Thiazolidinediones Increase Plasma-Adipose Tissue FFA Exchange Capacity and Enhance Insulin-Mediated Control of Systemic FFA Availability

Abstract

We studied the effects of thiazolidinedione treatment (rosiglitazone 1 or 10 micromol.kg(-1).day(-1) or darglitazone 1.3 micromol.kg(-1).day(-1) for 3 weeks) on lipid metabolism in obese Zucker rats. In the basal 7-h fasted state, rosiglitazone (10 micromol.kg(-1).day(-1)) and darglitazone corrected the hypertriglyceridemia by increasing plasma triglyceride (TG) clearance and decreasing hepatic TG production, as assessed using Triton WR 1339. Free fatty acid (FFA) metabolism was assessed using 3H-palmitate tracer by estimating rates of plasma FFA appearance (Ra), whole-body FFA oxidation (Rox), and tissue-specific nonoxidative FFA disposal (Rfs). Basal Ra, plasma FFA levels, and clearance were increased by both thiazolidinediones. Detailed studies were conducted with darglitazone, which under basal conditions increased Ra (+114%), Rox (+51%), and Rfs in adipose tissues. During euglycemic clamps performed at insulin levels corresponding to those observed postprandially, darglitazone increased the glucose infusion rate from 4.7 to 13.3 mg.min(-1) and, in contrast to the basal state, it decreased Ra (-67%), Rox (-84%), and Rfs in adipose tissue, muscle, and liver. We concluded that thiazolidinediones 1) ameliorate hypertriglyceridemia by lowered hepatic TG production and augmented TG clearance (two separate kinetic effects), 2) enhance insulin-mediated suppression of systemic FFA mobilization while increasing the capacity to mobilize FFA during fasting, 3) increase FFA trafficking into adipose tissue by increasing the ability of adipose tissue to take up and store FFA, and 4) enhance metabolic flexibility by improving glucoregulation under hyperinsulinemic conditions (possibly involving reduced skeletal muscle and liver exposure to fatty acids) and augmenting the capacity to utilize FFAs during fasting.

Direct demonstration of lipid sequestration as a mechanism by which rosiglitazone prevents fatty-acid-induced insulin resistance in the rat: comparison with metformin

“…Although a similar mechanism has been observed in obese Zucker rats treated with a TZD [12], the implications of the "lipid steal" mechanism in normal rats are different from those in obese Zucker rats. In the present study, the animals were normal in insulin sensitivity and lipid metabolism.…”

“…Although often cited, the "lipid steal" hypothesis for TZD action has to our knowledge only been directly demonstrated in a rodent model of extreme hyperinsulinaemia and obesity, the Zucker fatty rat [12]. Recently we used an acute model of insulin resistance induced by intralipid/heparin infusion [13] to show that normal rats pre-treated with pioglitazone were protected against the development of insulin resistance in muscle and liver.…”

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

“…These were, however, primarily designed to examine NEFA re-esterification under conditions that may have favoured the latter process. In contrast, studies that have specifically focused on in vivo NEFA kinetics in rats have shown that, in the fasting state, PPARγ agonists increase the capacity of WAT to release NEFAs [4,7]. In addition, human adipocytes stimulated to differentiate in the presence of rosiglitazone displayed increased basal and noradrenaline-stimulated lipolysis [23].…”

“…Because of its effect on plasma NEFAs, PPARγ agonism might also be expected to reduce lipolysis; however, previous studies investigating this issue have produced conflicting results. Whereas some studies have reported lower in vitro rates of glycerol and NEFA release from WAT [5,6], others that include in vivo NEFA kinetic approaches [4,7] suggest that PPARγ agonism stimulates lipolysis, an effect that would be counteracted by its concomitant action on NEFA reuptake and re-esterification.…”

“…All of these processes are affected by thiazolidinediones. Indeed, rosiglitazone has been shown to reduce NEFA uptake by the liver and muscle [3], and to increase NEFA uptake, intracellular re-esterification, and storage into triglycerides in WAT [4]. Because of its effect on plasma NEFAs, PPARγ agonism might also be expected to reduce lipolysis; however, previous studies investigating this issue have produced conflicting results.…”