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PLOS ONE  2011 

Regulation of Lipogenesis by Glucocorticoids and Insulin in Human Adipose Tissue

DOI: 10.1371/journal.pone.0026223

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Abstract:

Patients with glucocorticoid (GC) excess, Cushing's syndrome, develop a classic phenotype characterized by central obesity and insulin resistance. GCs are known to increase the release of fatty acids from adipose, by stimulating lipolysis, however, the impact of GCs on the processes that regulate lipid accumulation has not been explored. Intracellular levels of active GC are dependent upon the activity of 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) and we have hypothesized that 11β-HSD1 activity can regulate lipid homeostasis in human adipose tissue (Chub-S7 cell line and primary cultures of human subcutaneous (sc) and omental (om) adipocytes. Across adipocyte differentiation, lipogenesis increased whilst β-oxidation decreased. GC treatment decreased lipogenesis but did not alter rates of β-oxidation in Chub-S7 cells, whilst insulin increased lipogenesis in all adipocyte cell models. Low dose Dexamethasone pre-treatment (5 nM) of Chub-S7 cells augmented the ability of insulin to stimulate lipogenesis and there was no evidence of adipose tissue insulin resistance in primary sc cells. Both cortisol and cortisone decreased lipogenesis; selective 11β-HSD1 inhibition completely abolished cortisone-mediated repression of lipogenesis. GCs have potent actions upon lipid homeostasis and these effects are dependent upon interactions with insulin. These in vitro data suggest that manipulation of GC availability through selective 11β-HSD1 inhibition modifies lipid homeostasis in human adipocytes.

References

[1]  Calle EE, Thun MJ, Petrelli JM, Rodriguez C, Heath CW Jr (1999) Body-mass index and mortality in a prospective cohort of U.S. adults. N Engl J Med 341: 1097–1105.
[2]  Hausman DB, DiGirolamo M, Bartness TJ, Hausman GJ, Martin RJ (2001) The biology of white adipocyte proliferation. Obes Rev 2: 239–254.
[3]  Strawford A, Antelo F, Christiansen M, Hellerstein MK (2004) Adipose tissue triglyceride turnover, de novo lipogenesis, and cell proliferation in humans measured with 2H2O. Am J Physiol Endocrinol Metab 286: E577–E588.
[4]  Ruderman NB, Saha AK, Kraegen EW (2003) Minireview: malonyl CoA, AMP-activated protein kinase, and adiposity. Endocrinology 144: 5166–5171.
[5]  Scott JW, Norman DG, Hawley SA, Kontogiannis L, Hardie DG (2002) Protein kinase substrate recognition studied using the recombinant catalytic domain of AMP-activated protein kinase and a model substrate. J Mol Biol 317: 309–323.
[6]  Hauner H, Schmid P, Pfeiffer EF (1987) Glucocorticoids and insulin promote the differentiation of human adipocyte precursor cells into fat cells. J Clin Endocrinol Metab 64: 832–835.
[7]  Djurhuus CB, Gravholt CH, Nielsen S, Mengel A, Christiansen JS, et al. (2002) Effects of cortisol on lipolysis and regional interstitial glycerol levels in humans. Am J Physiol Endocrinol Metab 283: E172–E177.
[8]  Slavin BG, Ong JM, Kern PA (1994) Hormonal regulation of hormone-sensitive lipase activity and mRNA levels in isolated rat adipocytes. J Lipid Res 35: 1535–1541.
[9]  Gao Z, Zhang X, Zuberi A, Hwang D, Quon MJ, et al. (2004) Inhibition of insulin sensitivity by free fatty acids requires activation of multiple serine kinases in 3T3-L1 adipocytes. Mol Endocrinol 18: 2024–2034.
[10]  Tomlinson JW, Walker EA, Bujalska IJ, Draper N, Lavery GG, et al. (2004) 11beta-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response. Endocr Rev 25: 831–866.
[11]  Paulmyer-Lacroix O, Boullu S, Oliver C, Alessi MC, Grino M (2002) Expression of the mRNA coding for 11beta-hydroxysteroid dehydrogenase type 1 in adipose tissue from obese patients: an in situ hybridization study. J Clin Endocrinol Metab 87: 2701–2705.
[12]  Rask E, Walker BR, Soderberg S, Livingstone DE, Eliasson M, et al. (2002) Tissue-specific changes in peripheral cortisol metabolism in obese women: increased adipose 11beta-hydroxysteroid dehydrogenase type 1 activity. J Clin Endocrinol Metab 87: 3330–3336.
[13]  Rosenstock J, Banarer S, Fonseca VA, Inzucchi SE, Sun W, Yao W, et al. (2010) The 11-beta-hydroxysteroid dehydrogenase type 1 inhibitor INCB13739 improves hyperglycemia in patients with type 2 diabetes inadequately controlled by metformin monotherapy. Diabetes Care 33: 1516–1522. dc09-2315 [pii];10.2337/dc09-2315 [doi].
[14]  Gathercole LL, Bujalska IJ, Stewart PM, Tomlinson JW (2007) Glucocorticoid modulation of insulin signaling in human subcutaneous adipose tissue. J Clin Endocrinol Metab 92: 4332–4339.
[15]  Qiao L, Maclean PS, Schaack J, Orlicky DJ, Darimont C, et al. (2005) C/EBPalpha regulates human adiponectin gene transcription through an intronic enhancer. Diabetes 54: 1744–1754.
[16]  Jamdar SC (1978) Glycerolipid biosynthesis in rat adipose tissue. Influence of adipose-cell size and site of adipose tissue on triacylglycerol formation in lean and obese rats. Biochem J 170: 153–160.
[17]  Bujalska IJ, Gathercole LL, Tomlinson JW, Darimont C, Ermolieff J, et al. (2008) A novel selective 11beta-hydroxysteroid dehydrogenase type 1 inhibitor prevents human adipogenesis. J Endocrinol 197: 297–307.
[18]  Simacopoulos-Jeannet F, Brichard S, Rencurel F, Cusin I, Jeanrenaud B (1995) In vivo effects of hyperinsulinemia on lipogenic enzymes and glucose transporter expression in rat liver and adipose tissues. Metabolism 44: 228–233.
[19]  Zammit VA (1999) The malonyl-CoA-long-chain acyl-CoA axis in the maintenance of mammalian cell function. Biochem J 343 Pt 3: 505–515.
[20]  Villena JA, Roy S, Sarkadi-Nagy E, Kim KH, Sul HS (2004) Desnutrin, an adipocyte gene encoding a novel patatin domain-containing protein, is induced by fasting and glucocorticoids: ectopic expression of desnutrin increases triglyceride hydrolysis. J Biol Chem 279: 47066–47075.
[21]  Tomlinson JW, Sherlock M, Hughes B, Hughes SV, Kilvington F, et al. (2007) Inhibition of 11{beta}-HSD1 activity in vivo limits glucocorticoid exposure to human adipose tissue and decreases lipolysis. J Clin Endocrinol Metab 92: 857–64.
[22]  Lammert O, Grunnet N, Faber P, Bjornsbo KS, Dich J, et al. (2000) Effects of isoenergetic overfeeding of either carbohydrate or fat in young men 1. Br J Nutr 84: 233–245.
[23]  Volpe JJ, Marasa JC (1975) Hormonal regulation of fatty acid synthetase, acetyl-CoA carboxylase and fatty acid synthesis in mammalian adipose tissue and liver. Biochim Biophys Acta 380: 454–472.
[24]  Diamant S, Shafrir E (1975) Modulation of the activity of insulin-dependent enzymes of lipogenesis by glucocorticoids. Eur J Biochem 53: 541–546.
[25]  Wang Y, Jones VB, Urs S, Kim S, Soltani-Bejnood M, Quigley N, et al. (2004) The human fatty acid synthase gene and de novo lipogenesis are coordinately regulated in human adipose tissue. J Nutr 134: 1032–1038.
[26]  Abu-Elheiga L, Matzuk MM, Kordari P, Oh W, Shaikenov T, et al. (2005) Mutant mice lacking acetyl-CoA carboxylase 1 are embryonically lethal. Proc Natl Acad Sci U S A 102: 12011–12016.
[27]  Mao J, DeMayo FJ, Li H, Abu-Elheiga L, Gu Z, Shaikenov TE, et al. (2006) Liver-specific deletion of acetyl-CoA carboxylase 1 reduces hepatic triglyceride accumulation without affecting glucose homeostasis. Proc Natl Acad Sci U S A 103: 8552–8557.
[28]  Oh W, Abu-Elheiga L, Kordari P, Gu Z, Shaikenov T, et al. (2005) Glucose and fat metabolism in adipose tissue of acetyl-CoA carboxylase 2 knockout mice. Proc Natl Acad Sci U S A 102: 1384–1389.
[29]  Viana AY, Sakoda H, Anai M, Fujishiro M, Ono H, et al. (2006) Role of hepatic AMPK activation in glucose metabolism and dexamethasone-induced regulation of AMPK expression. Diabetes Res Clin Pract 73: 135–142.
[30]  Christ-Crain M, Kola B, Lolli F, Fekete C, Seboek D, Wittmann G, et al. (2008) AMP-activated protein kinase mediates glucocorticoid-induced metabolic changes: a novel mechanism in Cushing's syndrome. FASEB J 22: 1672–1683. fj.07-094144 [pii];10.1096/fj.07-094144 [doi].
[31]  Kola B, Christ-Crain M, Lolli F, Arnaldi G, Giacchetti G, et al. (2008) Changes in adenosine 5′-monophosphate-activated protein kinase as a mechanism of visceral obesity in Cushing's syndrome. J Clin Endocrinol Metab 93: 4969–4973. jc.2008-1297 [pii];10.1210/jc.2008-1297 [doi].
[32]  Tomlinson JJ, Boudreau A, Wu D, Abdou SH, Carrigan A, et al. (2010) Insulin sensitization of human preadipocytes through glucocorticoid hormone induction of forkhead transcription factors. Mol Endocrinol 24: 104–113. me.2009-0091 [pii];10.1210/me.2009-0091 [doi].
[33]  Pouliot MC, Despres JP, Nadeau A, Moorjani S, Prud'homme D, et al. (1992) Visceral obesity in men. Associations with glucose tolerance, plasma insulin, and lipoprotein levels. Diabetes 41: 826–834.
[34]  Fontbonne A, Thibult N, Eschwege E, Ducimetiere P (1992) Body fat distribution and coronary heart disease mortality in subjects with impaired glucose tolerance or diabetes mellitus: the Paris Prospective Study, 15-year follow-up. Diabetologia 35: 464–468.
[35]  Zierath JR, Livingston JN, Thorne A, Bolinder J, Reynisdottir S, et al. (1998) Regional difference in insulin inhibition of non-esterified fatty acid release from human adipocytes: relation to insulin receptor phosphorylation and intracellular signalling through the insulin receptor substrate-1 pathway. Diabetologia 41: 1343–1354.
[36]  Fried SK, Russell CD, Grauso NL, Brolin RE (1993) Lipoprotein lipase regulation by insulin and glucocorticoid in subcutaneous and omental adipose tissues of obese women and men. J Clin Invest 92: 2191–2198. 10.1172/JCI116821 [doi].
[37]  Laviola L, Perrini S, Cignarelli A, Natalicchio A, Leonardini A, De SF, et al. (2006) Insulin signaling in human visceral and subcutaneous adipose tissue in vivo. Diabetes 55: 952–961. 55/4/952 [pii].
[38]  Lundgren M, Buren J, Lindgren P, Myrnas T, Ruge T, Eriksson JW (2008) Sex- and Depot-specific Lipolysis Regulation in Human Adipocytes: Interplay between Adrenergic Stimulation and Glucocorticoids. Horm Metab Res 40: 854–60.
[39]  Alberts P, Nilsson C, Selen G, Engblom LO, Edling NH, Norling S, et al. (2003) Selective inhibition of 11{beta}-hydroxysteroid dehydrogenase type 1 improves hepatic insulin sensitivity in hyperglycemic mice strains. Endocrinology 144: 4755–4762.
[40]  Masuzaki H, Paterson J, Shinyama H, Morton NM, Mullins JJ, Seckl JR (2001) A transgenic model of visceral obesity and the metabolic syndrome. Science 294: 2166–2170.
[41]  Berthiaume M, Laplante M, Festuccia W, Gelinas Y, Poulin S, Lalonde J, et al. (2007) Depot-specific modulation of rat intraabdominal adipose tissue lipid metabolism by pharmacological inhibition of 11beta-hydroxysteroid dehydrogenase type 1. Endocrinology 148: 2391–2397.
[42]  Morgan SA, Sherlock M, Gathercole LL, Lavery GG, Lenaghan C, Bujalska IJ, et al. (2009) 11{beta}-hydroxysteroid dehydrogenase type 1 regulates glucocorticoid-induced insulin resistance in skeletal muscle. Diabetes 58: 2506–15.
[43]  Kim JK, Fillmore JJ, Sunshine MJ, Albrecht B, Higashimori T, et al. (2004) PKC-theta knockout mice are protected from fat-induced insulin resistance. J Clin Invest 114: 823–827.

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