Abstract
The glucocorticoid hormones alter the metabolism of the adipose tissue after an approximately 2-h lag period. The effects are mediated through the nuclear receptors that alter the expression of a wide variety of genes through the mechanisms that are similar to those seen in the other cells. There are many direct metabolic effects of the glucocorticoids on the adipose tissue metabolism, and every year, new effects are added to the list of proteins whose expression is influenced by the glucocorticoids. Furthermore, some enzymatic processes are affected by these hormones only in the presence of the other hormones such as growth hormone (GH) or insulin. Most of the effects of the glucocorticoids are on the gene transcription, and the effects on the mRNA are reflected in the altered levels of the target proteins. The glucocorticoids enhance the leptin release, while reducing that of the inflammatory adipokines and stimulating that of the lipoprotein lipase (LPL) in the presence of insulin. The activity of 11β-hydroxysteroid dehydrogenase type 1 (HSD1) is enhanced by the glucocorticoids along with that of α1 glycoprotein 1 and serum amyloid A release by the adipose tissue. In contrast, the tumor necrosis factor α (TNF)-stimulated lipolysis in the adipose tissue is blocked by the glucocorticoids. It is still unclear which, if any, of these effects account for the insulin resistance due to the glucocorticoids in the adipose tissue. However, recent work suggests that, at least in mice, the reduction in the osteocalcin release by the osteoblasts in the presence of the glucocorticoids accounts for much of the in vivo insulin resistance. In summary, there are multiple direct effects of the glucocorticoids, both anti-inflammatory and proinflammatory, on the adipose tissue.
The work was supported, in part, by the Cardiometabolic Research Foundation of Los Angeles CA, USA. The author does not have any conflict of interest related to this manuscript.
References
1. Yang N, Ray DW, Matthews LC. Current concepts in glucocorticoid resistance. Steroids 2012;77:1041–9.10.1016/j.steroids.2012.05.007Search in Google Scholar
2. Laskewitz AJ, van Dijk TH, Grefhorst A, van Lierop MJ, Schreurs M, Bloks VW, Reijngoud DJ, Dokter WH, Kuipers F, Groen AK. Chronic prednisolone treatment aggravates hyperglycemia in mice fed a high-fat diet but does not worsen dietary fat-induced insulin resistance. Endocrinology 2012;153:3713–23.10.1210/en.2011-1891Search in Google Scholar
3. van Lierop MJ, Alkema W, Laskewitz AJ, Dijkema R, van der Maaden HM, Smit MJ, Plate R, Conti PG, Jans CG, Timmers CM, van Boeckel CA, Lusher SJ, McGuire R, van Schaik RC, de Vlieg J, Smeets RL, Hofstra CL, Boots AM, van Duin M, Ingelse BA, Schoonen WG, Grefhorst A, van Dijk TH, Kuipers F, Dokter WH. Org 214007–0: A novel non-steroidal selective glucocorticoid receptor modulator with full anti-inflammatory properties and improved therapeutic index. PLoS One 2012;7:e48385.10.1371/journal.pone.0048385Search in Google Scholar
4. Fain JN. Effects of dexamethasone and growth hormone on fatty acid mobilization and glucose utilization in adrenalectomized rats. Endocrinology 1962;71:633–5.10.1210/endo-71-4-633Search in Google Scholar
5. Fain JN, Scow RO, Chernick SS. Effects of glucocorticoids on metabolism of adipose tissue in vitro. J Biol Chem 1962;238:54–8.10.1016/S0021-9258(19)83960-1Search in Google Scholar
6. Fain JN, Kovacev VP, Scow RO. Effect of growth hormone and dexamethasone on lipolysis and metabolism in isolated fat cells of the rat. J Biol Chem 1965;240:3522–9.10.1016/S0021-9258(18)97175-9Search in Google Scholar
7. Fain JN, Cheema P, Tichansky DS, Madan AK. Stimulation of human omental adipose tissue lipolysis by growth hormone plus dexamethasone. Mol Cell Endocrinol 2008;295:101–5.10.1016/j.mce.2008.05.014Search in Google Scholar PubMed
8. Fain JN, Cheema P, Maden AK, Tichansky DS. Dexamethasone and the inflammatory response in explants of human omental adipose tissue. Mol Cell Endocrinol 2012;315:292–8.10.1016/j.mce.2009.10.004Search in Google Scholar PubMed
9. Fain JN. Release of inflammatory mediators by human adipose tissue is enhanced in obesity and primarily by the nonfat cells: a review. Mediators Inflamm 2010;2010:513948.10.1155/2010/513948Search in Google Scholar PubMed PubMed Central
10. Fried SK, Russell CD, Grauso NL, Brolin RE. Lipoprotein lipase regulation by insulin and glucocorticoid in subcutaneous and omental adipose tissues of obese women and men. J Clin Invest 1993;92:2191–8.10.1172/JCI116821Search in Google Scholar PubMed PubMed Central
11. Kim JK, Fillmore JJ, Chen Y, Yu C, Moore IK, Pypaert M, Lutz EP, Kako Y, Velez-Carrasco W, Goldberg IJ, Breslow JL, Shulman GI. Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance. Proc Natl Acad Sci USA 2001;98:7522–7.10.1073/pnas.121164498Search in Google Scholar PubMed PubMed Central
12. Morton NM. Obesity and corticosteroids: 11 β-hydroxysteroid type 1 as a cause and therapeutic target in metabolic disease. Mol Cell Endocrinol 2010;316:154–64.10.1016/j.mce.2009.09.024Search in Google Scholar PubMed
13. Purnell JQ, Kahn SE, Samuels MH, Brandon D, Loriaux DL, Brunzell JD. Enhanced cortisol production rates, free cortisol, and 11β-HSD-1 expression correlate with visceral fat and insulin resistance in men: effect of weight loss. Am J Physiol Endocrinol Metab 2009;296:E351–7.10.1152/ajpendo.90769.2008Search in Google Scholar PubMed PubMed Central
14. Wolf G. Glucocorticoids in adipocytes stimulate visceral obesity. Nutr Rev 2002;60:148–51.10.1301/00296640260093823Search in Google Scholar PubMed
15. Veyrat-Durebex C, Deblon N, Caillon A, Andrew R, Altirriba J, Odermatt A, Rohner-Jeanrenaud F. Central glucocorticoid administration promotes weight gain and increased 11β-hydroxysteroid dehydrogenase type 1 expression in white adipose tissue. PLoS One 2012;7:e34002.10.1371/journal.pone.0034002Search in Google Scholar PubMed PubMed Central
16. Balachandran A, Guan H, Sellan M, van Uum S, Yang K. Insulin and dexamethasone dynamically regulate adipocyte 11β-hydroxysteroid dehydrogenase type 1. Endocrinol 2008;149:4069–79.10.1210/en.2008-0088Search in Google Scholar PubMed PubMed Central
17. Wamil M, Battle JH, Turban S, Kipari T, Seguret D, de Sousa Peixoto R, Nelson YB, Nowakowska D, Ferenbach D, Ramage L, Chapman KE, Hughes J, Dunbar DR, Seckl JR, Morton NM. Novel fat depot-specific mechanisms underlie resistance to visceral obesity and inflammation in 11β-hydroxysteroid dehydrogenase type 1-deficient mice. Diabetes 2011; 60:1158–67.10.2337/db10-0830Search in Google Scholar PubMed PubMed Central
18. Staab CA, Maser E. 11β-hydroxysteroid dehydrogenase type 1 is an important regulator at the interface of obesity and inflammation. J Steroid Biochem Mol Biol 2010;119:56–72.10.1016/j.jsbmb.2009.12.013Search in Google Scholar PubMed
19. Lee MJ, Fried SK. Glucocorticoids antagonize tumor necrosis factor-α-stimulated lipolysis and resistance to the antilipolytic effect of insulin in human adipocytes. Am J Physiol Endocrinol Metab 2012;303:E1126–33.10.1152/ajpendo.00228.2012Search in Google Scholar PubMed PubMed Central
20. Zhang HH, Kumar S, Barnett AH, Eggo MC. Dexamethasone inhibits tumor necrosis factor-α-induced apoptosis and interleukin-1β release in human subcutaneous adipocytes and preadipocytes. J Clin Endocrinol Metab 2001;86:2817–25.Search in Google Scholar
21. Trujillo ME, Lee MJ, Sullivan S, Feng J, Schneider SH, Greenberg AS, Fried SK. Tumor necrosis factor α and glucocorticoid synergistically increase leptin production in human adipose tissue: role for p38 mitogen-activated protein kinase. J Clin Endocrinol Metab 2006;91:1484–90.10.1210/jc.2005-1901Search in Google Scholar PubMed
22. Fain JN, Bahouth SW. Regulation of leptin release by mammalian adipose tissue. Biochem Biophys Res Commun 2000;274:571–5.10.1006/bbrc.2000.3168Search in Google Scholar
23. Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Speigelman BM. Increased adipose tissue expression of tumor necrosis factor-α in human obesity and insulin resistance. J Clin Invest 1995;95:2409–15.10.1172/JCI117936Search in Google Scholar
24. Lo J, Bernstein LE, Canavan B, Torriani M, Jackson MB, Ahima RS, Grinspoon SK. Effects of TNF-α neutralization on adipocytokines and skeletal muscle adiposity in the metabolic syndrome. Am J Physiol Endocrinol Metab 2007;293:E102–9.10.1152/ajpendo.00089.2007Search in Google Scholar
25. Karpe F. Dickmann JR, Frayn KN. Fatty acids, obesity, and insulin resistance: time for reevaluation. Diabetes 2011;60:2441–9.10.2337/db11-0425Search in Google Scholar
26. Magkos F, Fabbrini E, Conte C, Patterson BW, Klein S. Relationship between adipose tissue lipolytic activity and skeletal muscle insulin resistance in nondiabetic women. J Clin Endocrinol Metab 2012;97:E1219–23.10.1210/jc.2012-1035Search in Google Scholar
27. Kim JJ, Sears DD. TLR4 and insulin resistance. Gastroenterol Res Pract 2010;2010:212563.Search in Google Scholar
28. Fessler MB, Rudel LL, Brown JM. Toll-like receptor signaling links dietary fatty acids to the metabolic syndrome. Curr Opin Lipidol 2009;20:379–85.10.1097/MOL.0b013e32832fa5c4Search in Google Scholar
29. Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS. TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest 2006;116:3015–25.10.1172/JCI28898Search in Google Scholar
30. Fain JN. Correlative studies on the effects of obesity, diabetes and hypertension on gene expression in omental adipose tissue of obese women. Nutr Diabetes 2011;1:e17.10.1038/nutd.2011.14Search in Google Scholar
31. Fournier T, Medjoubi NN, Porquet D. α-1-acid glycoprotein. Biochim Biophys Acta 2000;1482:175–1.10.1016/S0167-4838(00)00153-9Search in Google Scholar
32. Lin Y, Rajala MW, Berger JP, Moller DE, Barzilai N, Scherer PE. Hyperglycemia-induced production of acute phase reactants in adipose tissue. J Biol Chem 2001;276:42077–83.10.1074/jbc.M107101200Search in Google Scholar PubMed
33. Lee YS, Choi JW, Hwang I, Lee JW, Lee JH, Kim AY, Huh JY, Koh YJ, Koh GY, Son HJ, Masuzaki H, Hotta K, Alfadda AA, Kim JB. Adipocytokine orosomucoid integrates inflammatory and metabolic signals to preserve energy homeostasis by resolving immoderate inflammation. J Biol Chem 2010;285:22174–85.10.1074/jbc.M109.085464Search in Google Scholar PubMed PubMed Central
34. Alfadda AA, Fatma S, Chishti MA, Al-Naami MY, Elawad R, Mendoza CD, Jo H, Lee YS. Orosomucoid serum concentrations and fat depot-specific mRNA and protein expression in humans. Mol Cells 2012;33:35–41.10.1007/s10059-012-2181-9Search in Google Scholar PubMed PubMed Central
35. Uhlar CM, Whitehead AS. Serum amyloid A, the major vertebrate acute-phase reactant. Eur J Biochem 1999;265:501–23.10.1046/j.1432-1327.1999.00657.xSearch in Google Scholar PubMed
36. Poitou C, Viguerie N, Cancello R, De Matteis R, Cinti S, Stich V, Coussieu C, Gauthier E, Courtine M, Zucker JD, Barsh GS, Saris W, Bruneval P, Basdevant A, Langin D, Clement K. Serum amyloid A: production by human white adipocyte and regulation by obesity and nutrition. Diabetologia 2005;48:519–28.10.1007/s00125-004-1654-6Search in Google Scholar PubMed
37. Lee MJ, Gong DW, Burkey BF, Fried SK. Pathways regulated by glucocorticoids in omental and subcutaneous human adipose tissues: a microarray study. Am J Physiol Endocrinol Metab 2011;300:E571–80.10.1152/ajpendo.00231.2010Search in Google Scholar PubMed PubMed Central
38. Yang RZ, Lee MJ, Hu H, Pollin TI, Ryan AS, Nicklas BJ, Snitker S, Horenstein RB, Hull K, Goldberg NH, Goldberg AP, Shuldiner SR, Fried SK, Gong DW. Acute-phase amyloid A: an inflammatory adipokine and potential link between obesity and its metabolic complications. PLoS Med 2006;3:e287.10.1371/journal.pmed.0030287Search in Google Scholar PubMed PubMed Central
39. Siklova-Vitkova M, Klimcakova E, Polak J, Kovacova Z, Tencerova M, Rossmeislova L, Bajzova M, Langin D, Stich V. Adipose tissue secretion and expression of adipocyte-produced and stromavascular fraction-produced adipokines vary during multiple phases of weight-reducing dietary intervention in obese women. J Clin Endocrinol Metab 2012;97:E1176–81.10.1210/jc.2011-2380Search in Google Scholar PubMed
40. Faty A, Ferre P, Commans S. The acute phase protein serum amyloid A induces lipolysis and inflammation in human adipocytes through distinct pathways. PLoS One 2012;7:e34031.10.1371/journal.pone.0034031Search in Google Scholar PubMed PubMed Central
41. Filippin-Monteiro FB, de Oliveira EM, Sandri S, Knebel FH, Albuquerque RC, Campa A. Serum amyloid A is a growth factor for 3T3-L1 adipocytes, inhibits differentiation and promotes insulin resistance. Int J Obes (Lond) 2012;36:1032–9.10.1038/ijo.2011.193Search in Google Scholar PubMed PubMed Central
42. Viguerie N, Picard F, Hul G, Roussel B, Barbe P, Iacovoni JS, Valle C, Langin D, Saris WH. Multiple effects of a short-term dexamethasone treatment in human skeletal muscle and adipose tissue. Physiol Genomics 2012;44:141–51.10.1152/physiolgenomics.00032.2011Search in Google Scholar PubMed
43. Pagano G, Cavallo-Perin P, Cassader M, Bruno A, Ozzello A, Masciola P, Dall’omo AM, Imbimbo B. J Clin Invest 1983;72:1814–20.10.1172/JCI111141Search in Google Scholar
44. Binnert C, Ruchat S, Nicod N, Tappy L. Dexamethasone-induced insulin resistance shows no gender difference in healthy humans. Diabetes Metab 2004;30:321–6.10.1016/S1262-3636(07)70123-4Search in Google Scholar
45. Alemany M. Do the interactions between glucocorticoids and sex hormones regulate the development of the metabolic syndrome? Front Endocrinol (Lausanne) 2012;3:27.10.3389/fendo.2012.00027Search in Google Scholar PubMed PubMed Central
46. Chanson P, Salenave S. Metabolic syndrome in Cushing’s syndrome. Neuroendocrinology 2010;92:96–101.10.1159/000314272Search in Google Scholar PubMed
47. Hwang YC, Jeong IK, Ahn KJ, Chung HY. Circulating osteocalcin level is associated with improved glucose tolerance, insulin secretion and sensitivity independent of the plasma adiponectin level. Osteoporos Int 2012;23:1337–42.10.1007/s00198-011-1679-xSearch in Google Scholar PubMed PubMed Central
48. Saleem U, Mosley TH Jr, Kullo IJ. Serum osteocalcin is associated with measures of insulin resistance, adipokine levels, and the presence of metabolic syndrome. Arterioscler Thromb Vasc Biol 2010;30:1474–8.10.1161/ATVBAHA.110.204859Search in Google Scholar PubMed PubMed Central
49. Ferron M, Wei J, Yoshizawa T, Del Fattore A, DePinho RA, Teti A, Ducy P, Karsenty G. Insulin signaling in osteoblasts integrates bone remodeling and energy metabolism. Cell 2010;142: 296–308.10.1016/j.cell.2010.06.003Search in Google Scholar PubMed PubMed Central
50. Brennan-Speranza TC, Henneicke H, Gasparini SJ, Blankenstein KI, Heinevetter U, Cogger VC, Svistounov D, Zhang Y, Cooney GJ, Buttgereit F, Dunstan CR, Gundberg C, Zhou H, Seibel MJ. Osteoblasts mediate the adverse effects of glucocorticoids on fuel metabolism. J Clin Invest 2012;122:4172–89.10.1172/JCI63377Search in Google Scholar PubMed PubMed Central
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