Pancreatic islet adaptation to fasting is dependent on peroxisome proliferator-activated receptor alpha transcriptional up-regulation of fatty acid oxidation.
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.
Center for Integrative Genomics, University of Lausanne, Switzerland.
Sandrine
S
Gremlich
Christopher
C
Nolan
Raphaël
R
Roduit
Rémy
R
Burcelin
Marie-Line
ML
Peyot
Viviane
V
Delghingaro-Augusto
Béatrice
B
Desvergne
Liliane
L
Michalik
Marc
M
Prentki
Walter
W
Wahli
D000222:Adaptation, Physiological; D000818:Animals; D005215:Fasting / Q000502:physiology*; D005227:Fatty Acids / Q000378:metabolism*; D015870:Gene Expression / Q000502:physiology; D005947:Glucose / Q000378:metabolism / Q000502:physiology; D005951:Glucose Tolerance Test; D006728:Hormones / Q000378:metabolism; D007328:Insulin / Q000097:blood; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D047493:PPAR alpha / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D014158:Transcription, Genetic; D015854:Up-Regulation
D005227:Fatty Acids; D006728:Hormones; D007328:Insulin; D047493:PPAR alpha; D005947:Glucose