title: Metabolic remodeling of human skeletal myocytes by cocultured adipocytes depends on the lipolytic state of the system.
abstract: OBJECTIVE
  Adipocyte infiltration of the musculoskeletal system is well recognized as a hallmark of aging, obesity, and type 2 diabetes. Intermuscular adipocytes might serve as a benign storage site for surplus lipid or play a role in disrupting energy homeostasis as a result of dysregulated lipolysis or secretion of proinflammatory cytokines. This investigation sought to understand the net impact of local adipocytes on skeletal myocyte metabolism.
  
  
  METHODS
  Interactions between these two tissues were modeled using a coculture system composed of primary human adipocytes and human skeletal myotubes derived from lean or obese donors. Metabolic analysis of myocytes was performed after coculture with lipolytically silent or activated adipocytes and included transcript and metabolite profiling along with assessment of substrate selection and insulin action.
  
  
  RESULTS
  Cocultured adipocytes increased myotube mRNA expression of genes involved in oxidative metabolism, regardless of the donor and degree of lipolytic activity. Adipocytes in the basal state sequestered free fatty acids, thereby forcing neighboring myotubes to rely more heavily on glucose fuel. Under this condition, insulin action was enhanced in myotubes from lean but not obese donors. In contrast, when exposed to lipolytically active adipocytes, cocultured myotubes shifted substrate use in favor of fatty acids, which was accompanied by intracellular accumulation of triacylglycerol and even-chain acylcarnitines, decreased glucose oxidation, and modest attenuation of insulin signaling.
  
  
  CONCLUSIONS
  The effects of cocultured adipocytes on myocyte substrate selection and insulin action depended on the metabolic state of the system. These findings are relevant to understanding the metabolic consequences of intermuscular adipogenesis.
authors: Sarah W. Stedman Nutrition and Metabolism Center, Duke University, Durham, North Carolina, USA.
authors: Jean-Paul
authors: JP
authors: Kovalik
authors: Dorothy
authors: D
authors: Slentz
authors: Robert D
authors: RD
authors: Stevens
authors: William E
authors: WE
authors: Kraus
authors: Joseph A
authors: JA
authors: Houmard
authors: James B
authors: JB
authors: Nicoll
authors: Y Renee
authors: YR
authors: Lea-Currie
authors: Karen
authors: K
authors: Everingham
authors: C Lawrence
authors: CL
authors: Kien
authors: Benjamin M
authors: BM
authors: Buehrer
authors: Deborah M
authors: DM
authors: Muoio
references: Proc Natl Acad Sci U S A. 2009 Oct 20;106(42):17787-92
references: 19805130
references: Obesity (Silver Spring). 2011 Feb;19(2):305-11
references: 20559306
references: Lancet. 1963 Apr 13;1(7285):785-9
references: 13990765
references: Hypertension. 2004 Dec;44(6):847-52
references: 15520303
references: Cell Metab. 2008 Jan;7(1):45-56
references: 18177724
references: Diabetes. 2002 Aug;51(8):2369-76
references: 12145147
references: Nat Med. 2004 Mar;10(3):268-74
references: 14770177
references: Diabetes. 2002 Jan;51(1):7-18
references: 11756317
references: Methods. 2005 Jun;36(2):207-24
references: 15894491
references: Trends Endocrinol Metab. 2000 Aug;11(6):212-7
references: 10878750
references: Expert Rev Cardiovasc Ther. 2008 Mar;6(3):343-68
references: 18327995
references: PLoS One. 2010 Feb 05;5(2):e9065
references: 20140090
references: J Clin Invest. 1997 May 1;99(9):2219-24
references: 9151794
references: Am J Physiol Endocrinol Metab. 2002 May;282(5):E1014-22
references: 11934665
references: Biochem Soc Trans. 2005 Nov;33(Pt 5):1078-81
references: 16246049
references: Diabetes. 1981 Dec;30(12):1000-7
references: 7030826
references: Diabetes. 2010 Jun;59(6):1407-15
references: 20200320
references: Am J Hypertens. 2009 Feb;22(2):151-5
references: 19151693
references: J Clin Invest. 1996 Jun 15;97(12):2705-13
references: 8675680
references: J Biol Chem. 1999 Aug 20;274(34):24202-10
references: 10446195
references: PLoS Med. 2007 May;4(5):e158
references: 17472435
references: Obesity (Silver Spring). 2006 Nov;14(11):1898-904
references: 17135604
references: J Biol Chem. 2003 Mar 21;278(12):10297-303
references: 12525490
references: J Biol Chem. 2002 Jul 19;277(29):26089-97
references: 12118038
references: Diabetes. 2002 Oct;51(10):2929-35
references: 12351429
references: Diabetes Metab Rev. 1998 Dec;14(4):263-83
references: 10095997
references: Am J Hum Genet. 1993 May;52(5):958-66
references: 8488845
references: Lancet. 2005 Oct 1;366(9492):1197-209
references: 16198769
references: Best Pract Res Clin Endocrinol Metab. 2005 Dec;19(4):471-82
references: 16311212
references: Ann Med. 2006;38(1):52-63
references: 16448989
references: Acta Physiol (Oxf). 2006 Jan;186(1):5-16
references: 16497175
references: Int J Obes Relat Metab Disord. 2003 Dec;27 Suppl 3:S6-11
references: 14704736
references: Circulation. 2005 Mar 22;111(11):1448-54
references: 15781756
references: J Clin Invest. 1999 Jan;103(2):253-9
references: 9916137
references: Am J Physiol Endocrinol Metab. 2009 Jul;297(1):E67-75
references: 19366875
references: Int J Obes (Lond). 2011 Jun;35(6):762-72
references: 20938440
references: Nat Rev Mol Cell Biol. 2008 Mar;9(3):193-205
references: 18200017
references: Diabetes. 2005 Nov;54(11):3154-60
references: 16249439
references: Diabetologia. 2005 Jul;48(7):1359-65
references: 15933859
references: Nat Med. 2001 Aug;7(8):941-6
references: 11479627
references: Cell Metab. 2005 Oct;2(4):251-61
references: 16213227
references: Diabetes. 2002 Apr;51(4):901-9
references: 11916905
references: Am J Physiol Endocrinol Metab. 2000 Nov;279(5):E1039-44
references: 11052958
references: Diabetes. 2009 Dec;58(12):2731-40
references: 19720798
references: J Clin Invest. 2009 Mar;119(3):573-81
references: 19188683
references: Int J Obes Relat Metab Disord. 2004 Aug;28(8):985-92
references: 15211372
references: Endocr Rev. 2002 Apr;23(2):201-29
references: 11943743
references: J Biol Chem. 2005 Sep 30;280(39):33588-98
references: 16079133
references: J Clin Endocrinol Metab. 2007 Jan;92(1):284-92
references: 17062764
references: Am J Physiol Endocrinol Metab. 2008 Aug;295(2):E407-12
references: 18544640
references: Trends Endocrinol Metab. 2003 Apr;14(3):137-45
references: 12670740