Abstract
Growth hormone receptor knockout mice (GHRKO) are characterized by high insulin sensitivity and extended lifespan. Interestingly, the secretory activity of visceral fat in GHRKO mice is altered, stimulating whole body insulin sensitivity. In this study, we transplanted normal (N) mice with visceral fat pads from GHRKO or N mice to determine the role of visceral fat on the insulin signaling. We found that the transplant of visceral fat from GHRKO mice to N mice (N-GHRKO) improved whole body insulin sensitivity when comparing with sham-operated mice (N-S) and with mice that received visceral fat from N mice (N-N). This was associated with increased hepatic insulin sensitivity as observed by the increased phosphorylated insulin receptor and increased hepatic expression of Pparα and Pparγ. In conclusion, we demonstrated that visceral fat transplant from GHRKO mice into normal mice enhanced insulin sensitivity and glucose tolerance. These results further confirm the differential physiological role played by visceral adipose tissue from GH receptor deficient mice, indicating that the increase of this fat depot can be associated with beneficial effects on insulin signaling and longevity.
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References
Atwood CS, Bowen RL (2011) The reproductive-cell cycle theory of aging: an update. Exp Gerontol 46(2–3):100–107
Barzilai N, She L, Liu BQ, Vuguin P, Cohen P, Wang J, Rossetti L (1999) Surgical removal of visceral fat reverses hepatic insulin resistance. Diabetes 48(1):94–98
Berryman DE, Glad CA, List EO, Johannsson G (2013) The GH/IGF-1 axis in obesity: pathophysiology and therapeutic considerations. Nat Rev Endocrinol 9(6):346–356
Bowen RL, Atwood CS (2004) Living and dying for sex. A theory of aging based on the modulation of cell cycle signaling by reproductive hormones. Gerontology 50(5):265–290
Coschigano KT, Holland AN, Riders ME, List EO, Flyvbjerg A, Kopchick JJ (2003) Deletion, but not antagonism, of the mouse growth hormone receptor results in severely decreased body weights, insulin, and insulin-like growth factor I levels and increased life span. Endocrinology 144(9):3799–3810
Erman A, Veilleux A, Tchernof A, Goodyer CG (2011a) Human growth hormone receptor (GHR) expression in obesity: I. GHR mRNA expression in omental and subcutaneous adipose tissues of obese women. Int J Obes 35(12):1511–1519
Erman A, Wabitsch M, Goodyer CG (2011b) Human growth hormone receptor (GHR) expression in obesity: II. Regulation of the human GHR gene by obesity-related factors. Int J Obes 35(12):1520–1529
Gabriely I, Ma XH, Yang XM, Atzmon G, Rajala MW, Berg AH, Scherer P, Rossetti L, Barzilai N (2002) Removal of visceral fat prevents insulin resistance and glucose intolerance of aging: an adipokine-mediated process? Diabetes 51(10):2951–2958
He W, Barak Y, Hevener A, Olson P, Liao D, Le J, Nelson M, Ong E, Olefsky JM, Evans RM (2003) Adipose-specific peroxisome proliferator-activated receptor gamma knockout causes insulin resistance in fat and liver but not in muscle. Proc Natl Acad Sci U S A 100(26):15712–15717
Item F, Konrad D (2012) Visceral fat and metabolic inflammation: the portal theory revisited. Obes Rev 13(Suppl 2):30–39
Leonardini A, Laviola L, Perrini S, Natalicchio A, Giorgino F (2009) Cross-talk between PPARgamma and insulin signaling and modulation of insulin sensitivity. PPAR Res 2009:818945
Leone TC, Weinheimer CJ, Kelly DP (1999) A critical role for the peroxisome proliferator-activated receptor alpha (PPARalpha) in the cellular fasting response: the PPARalpha-null mouse as a model of fatty acid oxidation disorders. Proc Natl Acad Sci U S A 96(13):7473–7478
List EO, Sackmann-Sala L, Berryman DE, Funk K, Kelder B, Gosney ES, Okada S, Ding J, Cruz-Topete D, Kopchick JJ (2011) Endocrine parameters and phenotypes of the growth hormone receptor gene disrupted (GHR-/-) mouse. Endocr Rev 32(3):356–386
Masternak MM, Bartke A (2007) PPARs in calorie restricted and genetically long-lived mice. PPAR Res 2007:28436
Masternak MM, Al-Regaiey KA, Del Rosario Lim MM, Bonkowski MS, Panici JA, Przybylski GK, Bartke A (2005) Caloric restriction results in decreased expression of peroxisome proliferator-activated receptor superfamily in muscle of normal and long-lived growth hormone receptor/binding protein knockout mice. J Gerontol A Biol Sci Med Sci 60(10):1238–1245
Masternak MM, Bartke A, Wang F, Spong A, Gesing A, Fang Y, Salmon AB, Hughes LF, Liberati T, Boparai R, Kopchick JJ, Westbrook R (2012) Metabolic effects of intra-abdominal fat in GHRKO mice. Aging Cell 11(1):73–81
Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28(7):412–419
Menon V, Zhi X, Hossain T, Bartke A, Spong A, Gesing A, Masternak MM (2014) The contribution of visceral fat to improved insulin signaling in Ames dwarf mice. Aging Cell 13(3):497–506
Nikoulina SE, Ciaraldi TP, Mudaliar S, Mohideen P, Carter L, Henry RR (2000) Potential role of glycogen synthase kinase-3 in skeletal muscle insulin resistance of type 2 diabetes. Diabetes 49(2):263–271
Salih DA, Brunet A (2008) FoxO transcription factors in the maintenance of cellular homeostasis during aging. Curr Opin Cell Biol 20(2):126–136
Shin JA, Jeong SI, Kim M, Yoon JC, Kim HS, Park EM (2015) Visceral adipose tissue inflammation is associated with age-related brain changes and ischemic brain damage in aged mice. Brain Behav Immun 50:221–231
Stout MB, Swindell WR, Zhi X, Rohde K, List EO, Berryman DE, Kopchick JJ, Gesing A, Fang Y, Masternak MM (2015) Transcriptome profiling reveals divergent expression shifts in brown and white adipose tissue from long-lived GHRKO mice. Oncotarget 6(29):26702–26715
Acknowledgements
This work was supported by the National Institute on Aging (NIA) and NIDDK (grant numbers AG031736, AG032290, AG19899, DK081413) and Polish National Science Centre (DEC-2012/04/M/NZ4/00198; grant number 507/1-107-05/507-10-050 of the Medical University of Lodz, Poland to A.G.).
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All the procedures in this study were approved by the Institutional Animal Care and Use Committee of the University of Central Florida.
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Bennis, M.T., Schneider, A., Victoria, B. et al. The role of transplanted visceral fat from the long-lived growth hormone receptor knockout mice on insulin signaling. GeroScience 39, 51–59 (2017). https://doi.org/10.1007/s11357-017-9957-y
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DOI: https://doi.org/10.1007/s11357-017-9957-y