Stimulation of lipolysis by tumor necrosis factor-alpha in 3T3-L1 adipocytes is glucose dependent: implications for long-term regulation of lipolysis.
Tumor necrosis factor-alpha (TNF-alpha) and hyperglycemia both impair insulin sensitivity in vivo. This may be secondary to stimulation of adipose tissue lipolysis and consequent increased circulating free fatty acids (FFAs). Here we report that neither TNF-alpha nor glucose alone has a pronounced effect on lipolysis in 3T3-L1 adipocytes. However, the combination of TNF-alpha plus glucose markedly stimulates lipolysis. Glucose does not affect the ability of isoproterenol to stimulate lipolysis. Alternative substrates such as acetate, pyruvate, and lactate do not allow the TNF-alpha effect. Mannose was almost as effective as glucose; fructose was marginally effective, but galactose was ineffective. The effectiveness of the sugars corresponded with production of lactate, i.e., the cells readily produced lactate from glucose or mannose, slightly from fructose, and not at all from galactose. The ability of TNF-alpha to phosphorylate extracellular signal-regulated kinase 1 (ERK1) and ERK2 and to downregulate perilipin (which has been implicated in the lipolytic effect of TNF-alpha) was not affected by glucose. We conclude that the lipolytic action of TNF-alpha is influenced by glucose in 3T3-L1 adipocytes. The findings suggest that glucose metabolism is required for the lipolytic response to TNF-alpha but not for early signaling events. These findings suggest novel mechanisms by which TNF-alpha and hyperglycemia raise FFA levels and induce insulin resistance.
Green
Allan
A
Bassett Research Institute, Bassett Healthcare, Cooperstown, New York 13326, USA. allan.green@basett.org
Rumberger
John M
JM
Stuart
Charles A
CA
Ruhoff
Mary S
MS
D016475:3T3 Cells; D000085:Acetates / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology*; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D007700:Kinetics; D007773:Lactates / Q000378:metabolism; D008066:Lipolysis / Q000187:drug effects*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D000070778:Perilipin-1; D010750:Phosphoproteins / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D011773:Pyruvates / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000085:Acetates; D002352:Carrier Proteins; D007773:Lactates; D000070778:Perilipin-1; D010750:Phosphoproteins; D011773:Pyruvates; D014409:Tumor Necrosis Factor-alpha; D000255:Adenosine Triphosphate; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D005947:Glucose