Growth hormone’s impact on adipose tissue and agingGrowth Hormone’s Impact on Adipose Tissue and Aging

Main Article Content

Darlene E. Berryman http://orcid.org/0000-0003-4240-9229 Edward O. List Grace Lach Jonathan A. Young Zoe A. Kington John J. Kopchick

Abstract

A reduction in growth hormone has repeatedly been shown to improve healthspan and lifespan in mice and attenuate age-related conditions in subsets of comparable clinical populations. While aging results in progressive physiological changes in many tissues that leads to declines in biological function, this review will focus on the role of growth hormone in adipose tissue with respect to the aging process. Growth hormone dramatically and uniquely alters adipose tissue mass, composition, function and distribution, with decreases in hormone action resulting in a counterintuitive “healthy obese” state. As clinical studies are somewhat limited, much of our understanding of this hormone’s unique effect on adipose tissue and aging comes from mouse lines with specific alterations to the growth hormone axis. Thus, this review will provide an overview of the healthspan and lifespan consequences of growth hormone action in mouse lines and briefly describe comparable clinical conditions. The review will also summarize the general changes in adipose tissue with normal aging as well as the unique changes in this tissue in response to growth hormone.

Keywords: Growth Hormone, Growth Hormone’s Impact, Aging, Adipose Tissue, Growth Hormone’s Impact on Adipose Tissue, Growth Hormone’s Impact on Aging

Article Details

How to Cite
BERRYMAN, Darlene E. et al. Growth hormone’s impact on adipose tissue and agingGrowth Hormone’s Impact on Adipose Tissue and Aging. Medical Research Archives, [S.l.], v. 11, n. 1, jan. 2023. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/3542>. Date accessed: 21 nov. 2024. doi: https://doi.org/10.18103/mra.v11i1.3542.
Section
Review Articles

References

1. Pilcher H. Money for old mice. Nature. 2003/09/22 2003; doi: 10.1038/news030915-13
2. Arum O, Rickman DJ, Kopchick JJ, Bartke A. The slow-aging growth hormone receptor/binding protein gene-disrupted (GHR-KO) mouse is protected from aging-resultant neuromusculoskeletal frailty. Age (Dordr). Feb 2014;36(1):117-27. doi: 10.1007/s11357-013-9551-x
3. Ikeno Y, Hubbard GB, Lee S, et al. Reduced incidence and delayed occurrence of fatal neoplastic diseases in growth hormone receptor/binding protein knockout mice. J Gerontol A Biol Sci Med Sci. May 2009;64(5):522-9. doi: 10.1093/gerona/glp017
4. Coschigano KT, Holland AN, Riders ME, List EO, Flyvbjerg A, Kopchick JJ. 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. Sep 2003;144(9):3799-810. doi: 10.1210/en.2003-0374
5. Hascup KN, Lynn MK, Fitzgerald PJ, et al. Enhanced Cognition and Hypoglutamatergic Signaling in a Growth Hormone Receptor Knockout Mouse Model of Successful Aging. J Gerontol A Biol Sci Med Sci. Mar 1 2017; 72(3):329-337. doi: 10.1093/gerona/glw088
6. Guevara-Aguirre J, Balasubramanian P, Guevara-Aguirre M, et al. Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans. Sci Transl Med. Feb 16 2011;3(70):70ra13. doi: 10.1126/scitranslmed.3001845
7. Aguiar-Oliveira MH, Bartke A. Growth Hormone Deficiency: Health and Longevity. Endocr Rev. Apr 1 2019;40(2):575-601. doi: 10.1210/er.2018-00216
8. Santos AL, Sinha S. Obesity and aging: Molecular mechanisms and therapeutic approaches. Ageing Res Rev. May 2021; 67:101268. doi: 10.1016/j.arr.2021.101268
9. Qian Y, Berryman DE, Basu R, et al. Mice with gene alterations in the GH and IGF family. Pituitary. Feb 2022;25(1):1-51. doi: 10.1007/s11102-021-01191-y
10. Brooks AJ, Wooh JW, Tunny KA, Waters MJ. Growth hormone receptor; mechanism of action. Int J Biochem Cell Biol. 2008;40(10): 1984-9. doi: 10.1016/j.biocel.2007.07.008
11. Frank SJ. Classical and novel GH receptor signaling pathways. Mol Cell Endocrinol. Dec 1 2020;518:110999. doi: 10.1016/j.mce.2020.110999
12. Troike KM, Henry BE, Jensen EA, et al. Impact of Growth Hormone on Regulation of Adipose Tissue. Compr Physiol. Jun 18 2017; 7(3):819-840. doi: 10.1002/cphy.c160027
13. Vikman K, Carlsson B, Billig H, Eden S. Expression and regulation of growth hormone (GH) receptor messenger ribonucleic acid (mRNA) in rat adipose tissue, adipocytes, and adipocyte precursor cells: GH regulation of GH receptor mRNA. Endocrinology. Sep 1991;129(3):1155-61. doi: 10.1210/endo-129-3-1155
14. Back K, Arnqvist HJ. Changes in insulin and IGF-I receptor expression during differentiation of human preadipocytes. Growth Horm IGF Res. Apr 2009;19(2):101-11. doi: 10.1016/j.ghir.2008.06.004
15. Hattori N. Expression, regulation and biological actions of growth hormone (GH) and ghrelin in the immune system. Growth Horm IGF Res. Jun 2009;19(3):187-97. doi: 10.1016/j.ghir.2008.12.001
16. Bartke A, Sun LY, Longo V. Somatotropic signaling: trade-offs between growth, reproductive development, and longevity. Physiol Rev. Apr 2013;93(2):571-98. doi: 10.1152/physrev.00006.2012
17. Junnila RK, List EO, Berryman DE, Murrey JW, Kopchick JJ. The GH/IGF-1 axis in ageing and longevity. Nat Rev Endocrinol. Jun 2013;9(6):366-376. doi: 10.1038/nrendo.2013.67
18. Snell GD. Dwarf, a New Mendelian Recessive Character of the House Mouse. Proc Natl Acad Sci U S A. Sep 15 1929;15(9):733-4. doi: 10.1073/pnas.15.9.733
19. Bartke A, Westbrook R. Metabolic characteristics of long-lived mice. Front Genet. 2012;3:288. doi: 10.3389/fgene.2012.00288
20. Bartke A, Brown-Borg H. Life extension in the dwarf mouse. Curr Top Dev Biol. 2004; 63:189-225. doi: 10.1016/S0070-2153(04)63006-7
21. Zhou Y, Xu BC, Maheshwari HG, et al. A mammalian model for Laron syndrome produced by targeted disruption of the mouse growth hormone receptor/binding protein gene (the Laron mouse). Proc Natl Acad Sci U S A. Nov 25 1997;94(24):13215-20. doi: 10.1073/pnas.94.24.13215
22. Berryman DE, List EO, Palmer AJ, et al. Two-year body composition analyses of long-lived GHR null mice. J Gerontol A Biol Sci Med Sci. Jan 2010;65(1):31-40. doi: 10.1093/gerona/glp175
23. List EO, Berryman DE, Buchman M, et al. GH Knockout Mice Have Increased Subcutaneous Adipose Tissue With Decreased Fibrosis and Enhanced Insulin Sensitivity. Endocrinology. Jul 1 2019;160(7): 1743-1756. doi: 10.1210/en.2019-00167
24. Palmiter RD, Brinster RL. Germ-line transformation of mice. Annu Rev Genet. 1986;20:465-99. doi: 10.1146/annurev.ge.20.120186.002341
25. Kopchick JJ, Bellush LL, Coschigano KT. Transgenic models of growth hormone action. Annu Rev Nutr. 1999;19:437-61. doi: 10.1146/annurev.nutr.19.1.437
26. Palmer AJ, Chung MY, List EO, et al. Age-related changes in body composition of bovine growth hormone transgenic mice. Endocrinology. Mar 2009;150(3):1353-60. doi: 10.1210/en.2008-1199
27. Bartke A. Can growth hormone (GH) accelerate aging? Evidence from GH-transgenic mice. Neuroendocrinology. Oct 2003;78(4):210-6. doi: 10.1159/000073704
28. Chen WY, White ME, Wagner TE, Kopchick JJ. Functional antagonism between endogenous mouse growth hormone (GH) and a GH analog results in dwarf transgenic mice. Endocrinology. Sep 1991;129(3):1402-8. doi: 10.1210/endo-129-3-1402
29. Yang T, Householder LA, Lubbers ER, et al. Growth hormone receptor antagonist transgenic mice are protected from hyperinsulinemia and glucose intolerance despite obesity when placed on a HF diet. Endocrinology. Feb 2015;156(2):555-64. doi: 10.1210/en.2014-1617
30. Luque RM, Lin Q, Cordoba-Chacon J, et al. Metabolic impact of adult-onset, isolated, growth hormone deficiency (AOiGHD) due to destruction of pituitary somatotropes. PLoS One. Jan 19 2011;6(1):e15767. doi: 10.1371/journal.pone.0015767
31. Poudel SB, Dixit M, Yildirim G, et al. Sexual dimorphic impact of adult-onset somatopause on life span and age-induced osteoarthritis. Aging Cell. Aug 2021;20(8): e13427. doi: 10.1111/acel.13427
32. Junnila RK, Duran-Ortiz S, Suer O, et al. Disruption of the GH Receptor Gene in Adult Mice Increases Maximal Lifespan in Females. Endocrinology. Dec 2016;157(12):4502-4513. doi: 10.1210/en.2016-1649
33. Duran-Ortiz S, List EO, Ikeno Y, et al. Growth hormone receptor gene disruption in mature-adult mice improves male insulin sensitivity and extends female lifespan. Aging Cell. Dec 2021;20(12):e13506. doi: 10.1111/acel.13506
34. List EO, Berryman DE, Buchman M, et al. Adipocyte-Specific GH Receptor-Null (AdGHRKO) Mice Have Enhanced Insulin Sensitivity With Reduced Liver Triglycerides. Endocrinology. Jan 1 2019;160(1):68-80. doi: 10.1210/en.2018-00850
35. List EO, Berryman DE, Slyby J, et al. Disruption of Growth Hormone Receptor in Adipocytes Improves Insulin Sensitivity and Lifespan in Mice. Endocrinology. Oct 1 2022;163(10)doi: 10.1210/endocr/bqac129
36. Laron Z, Klinger B. Laron syndrome: clinical features, molecular pathology and treatment. Horm Res. 1994;42(4-5):198-202. doi: 10.1159/000184193
37. Goncalves FT, Fridman C, Pinto EM, et al. The E180splice mutation in the GHR gene causing Laron syndrome: witness of a Sephardic Jewish exodus from the Iberian Peninsula to the New World? Am J Med Genet A. May 2014;164A(5):1204-8. doi: 10.1002/ajmg.a.36444
38. Guevara-Aguirre J, Rosenbloom AL. Obesity, diabetes and cancer: insight into the relationship from a cohort with growth hormone receptor deficiency. Diabetologia. Jan 2015;58(1):37-42. doi: 10.1007/s00125-014-3397-3
39. Steuerman R, Shevah O, Laron Z. Congenital IGF1 deficiency tends to confer protection against post-natal development of malignancies. Eur J Endocrinol. Apr 2011; 164(4):485-9. doi: 10.1530/EJE-10-0859
40. Laron Z. The GH-IGF1 axis and longevity. The paradigm of IGF1 deficiency. Hormones (Athens). Jan-Mar 2008;7(1):24-7. doi: 10.14310/horm.2002.1111034
41. Alatzoglou KS, Dattani MT. Genetic causes and treatment of isolated growth hormone deficiency-an update. Nat Rev Endocrinol. Oct 2010;6(10):562-76. doi: 10.1038/nrendo.2010.147
42. Oliveira CR, Salvatori R, Barreto-Filho JA, et al. Insulin sensitivity and beta-cell function in adults with lifetime, untreated isolated growth hormone deficiency. J Clin Endocrinol Metab. Mar 2012;97(3):1013-9. doi: 10.1210/jc.2011-2590
43. Holdaway IM, Rajasoorya RC, Gamble GD. Factors influencing mortality in acromegaly. J Clin Endocrinol Metab. Feb 2004;89(2):667-74. doi: 10.1210/jc.2003-031199
44. Ruchala M, Wolinski K. Health-Related Complications of Acromegaly-Risk of Malignant Neoplasms. Front Endocrinol (Lausanne). 2019;10:268. doi: 10.3389/fendo.2019.00268
45. Colao A, Ferone D, Marzullo P, Lombardi G. Systemic complications of acromegaly: epidemiology, pathogenesis, and management. Endocr Rev. Feb 2004;25(1):102-52. doi: 10.1210/er.2002-0022
46. Holdaway IM, Bolland MJ, Gamble GD. A meta-analysis of the effect of lowering serum levels of GH and IGF-I on mortality in acromegaly. Eur J Endocrinol. Aug 2008;159 (2):89-95. doi: 10.1530/EJE-08-0267
47. Raguso CA, Kyle U, Kossovsky MP, et al. A 3-year longitudinal study on body composition changes in the elderly: role of physical exercise. Clin Nutr. Aug 2006;25(4): 573-80. doi: 10.1016/j.clnu.2005.10.013
48. Jungert A, Eichner G, Neuhauser-Berthold M. Trajectories of Body Composition during Advanced Aging in Consideration of Diet and Physical Activity: A 20-Year Longitudinal Study. Nutrients. Nov 25 2020; 12(12)doi: 10.3390/nu12123626
49. Hughes VA, Frontera WR, Roubenoff R, Evans WJ, Singh MA. Longitudinal changes in body composition in older men and women: role of body weight change and physical activity. Am J Clin Nutr. Aug 2002;76(2):473-81. doi: 10.1093/ajcn/76.2.473
50. Palliyaguru DL, Shiroma EJ, Nam JK, et al. Fasting blood glucose as a predictor of mortality: Lost in translation. Cell Metab. Nov 2 2021;33(11):2189-2200 e3. doi: 10.1016/j.cmet.2021.08.013
51. Sackmann-Sala L, Berryman DE, Lubbers ER, et al. Decreased insulin sensitivity and increased oxidative damage in wasting adipose tissue depots of wild-type mice. Age (Dordr). Oct 2012;34(5):1225-37. doi: 10.1007/s11357-011-9304-7
52. Kuk JL, Saunders TJ, Davidson LE, Ross R. Age-related changes in total and regional fat distribution. Ageing Res Rev. Oct 2009;8 (4):339-48. doi: 10.1016/j.arr.2009.06.001
53. Schwartz RS, Shuman WP, Bradbury VL, et al. Body fat distribution in healthy young and older men. J Gerontol. Nov 1990;45(6): M181-5. doi: 10.1093/geronj/45.6.m181
54. Von Bank H, Kirsh C, Simcox J. Aging adipose: Depot location dictates age-associated expansion and dysfunction. Ageing Res Rev. May 2021;67:101259. doi: 10.1016/j.arr.2021.101259
55. Liu R, Pulliam DA, Liu Y, Salmon AB. Dynamic differences in oxidative stress and the regulation of metabolism with age in visceral versus subcutaneous adipose. Redox Biol. Dec 2015;6:401-408. doi: 10.1016/j.redox.2015.07.014
56. Cartwright MJ, Tchkonia T, Kirkland JL. Aging in adipocytes: potential impact of inherent, depot-specific mechanisms. Exp Gerontol. Jun 2007;42(6):463-71. doi: 10.1016/j.exger.2007.03.003
57. Petr MA, Alfaras I, Krawcyzk M, et al. A cross-sectional study of functional and metabolic changes during aging through the lifespan in male mice. Elife. Apr 20 2021;10. doi: 10.7554/eLife.62952
58. Matacchione G, Perugini J, Di Mercurio E, et al. Senescent macrophages in the human adipose tissue as a source of inflammaging. Geroscience. Aug 2022;44(4):1941-1960. doi: 10.1007/s11357-022-00536-0
59. Tchkonia T, Morbeck DE, Von Zglinicki T, et al. Fat tissue, aging, and cellular senescence. Aging Cell. Oct 2010;9(5):667-84. doi: 10.1111/j.1474-9726.2010.00608.x
60. Schaum N, Lehallier B, Hahn O, et al. Ageing hallmarks exhibit organ-specific temporal signatures. Nature. Jul 2020;583 (7817):596-602. doi: 10.1038/s41586-020-2499-y
61. Camell CD, Gunther P, Lee A, et al. Aging Induces an Nlrp3 Inflammasome-Dependent Expansion of Adipose B Cells That Impairs Metabolic Homeostasis. Cell Metab. Dec 3 2019;30(6):1024-1039 e6. doi: 10.1016/j.cmet.2019.10.006
62. Cruz-Migoni S, Caamano J. Fat-Associated Lymphoid Clusters in Inflammation and Immunity. Front Immunol. 2016;7:612. doi: 10.3389/fimmu.2016.00612
63. Lee G, Kim YY, Jang H, et al. SREBP1c-PARP1 axis tunes anti-senescence activity of adipocytes and ameliorates metabolic imbalance in obesity. Cell Metab. May 3 2022;34(5):702-718 e5. doi: 10.1016/j.cmet.2022.03.010
64. Barinda AJ, Ikeda K, Nugroho DB, et al. Publisher Correction: Endothelial progeria induces adipose tissue senescence and impairs insulin sensitivity through senescence associated secretory phenotype. Nat Commun. Jul 28 2020;11(1):3837. doi: 10.1038/s41467-020-17695-3
65. Doshida Y, Sano H, Iwabuchi S, et al. Age-associated changes in the transcriptomes of non-cultured adipose-derived stem cells from young and old mice assessed via single-cell transcriptome analysis. PLoS One. 2020; 15(11):e0242171. doi: 10.1371/journal.pone.0242171
66. Maredziak M, Marycz K, Tomaszewski KA, Kornicka K, Henry BM. The Influence of Aging on the Regenerative Potential of Human Adipose Derived Mesenchymal Stem Cells. Stem Cells Int. 2016;2016:2152435. doi: 10.1155/2016/2152435
67. Hall BM, Gleiberman AS, Strom E, et al. Immune checkpoint protein VSIG4 as a biomarker of aging in murine adipose tissue. Aging Cell. Oct 2020;19(10):e13219. doi: 10.1111/acel.13219
68. Donato AJ, Henson GD, Hart CR, et al. The impact of ageing on adipose structure, function and vasculature in the B6D2F1 mouse: evidence of significant multisystem dysfunction. J Physiol. Sep 15 2014;592(18): 4083-96. doi: 10.1113/jphysiol.2014.274175
69. Zhang L, Ebenezer PJ, Dasuri K, et al. Aging is associated with hypoxia and oxidative stress in adipose tissue: implications for adipose function. Am J Physiol Endocrinol Metab. Oct 2011;301(4):E599-607. doi: 10.1152/ajpendo.00059.2011
70. Djian P, Roncari AK, Hollenberg CH. Influence of anatomic site and age on the replication and differentiation of rat adipocyte precursors in culture. J Clin Invest. Oct 1983;72(4):1200-8. doi: 10.1172/JCI111075
71. White UA, Fitch MD, Beyl RA, Hellerstein MK, Ravussin E. Racial differences in in vivo adipose lipid kinetics in humans. J Lipid Res. Sep 2018;59(9):1738-1744. doi: 10.1194/jlr.P082628
72. Varghese M, Song J, Singer K. Age and Sex: Impact on adipose tissue metabolism and inflammation. Mech Ageing Dev. Oct 2021;199:111563. doi: 10.1016/j.mad.2021.111563
73. Yaghootkar H, Whitcher B, Bell JD, Thomas EL. Ethnic differences in adiposity and diabetes risk - insights from genetic studies. J Intern Med. Sep 2020;288(3):271-283. doi: 10.1111/joim.13082
74. De Boer H, Blok GJ, Voerman HJ, De Vries PM, van der Veen EA. Body composition in adult growth hormone-deficient men, assessed by anthropometry and bioimpedance analysis. J Clin Endocrinol Metab. Sep 1992;75(3):833-7. doi: 10.1210/jcem.75.3.1517374
75. Rodriguez-Arnao J, Jabbar A, Fulcher K, Besser GM, Ross RJ. Effects of growth hormone replacement on physical performance and body composition in GH deficient adults. Clin Endocrinol (Oxf). Jul 1999;51(1):53-60. doi: 10.1046/j.1365-2265.1999.00737.x
76. Laron Z, Kauli R. Fifty seven years of follow-up of the Israeli cohort of Laron Syndrome patients-From discovery to treatment. Growth Horm IGF Res. Jun 2016;28:53-6. doi: 10.1016/j.ghir.2015.08.004
77. Bengtsson BA, Brummer RJ, Eden S, Bosaeus I. Body composition in acromegaly. Clin Endocrinol (Oxf). Feb 1989;30(2):121-30. doi: 10.1111/j.1365-2265.1989.tb03733.x
78. Berryman DE, List EO, Coschigano KT, Behar K, Kim JK, Kopchick JJ. Comparing adiposity profiles in three mouse models with altered GH signaling. Growth Horm IGF Res. Aug 2004;14(4):309-18. doi: 10.1016/j.ghir.2004.02.005
79. Berryman DE, List EO, Kohn DT, Coschigano KT, Seeley RJ, Kopchick JJ. Effect of growth hormone on susceptibility to diet-induced obesity. Endocrinology. Jun 2006; 147(6):2801-8. doi: 10.1210/en.2006-0086
80. Olsson B, Bohlooly YM, Fitzgerald SM, et al. Bovine growth hormone transgenic mice are resistant to diet-induced obesity but develop hyperphagia, dyslipidemia, and diabetes on a high-fat diet. Endocrinology. Feb 2005;146(2):920-30. doi: 10.1210/en.2004-1232
81. Householder LA, Comisford R, Duran-Ortiz S, et al. Increased fibrosis: A novel means by which GH influences white adipose tissue function. Growth Horm IGF Res. Apr 2018;39:45-53. doi: 10.1016/j.ghir.2017.12.010
82. Benencia F, Harshman S, Duran-Ortiz S, et al. Male bovine GH transgenic mice have decreased adiposity with an adipose depot-specific increase in immune cell populations. Endocrinology. May 2015;156(5):1794-803. doi: 10.1210/en.2014-1794
83. Duran-Ortiz S, Young JA, Jara A, et al. Differential gene signature in adipose tissue depots of growth hormone transgenic mice. J Neuroendocrinol. Nov 2020;32(11):e12893. doi: 10.1111/jne.12893
84. Lubbers ER, List EO, Jara A, et al. Adiponectin in mice with altered GH action: links to insulin sensitivity and longevity? J Endocrinol. Mar 2013;216(3):363-74. doi: 10.1530/JOE-12-0505
85. Olarescu NC, Berryman DE, Householder LA, et al. GH action influences adipogenesis of mouse adipose tissue-derived mesenchymal stem cells. J Endocrinol. Jul 2015;226(1):13-23. doi: 10.1530/JOE-15-0012
86. Stout MB, Tchkonia T, Pirtskhalava T, et al. Growth hormone action predicts age-related white adipose tissue dysfunction and senescent cell burden in mice. Aging (Albany NY). Jul 2014;6(7):575-86. doi: 10.18632/aging.100681
87. Lee MJ, Fried SK. Sex-dependent Depot Differences in Adipose Tissue Development and Function; Role of Sex Steroids. J Obes Metab Syndr. Sep 2017;26(3):172-180. doi: 10.7570/jomes.2017.26.3.172
88. Kahn CR, Wang G, Lee KY. Altered adipose tissue and adipocyte function in the pathogenesis of metabolic syndrome. J Clin Invest. Oct 1 2019;129(10):3990-4000. doi: 10.1172/JCI129187
89. Stout MB, Swindell WR, Zhi X, et al. Transcriptome profiling reveals divergent expression shifts in brown and white adipose tissue from long-lived GHRKO mice. Oncotarget. Sep 29 2015;6(29):26702-15. doi: 10.18632/oncotarget.5760
90. Berryman DE, List EO. Growth Hormone's Effect on Adipose Tissue: Quality versus Quantity. Int J Mol Sci. Jul 26 2017;18(8) doi: 10.3390/ijms18081621
91. Comisford R, Lubbers ER, Householder LA, et al. Growth Hormone Receptor Antagonist Transgenic Mice Have Increased Subcutaneous Adipose Tissue Mass, Altered Glucose Homeostasis and No Change in White Adipose Tissue Cellular Senescence. Gerontology. 2016;62(2):163-72. doi: 10.1159/000439050
92. Young JA, Henry BE, Benencia F, et al. GHR(-/-) Mice are protected from obesity-related white adipose tissue inflammation. J Neuroendocrinol. Nov 2020;32(11):e12854.doi: 10.1111/jne.12854
93. Masternak MM, Bartke A, Wang F, et al. Metabolic effects of intra-abdominal fat in GHRKO mice. Aging Cell. Feb 2012;11(1):73-81. doi: 10.1111/j.1474-9726.2011.00763.x
94. Menon V, Zhi X, Hossain T, et al. The contribution of visceral fat to improved insulin signaling in Ames dwarf mice. Aging Cell. Jun 2014;13(3):497-506. doi: 10.1111/acel.12201
95. Spadaro O, Goldberg EL, Camell CD, et al. Growth Hormone Receptor Deficiency Protects against Age-Related NLRP3 Inflammasome Activation and Immune Senescence. Cell Rep. Feb 23 2016;14(7): 1571-1580. doi: 10.1016/j.celrep.2016.01.044
96. Liu Z, Wu KKL, Jiang X, Xu A, Cheng KKY. The role of adipose tissue senescence in obesity- and ageing-related metabolic disorders. Clin Sci (Lond). Jan 31 2020;134(2): 315-330. doi: 10.1042/CS20190966
97. Li Y, Knapp JR, Kopchick JJ. Enlargement of interscapular brown adipose tissue in growth hormone antagonist transgenic and in growth hormone receptor gene-disrupted dwarf mice. Exp Biol Med (Maywood). Feb 2003;228(2):207-15. doi: 10.1177/153537020322800212
98. Darcy J, McFadden S, Bartke A. Altered structure and function of adipose tissue in long-lived mice with growth hormone-related mutations. Adipocyte. Apr 3 2017;6(2):69-75. doi: 10.1080/21623945.2017.1308990
99. Duran-Ortiz S, Noboa V, Kopchick JJ. Disruption of the GH receptor gene in adult mice and in insulin sensitive tissues. Growth Horm IGF Res. Feb 2018;38:3-7. doi: 10.1016/j.ghir.2017.11.003
100. Young J, Bell S, Qian Y, Hyman C, Berryman DE. Mouse models of growth hormone insensitivity. Rev Endocr Metab Disord. Mar 2021;22(1):17-29. doi: 10.1007/s11154-020-09600-6
101. Kopchick JJ, Berryman DE, Puri V, Lee KY, Jorgensen JOL. The effects of growth hormone on adipose tissue: old observations, new mechanisms. Nat Rev Endocrinol. Mar 2020;16(3):135-146. doi: 10.1038/s41574-019-0280-9
102. List EO, Duran-Ortiz S, Kopchick JJ. Effects of tissue-specific GH receptor knockouts in mice. Mol Cell Endocrinol. Sep 15 2020;515:110919. doi: 10.1016/j.mce.2020.110919
103. Brooks NE, Hjortebjerg R, Henry BE, List EO, Kopchick JJ, Berryman DE. Fibroblast growth factor 21, fibroblast growth factor receptor 1, and beta-Klotho expression in bovine growth hormone transgenic and growth hormone receptor knockout mice. Growth Horm IGF Res. Oct - Dec 2016;30-31:22-30. doi: 10.1016/j.ghir.2016.08.003
104. Bolamperti S, Guidobono F, Rubinacci A, Villa I. The Role of Growth Hormone in Mesenchymal Stem Cell Commitment. Int J Mol Sci. Oct 23 2019;20(21). doi: 10.3390/ijms20215264
105. Ran L, Wang X, Mi A, et al. Loss of Adipose Growth Hormone Receptor in Mice Enhances Local Fatty Acid Trapping and Impairs Brown Adipose Tissue Thermogenesis. iScience. Jun 28 2019;16: 106-121. doi: 10.1016/j.isci.2019.05.020
106. Duran-Ortiz S, Bell S, Kopchick JJ. Standardizing protocols dealing with growth hormone receptor gene disruption in mice using the Cre-lox system. Growth Horm IGF Res. Oct-Dec 2018;42-43:52-57. doi: 10.1016/j.ghir.2018.08.003
107. Berryman DE, Lubbers ER, Magon V, List EO, Kopchick JJ. A dwarf mouse model with decreased GH/IGF-1 activity that does not experience life-span extension: potential impact of increased adiposity, leptin, and insulin with advancing age. J Gerontol A Biol Sci Med Sci. Feb 2014;69(2):131-41. doi: 10.1093/gerona/glt069
108. Hill CM, Fang Y, Miquet JG, Sun LY, Masternak MM, Bartke A. Long-lived hypopituitary Ames dwarf mice are resistant to the detrimental effects of high-fat diet on metabolic function and energy expenditure. Aging Cell. Jun 2016;15(3):509-21. doi: 10.1111/acel.12467
109. Darcy J, McFadden S, Fang Y, et al. Brown Adipose Tissue Function Is Enhanced in Long-Lived, Male Ames Dwarf Mice. Endocrinology. Dec 2016;157(12):4744-4753. doi: 10.1210/en.2016-1593
110. Hunter WS, Croson WB, Bartke A, Gentry MV, Meliska CJ. Low body temperature in long-lived Ames dwarf mice at rest and during stress. Physiol Behav. Sep 1999;67(3):433-7. doi: 10.1016/s0031-9384(99)00098-0
111. List EO, Basu R, Duran-Ortiz S, Krejsa J, Jensen EA. Mouse models of growth hormone deficiency. Rev Endocr Metab Disord. Mar 2021;22(1):3-16. doi: 10.1007/s11154-020-09601-5
112. Li X, Frazier JA, Spahiu E, McPherson M, Miller RA. Muscle-dependent regulation of adipose tissue function in long-lived growth hormone-mutant mice. Aging (Albany NY). May 28 2020;12(10):8766-8789. doi: 10.18632/aging.103380
113. Longo VD, Antebi A, Bartke A, et al. Interventions to Slow Aging in Humans: Are We Ready? Aging Cell. Aug 2015;14(4):497-510. doi: 10.1111/acel.12338