Distinct long-term regulation of glycerol and non-esterified fatty acid release by insulin and TNF-α in 3T3-L1 adipocytes

Abstract

The regulation of adipocyte lipolysis is increasingly recognized to play a part in the pathophysiology of obesity, insulin resistance and Type II (non-insulindependent) diabetes mellitus. Both non-esterified fatty acids (NEFA) and glycerol, the two end products of lipolysis, are potential mediators for metabolic (dys)regulation, which is associated with these common conditions [1,2]. Prolonged increases in NEFA concentrations could induce or aggravate skeletal muscle insulin resistance [3], impair pancreatic betacell function [4] and result in glucose overproduction [5,6]. Glycerol has recently been suggested to be used by skeletal muscle as a precursor for intra-muscular triacylglycerol synthesis [2], which in turn when excessive, could result in skeletal muscle insulin Diabetologia (2001) Abstract Aims/hypothesis. Adipose tissue lipolysis plays a central part in total body fuel metabolism. Our study was to assess the long-term regulation of glycerol and non-esterified fatty acid (NEFA) release by insulin or TNF-a. Methods. Fully differentiated 3T3-L1 adipocytes were exposed for up to 22 h to insulin or TNF-a. Results. Long-term insulin treatment resulted in increased basal glycerol release, reaching sixfold at 22 h with 1 nmol/l insulin. Partial inhibition was observed by pharmacologically inhibiting phosphatidylinositol 3-kinase or the mitogen-activated kinase kinase ± extracellular signal-regulated kinase cascades. This represented 50±60 % of the response induced by 1 nmol/l TNF-a and approximately 40 % of the glycerol release maximally stimulated by isoproterenol (1 mmol/l, 30 min). The cellular mechanism seemed to be distinct from that of TNF-a: First, glycerol release in response to long-term insulin was progressive with time and did not display a lag-time characteristic of the effect of TNF-a. Second, pretreatment and co-treatment of the cells with troglitazone greatly inhibited TNF-a-induced glycerol release (128.5 10.2 to 35.4 2.1 nmol/mg protein per h) but not the effect of insulin, which was exaggerated. Third, hormone-sensitive lipase protein content was decreased (45 %) by TNF-a but not following longterm insulin. Finally, TNF-a was associated with NEFA release to the medium, whereas long-term insulin treatment was not. Moreover, glycerol release during isoproterenol-stimulated lipolysis was additive to the effect of long-term insulin, whereas NEFA release was inhibited by nearly 90 %. Conclusions interpretation. Contradictory to its shortterm inhibitory effect, long-term insulin stimulates glycerol release with concomitant stimulation of NEFA re-esterification. [Diabetologia (2001)

Insulin and Rosiglitazone Regulation of Lipolysis and Lipogenesis in Human Adipose Tissue In Vitro

“…This is the first report to address the long-term effects of insulin on human adipocyte lipid metabolism, and our findings are consistent with clinical observations of the association of hyperinsulinemia with increased lipolytic rate and fat accumulation in type 2 diabetes (4,21). Our findings are also consistent with previous studies investigating the effect of both chronic high insulin and glucose on mature rat adipocytes and differentiated 3T3-L1 adipocytes (7,25). These studies demonstrate that the combination of chronic high glucose and insulin stimulates lipolysis, which is in contrast to previous studies that have examined the acute effects by insulin (4,(21)(22)(23).…”

PPARγ agonism increases rat adipose tissue lipolysis, expression of glyceride lipases, and the response of lipolysis to hormonal control

“…The present study confirmed that rosiglitazone increases the response of WAT lipolysis to the inhibitory action of insulin [4]. It is worth noting that the inhibitory effect of insulin on NEFA was stronger than that on glycerol release, because of its additive effect on NEFA re-esterification to triglycerides [36,37]. Despite the stronger antilipolytic effect of insulin on WAT lipolysis, explants of rosiglitazone-treated rats exposed to insulin concentrations approximating those found in vivo under fasting and postprandial conditions maintained a higher rate of NEFA release than controls.…”

Silencing Jnk1 and Jnk2 accelerates basal lipolysis and promotes fatty acid re-esterification in mouse adipocytes

“…Notably, insulin did not affect the kinetics of glycerol release in JNK-intact cells over a 120 min period, but increased glycerol release in JNK1-and JNK2-deficient cells at 120 min. Although both the acute and chronic stimulatory effects of insulin on adipocyte glycerol release have been demonstrated [39,40], this is the first report that JNK1-or JNK2-deficiency increases the stimulatory effect of insulin on glycerol release and that JNK1/JNK2-deficiency is more important in the regulation of lipolysis than insulin.…”