Pancreatic Islet Adaptation to Fasting Is Dependent on Peroxisome Proliferator-Activated Receptor α Transcriptional Up-Regulation of Fatty Acid Oxidation

Abstract

The cellular response to fasting and starvation in tissues such as heart, skeletal muscle, and liver requires peroxisome proliferator-activated receptor-alpha (PPARalpha)-dependent up-regulation of energy metabolism toward fatty acid oxidation (FAO). PPARalpha null (PPARalphaKO) mice develop hyperinsulinemic hypoglycemia in the fasting state, and we previously showed that PPARalpha expression is increased in islets at low glucose. On this basis, we hypothesized that enhanced PPARalpha expression and FAO, via depletion of lipid-signaling molecule(s) for insulin exocytosis, are also involved in the normal adaptive response of the islet to fasting. Fasted PPARalphaKO mice compared with wild-type mice had supranormal ip glucose tolerance due to increased plasma insulin levels. Isolated islets from the PPARalpha null mice had a 44% reduction in FAO, normal glucose use and oxidation, and enhanced glucose-induced insulin secretion. In normal rats, fasting for 24 h increased islet PPARalpha, carnitine palmitoyltransferase 1, and uncoupling protein-2 mRNA expression by 60%, 62%, and 82%, respectively. The data are consistent with the view that PPARalpha, via transcriptionally up-regulating islet FAO, can reduce insulin secretion, and that this mechanism is involved in the normal physiological response of the pancreatic islet to fasting such that hypoglycemia is avoided.

Caloric restriction and intermittent fasting: Two potential diets for successful brain aging

“…Hence through PPAR activation extra supplies of glucose can be mobilized and alternate energy sources can be exploited. As well as PGC regulation during fasting, PPARα is also upregulated by fasting in liver, small and large intestine, thymus (Escher et al, 2001), and pancreas (Gremlich et al, 2005). A large number of genes involved in fatty acid β-oxidation, known to be regulated by PPARα are also increased in expression in response to fasting.…”

Beta cell compensation for insulin resistance in Zucker fatty rats: increased lipolysis and fatty acid signalling

“…Fed rats were anaesthetised between 08.00 and 09.00 h with sodium pentobarbital and then killed by exsanguination, and pancreatic islets were isolated as described previously [21]. Prior to initiating experiments or collecting islets for analysis, islets were rested for 1 h in regular RPMI 1640 medium supplemented with 10% fetal calf serum, 10 mmol/l HEPES (pH 7.4), 1 mmol/l sodium pyruvate, 100 U/ml penicillin and 100 μg/ml streptomycin (RPMI complete) at 11 mmol/l glucose at 37°C in a humidified atmosphere containing 5% CO 2 .…”

“…RT-PCR analyses of ZF and ZL islets were performed according to methods previously described [21], as detailed in the ESM.…”

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

“…In Pparα (also known as Ppara)-null mice, the fasting state induces hyperinsulinaemic hypoglycaemia [11,12]. Pancreatic islets isolated from Pparα-null mice exhibit normal glucose oxidation and enhanced glucoseinduced insulin secretion [13], an effect that might be the direct consequence of PPARα abrogation or an adaptation secondary to hepatic changes [11]. PPARα action is not limited to hepatic tissue and, along with adipose tissue and muscles, pancreatic beta cells also produce PPARα [14].…”