WY14,643, a Peroxisome Proliferator-activated Receptor α (PPARα) Agonist, Improves Hepatic and Muscle Steatosis and Reverses Insulin Resistance in Lipoatrophic A-ZIP/F-1 Mice

Abstract

WY14,643 is a specific peroxisome proliferator-activated receptor ␣ (PPAR␣) agonist with strong hypolipidemic effects. Here we have examined the effect of WY14,643 in the A-ZIP/F-1 mouse, a model of severe lipoatrophic diabetes. With 1 week of treatment, all doses of WY14,643 that were tested normalized serum triglyceride and fatty acid levels. Glucose and insulin levels also improved but only with high doses and longer treatment duration. WY14,643 reduced liver and muscle triglyceride content and increased levels of mRNA encoding fatty acid oxidation enzymes. In liver, the elevated lipogenic mRNA profile (including PPAR␥) in A-ZIP/F-1 mice remained unchanged. These results suggest that WY14,643 acts by increasing ␤-oxidation rather by than decreasing lipogenesis or lipid uptake. Hyperinsulinemic euglycemic clamp studies indicated that WY14,643 treatment improved liver more than muscle insulin sensitivity and that hepatic mRNA levels of gluconeogenic enzymes were reduced. Combination treatment with both WY14,643 and a PPAR␥ ligand, rosiglitazone, did not lower glucose levels more effectively than did treatment with WY14,643 alone. These data support the hypothesis that reducing intracellular triglycerides in non-adipose tissues improves insulin sensitivity and suggest that further investigation of the role of PPAR␣ agonists in the treatment of lipoatrophic diabetes is warranted.

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

“…Studies in animals indicate that PPAR-α agonists increase hepatic fat oxidation and reduce hepatic fat content in association with enhanced insulin-mediated suppression of EGP [3,7,43,48]. Although hepatic fat oxidation was not measured in the present study, we did not observe a significant reduction in hepatic fat content or an increase in hepatic insulin sensitivity (in contrast to PIO therapy) following FENO therapy.…”

“…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].…”

Central role of PPARα-dependent hepatic lipid turnover in dietary steatohepatitis in mice

“…Other studies have shown in rats fed a high-fat, 29 highfructose, 30 or choline-deficient diet, 31 and in the A-ZIP/ F-1 mouse, 32 that administration of a PPAR␣ agonist reduces or prevents the development of hepatic steatosis. Although rats fed a choline-deficient diet may develop a mild form of steatohepatitis, 31,33 the present study shows that a PPAR␣ agonist can prevent steatohepatitis in a model characterized by moderate inflammatory changes, hepatocellular degeneration, and ultimately progressive pericellular fibrosis.…”

Metabolic Adaptations in the Absence of Perilipin

“…Increased ␤-oxidation is often associated with increased insulin sensitivity (40,41). In the plin Ϫ/Ϫ mice, there is increased ␤-oxidation but no major change in insulin sensitivity when the animals are young.…”