PPARα activation reverses adverse effects induced by high-saturated-fat feeding on pancreatic β-cell function in late pregnancy

Abstract

Holness MJ, Smith ND, Greenwood GK, Sugden MC. PPAR␣ activation reverses adverse effects induced by high-saturated-fat feeding on pancreatic ␤-cell function in late pregnancy. Am J Physiol Endocrinol Metab 292: E1087-E1094, 2007. First published December 12, 2006; doi:10.1152/ajpendo.00375.2006.-We examined whether the additional demand for insulin secretion imposed by dietary saturated fat-induced insulin resistance during pregnancy is accommodated at late pregnancy, already characterized by insulin resistance. We also assessed whether effects of dietary saturated fat are influenced by PPAR␣ activation or substitution of 7% of dietary fatty acids (FAs) with long-chain -3 FA, manipulations that improve insulin action in the nonpregnant state. Glucose tolerance at day 19 of pregnancy in the rat was impaired by high-saturated-fat feeding throughout pregnancy. Despite modestly enhanced glucose-stimulated insulin secretion (GSIS) in vivo, islet perifusions revealed an increased glucose threshold and decreased glucose responsiveness of GSIS in the saturated-fat-fed pregnant group. Thus, insulin resistance evoked by dietary saturated fat is partially countered by augmented insulin secretion, but compensation is compromised by impaired islet function. Substitution of 7% of saturated FA with long-chain -3 FA suppressed GSIS in vivo but did not modify the effect of saturated-fat feeding to impair GSIS by perifused islets. PPAR␣ activation (24 h) rescued impaired islet function that was identified using perifused islets, but GSIS in vivo was suppressed such that glucose tolerance was not improved, suggesting modification of the feedback loop between insulin action and secretion.

Role of nuclear receptors in the modulation of insulin secretion in lipid-induced insulin resistance

“…Glucose tolerance was impaired and islet perifusions revealed an increased glucose threshold and decreased glucose responsiveness of GSIS [95]. We concluded that pregnancy alters the lipid responsiveness of the β-cell, such that increased delivery of lipid from the diet compromises rather than augments β-cell function.…”

“…We addressed whether an additional demand for insulin secretion imposed by dietary saturated fat could be accommodated during late pregnancy [95]. Glucose tolerance was impaired and islet perifusions revealed an increased glucose threshold and decreased glucose responsiveness of GSIS [95].…”

“…We concluded that pregnancy alters the lipid responsiveness of the β-cell, such that increased delivery of lipid from the diet compromises rather than augments β-cell function. We therefore assessed whether effects of dietary saturated fat during pregnancy were augmented or ameliorated by PPARα activation [95]. Acute (24 h) PPARα activation rescued the impaired islet function that had been identified using perifused islets, suggesting that impaired GSIS might be due to excess lipid accumulation within the islet.…”

Peroxisome proliferator-activated receptor α (PPARα) protects against oleate-induced INS-1E beta cell dysfunction by preserving carbohydrate metabolism

“…The same study reported that PPARα agonists protected human islets from palmitateinduced lipotoxicity [21]. In pregnant rats fed a high-fat diet, in vivo administration of a PPARα agonist has been shown to prevent loss of glucose-stimulated insulin secretion [24]. In another in vivo study, chronic treatment with a PPARα agonist inhibited the development of diabetes in the Zucker Diabetic Fatty rat, essentially by improving the pancreatic insulin response [22].…”

Molecular Mechanisms and Therapeutic Targets in Steatosis and Steatohepatitis

“…Other positive treatment effect of n-3 PUFAs has been related to their interference with insulinotropic effects of saturated fatty acids, lowering insulin-dependent stimulation of lipogenic genes in the liver (Holness et al, 2004). PUFA-mediated activation of PPAR␣ was demonstrated to antagonize detrimental effects on pancreatic ␤-cells in vitro, being able to rescue ␤-cell function (Holness et al, 2007) and advantageous effects of PUFA supplementation in steatosis were suggested to result from an improvement of peripheral insulin resistance, which was demonstrated in vitro but not supported by findings in vivo (Fickova et al, 1998;Ryan et al, 2000;Holness et al, 2004). Finally, another putative protection mechanism of unsaturated fatty acids in steatosis and steatohepatitis was attributed to their antioxidant effects, serving as a cellular reservoir for undue lipid peroxidation (Davis et al, 2006;Oliveira et al, 2006).…”