Peroxisome Proliferator—Activated Receptor (PPAR)-αActivation Lowers Muscle Lipids and Improves Insulin Sensitivity in High Fat—Fed Rats

Abstract

Peroxisome proliferator-activated receptor (PPAR)-␣ agonists lower circulating lipids, but the consequences for muscle lipid metabolism and insulin sensitivity are not clear. We investigated whether PPAR-␣ activation improves insulin sensitivity in insulin-resistant rats and compared the effects with PPAR-␥ activation. Threeweek high fat-fed male Wistar rats were untreated or treated with the specific PPAR-␣ agonist WY14643 or the PPAR-␥ agonist pioglitazone (both 3 mg · kg -1 · day -1 ) for the last 2 weeks of high-fat feeding. Like pioglitazone, WY14643 lowered basal plasma levels of glucose, triglycerides (-16% vs. untreated), and leptin (-52%), and also muscle triglyceride (-34%) and total long-chain acyl-CoAs (LCACoAs) (-41%) (P < 0.05). In contrast to pioglitazone, WY14643 substantially reduced visceral fat weight and total liver triglyceride content (P < 0.01) without increasing body weight gain. WY14643 and pioglitazone similarly enhanced wholebody insulin sensitivity (clamp glucose infusion rate increased 35 and 37% and glucose disposal 22 and 15%, respectively, vs. untreated). Both agents enhanced insulin-mediated muscle glucose metabolic index (Rg') and reduced muscle triglyceride and LCACoA accumulation (P < 0.05). Although pioglitazone had more potent effects than WY14643 on muscle insulin sensitization, this was associated with its greater effect to reduce muscle LCACoA accumulation. Overall insulinmediated muscle Rg' was inversely correlated with the content of LCACoAs (r = -0.74, P = 0.001) and with plasma triglyceride levels (r = -0.77, P < 0.001). We conclude that even though WY14643 and pioglitazone, representing PPAR-␣ and PPAR-␥ activation, respectively, may alter muscle lipid supply by different mechanisms, both significantly improve muscle insulin action in the high fat-fed rat model of insulin resistance, and this effect is proportional to the degree to which they reduce muscle lipid accumulation. Diabetes 50:411-417, 2001

Effects of peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ agonists on glucose and lipid metabolism in patients with type 2 diabetes mellitus

“…FENO and gemfibrozil) for the treatment of hypertriacylglycerolaemia in type 2 diabetic patients, their effect on insulin sensitivity in humans has not been rigorously examined and conflicting results have been reported [9][10][11][12][13][14]. Studies in rodents conclusively demonstrate that PPAR-α activation with FENO and other more potent PPAR-α agents enhances peripheral (muscle) and hepatic insulin sensitivity [4][5][6][7][8]. Although PPAR-α-null mice do not manifest any obvious alteration in insulin sensitivity [42], PPAR-α activation in nutritional (high-fat diet), genetic (Zucker obese fa/fa rat), and lipoatrophic (A-ZIP/ F-1) models of insulin resistance markedly improves insulin sensitivity [4,7,43] and reduces visceral fat in the two former models.…”

“…Intracellular fatty acids and their derivatives interfere with insulin-stimulated glucose metabolism, through an effect on the insulin-signalling pathway, possibly by activating protein kinase C [1,44]. In rodents it has been suggested that PPAR-α activation increases fatty acid oxidation, thus decreasing intramyocellular lipid content and improving insulin sensitivity [4][5][6][7]. In contrast, PPAR-α-null mice are protected from high-fat diet-induced insulin resistance [42].…”

“…PPAR-α agonists have been used to treat hypertriacylglycerolaemia and reduce cardiovascular risk [2,3]. Studies in rodents clearly demonstrate that PPAR-α agonists improve hepatic and muscle insulin resistance, decrease hepatic and intramuscular fat content, reduce plasma NEFA and enhance adiponectin (AD) expression [4][5][6][7][8]. Some [9][10][11], but not all [12][13][14], studies in humans with hypertriacylglycerolaemia and/or type 2 diabetes suggest that PPAR-α agonists, i.e.…”

Undernutrition during suckling in rats elevates plasma adiponectin and its receptor in skeletal muscle regardless of diet composition: a protective effect?

“…39,40 Rats undernourished during postnatal development had elevated expression of PPARa as well as the oxidative enzyme COX4 in skeletal muscle. Taken together, these results suggest that rats undernourished during suckling may have a greater ability to oxidize fatty acids, utilize glucose and increase insulin sensitivity.…”

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

“…However, both compounds increased AMPK activity in liver, implying that activation of this enzyme may mediate some of the insulin-sensitising effects of both drugs in liver. Our earlier work using the high-fat fed rat model of insulin resistance showed that the insulin-sensitising action of TZDs is accompanied by attenuated lipid accumulation in muscle and liver [5,28]. It has been proposed that TZDs act primarily in adipocytes and sequester circulating lipids in adipose tissue [2].…”