Fatty acid-induced mitochondrial uncoupling in adipocytes as a key protective factor against insulin resistance and beta cell dysfunction: a new concept in the pathogenesis of obesity-associated type 2 diabetes mellitus.
Type 2 diabetes is associated with excessive food intake and a sedentary lifestyle. Local inflammation of white adipose tissue induces cytokine-mediated insulin resistance of adipocytes. This results in enhanced lipolysis within these cells. The fatty acids that are released into the cytosol can be removed by mitochondrial beta-oxidation. The flux through this pathway is normally limited by the rate of ADP supply, which in turn is determined by the metabolic activity of the adipocyte. It is expected that the latter does not adapt to an increased rate of lipolysis. We propose that elevated fatty acid concentrations in the cytosol of adipocytes induce mitochondrial uncoupling and thereby allow mitochondria to remove much larger amounts of fatty acids. By this, release of fatty acids out of adipocytes into the circulation is prevented. When the rate of fatty acid release into the cytosol exceeds the beta-oxidation capacity, cytosolic fatty acid concentrations increase and induce mitochondrial toxicity. This results in a decrease in beta-oxidation capacity and the entry of fatty acids into the circulation. Unless these released fatty acids are removed by mitochondrial oxidation in active muscles, these fatty acids result in ectopic triacylglycerol deposits, induction of insulin resistance, beta cell damage and diabetes. Thiazolidinediones improve mitochondrial function within adipocytes and may in this way alleviate the burden imposed by the excessive fat accumulation associated with the metabolic syndrome. Thus, the number and activity of mitochondria within adipocytes contribute to the threshold at which fatty acids are released into the circulation, leading to insulin resistance and type 2 diabetes.
Maassen
J A
JA
Department of Molecular Cell Biology, Leiden University Medical Centre, Postal Zone S01-P, PO Box 9600, 2300RC, Leiden, The Netherlands. j.a.maassen@lumc.nl
Romijn
J A
JA
Heine
R J
RJ
D017667:Adipocytes / Q000502:physiology*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000503:physiopathology*; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000502:physiology*; D007473:Ion Channels / Q000502:physiology; D008019:Life Style; D008928:Mitochondria / Q000502:physiology; D024101:Mitochondrial Proteins / Q000502:physiology; D008954:Models, Biological; D009765:Obesity / Q000150:complications / Q000503:physiopathology*; D000071256:Uncoupling Protein 1
D007473:Ion Channels; D024101:Mitochondrial Proteins; D000071256:Uncoupling Protein 1
J Bioenerg Biomembr. 1999 Oct;31(5):431-45
10653472
Diabetes. 2007 Apr;56(4):901-11
17395738
Ann Intern Med. 2001 May 1;134(9 Pt 1):721-8
11329229
J Biol Chem. 2002 Jan 11;277(2):1085-91
11694522
Diabetes. 2002 Feb;51 Suppl 1:S234-9
11815485
Diabetes. 2002 Mar;51(3):624-30
11872659
AIDS. 2002 Nov 8;16(16):2183-93
12409740
Ann Pharmacother. 2002 Nov;36(11):1807
12432895
Mol Cell Biol. 2003 Feb;23(3):1085-94
12529412
Int J Obes Relat Metab Disord. 2003 Feb;27(2):147-61
12586994
Diabetes Res Clin Pract. 2003 Mar;59(3):207-17
12590018
Diabetologia. 2003 Jan;46(1):3-19
12637977
Nat Genet. 2003 Jul;34(3):267-73
12808457
Curr Atheroscler Rep. 2003 Sep;5(5):364-71
12911846
Endocrinology. 2003 Sep;144(9):3765-73
12933646
J Clin Invest. 2003 Dec;112(12):1821-30
14679177
Diabetes. 2004 Feb;53 Suppl 1:S103-9
14749274
Diabetes Res Clin Pract. 2004 Mar;63(3):225-9
14757294
Horm Metab Res. 2004 Apr;36(4):203-9
15114517
Br J Nutr. 2004 Sep;92(3):347-55
15469638
Can J Biochem. 1978 Feb;56(2):111-6
630455
Biochim Biophys Acta. 1978 Sep 7;503(3):437-49
150857
J Ultrastruct Mol Struct Res. 1988 Nov-Dec;101(2-3):199-209
3151905
Nat Genet. 1992 Aug;1(5):368-71
1284550
Diabetes. 1994 Nov;43(11):1271-8
7926300
Diabetes. 1996 Jul;45(7):947-53
8666147
Lancet. 1999 Sep 25;354(9184):1112-5
10509516
J Clin Invest. 2004 Nov;114(9):1281-9
15520860
Biochim Biophys Acta. 1962 Aug 27;62:509-18
13871487
Endocr Rev. 2004 Dec;25(6):899-918
15583022
Diabetes Metab Res Rev. 2005 Jan-Feb;21(1):3-14
15386813
J Clin Virol. 2005 May;33(1):60-4
15797366
Diabetes. 2005 May;54(5):1392-9
15855325
Nature. 2005 May 26;435(7041):502-6
15917810
Diabetes. 2005 Jun;54(6):1892-5
15919814
Exerc Sport Sci Rev. 2005 Jul;33(3):150-4
16006823
Biochem Soc Trans. 2005 Nov;33(Pt 5):1073-7
16246048
Circulation. 2005 Oct 25;112(17):2686-95
16246967
Int J Obes (Lond). 2005 Sep;29 Suppl 2:S111-5
16385762
Am J Clin Nutr. 2006 Feb;83(2):461S-465S
16470013
Diabetologia. 2006 Apr;49(4):784-91
16501941
J Anim Sci. 2006 Oct;84(10):2673-83
16971568
Biochim Biophys Acta. 2006 Sep-Oct;1757(9-10):1330-7
16697347
Kidney Int. 2006 Nov;70(9):1560-6
16955100
Diabetologia. 2007 Mar;50(3):666-75
17242918
Obesity (Silver Spring). 2007 Mar;15(3):653-63
17372316