of Movement SciencesUniversity of IdahoMoscowUSA
  5. 5.School of the EnvironmentWashington State UniversityPullmanUSA

Personalised recommendations