Salicylate Blocks Lipolytic Actions of Tumor Necrosis Factor-α in Primary Rat Adipocytes

Abstract

Increased systemic free fatty acids (FFA) impair insulin sensitivity. In obese and diabetic subjects, production of tumor necrosis factor-␣ (TNF-␣), a proinflammatory cytokine, is elevated. TNF-␣ has a variety of effects by inducing inflammation, decreasing glucose utilization, and stimulating adipocyte lipolysis to release FFA to plasma. High doses of nonsteroidal anti-inflammatory drug salicylates have long been recognized to lower blood FFA and glucose in humans, although the mechanisms are not fully understood. In this report, we show that sodium salicylate at therapeutic concentrations directly blocks TNF-␣-stimulated lipolysis and therefore inhibits FFA release from primary rat adipocytes. To elucidate the cellular basis of this action, we show that salicylate suppresses TNF-␣-induced extracellular signal-related kinase activation and intracellular cAMP elevation, two early events during the lipolysis response to TNF-␣. Furthermore, salicylate prevents the down-regulation of cyclic-nucleotide phosphodiesterase 3B, an enzyme responsible for cAMP hydrolysis. Perilipins coat intracellular lipid droplet surface by restricting lipase access to the triacylglycerol substrates. TNF-␣ down-regulates perilipin but promotes its phosphorylation during lipolysis stimulation; these actions are efficiently reversed by salicylate. Salicylate slightly reduces basal but completely inhibits TNF-␣-liberated lipase activity. In contrast, neither salicylate nor TNF-␣ alters the protein levels of hormone-sensitive lipase and adipose triglyceride lipase. In addition, sodium salicylate restricts basal lipolysis simulated by a high concentration of glucose and significantly diminishes the high glucose-enhanced lipolysis response to TNF-␣. These results provide novel evidence that salicylate directly blocks TNF-␣-mediated FFA efflux from adipocytes, hence reducing plasma FFA levels and increasing insulin sensitivity.

Adipocytokine Orosomucoid Integrates Inflammatory and Metabolic Signals to Preserve Energy Homeostasis by Resolving Immoderate Inflammation

“…To test whether ORM delays TNF␣-induced lipolysis in adipocytes, we examined the levels of perilipin mRNA and lipolysis after ORM treatment. As reported previously (32), the administration of salicylate reversed the effects of TNF␣ on perilipin expression and glycerol release (Fig. 7, E and F).…”

“…It has been reported that TNF␣ induces lipolysis and facilitates the release of FFAs by suppressing perilipin expression and augmenting hormone-sensitive lipase activity (5, 6, 31), which are repressed by an anti-inflammatory drug, salicylate (32). To test whether ORM delays TNF␣-induced lipolysis in adipocytes, we examined the levels of perilipin mRNA and lipolysis after ORM treatment.…”

Bacterial Endotoxin Stimulates Adipose Lipolysis via Toll-Like Receptor 4 and Extracellular Signal-regulated Kinase Pathway

“…Fatty Acid Assay-The FFA content in the culture medium was determined by colorimetric assay as described (13). Briefly, 50 l of culture medium was mixed with 120 l of isooctane and 80 l of cupric acetate-pyridine and centrifuged for 10 min at 12,000 ϫ g at room temperature.…”

“…Catecholamines stimulate lipolysis via elevating cellular cAMP level and activating cAMP-dependent protein kinase A (PKA) (10). Cytokines such as TNF-␣ and interleukins induce chronic lipolysis (11)(12)(13). Although catecholamines and cytokines are increased in the circulation in endotoxemia (3-6), they seem not to be the only lipolytic stimulators that account for elevated level of serum FFA.…”

Molecular Mechanisms and Therapeutic Targets in Steatosis and Steatohepatitis

“…The positive influence of different drugs, such as metformin, thiazolidinediones, and salicylates, on NAFLD has been related, at least in part, to their modulation of peripheral lipolysis (Ren et al, 2006). In particular, thiazolidinediones and salicylates are thought to reduce TNF-␣-induced lipolysis, the latter of which potentially involves a mechanism that prevents reduction of perilipin A (Souza et al, 1998;Zu et al, 2008). Furthermore, salicylates are thought to prevent inflammation by inhibition of IKK-␤ and NF-B and were recently suggested for the treatment of insulin resistance and type 2 diabetes (Chen, 2005;Lappas et al, 2005;Möhlig et al, 2006).…”