Activation of PPARδ promotes mitochondrial energy metabolism and decreases basal insulin secretion in palmitate-treated β-cells.
The peroxisome proliferator-activated receptor δ (PPARδ) regulates the expression of genes involved in cellular lipid and cell energy metabolism in many metabolically active tissues, such as liver, muscle, and fat, and plays a role in the cellular response to stress and environmental stimuli. The particular role of PPARδ in insulin-secreting β-cells, however, is not well understood; we recently identified the cell-specific role of PPARδ on mitochondrial energy metabolism and insulin secretion in lipotoxic β-cells. After treatment of HIT-T15 cells, a syrian hamster pancreatic β-cell line, with high concentrations of palmitate and/or the specific PPARδ agonist GW501516, we detected the gene expression changes for transcripts, such as peroxisome proliferator-activated receptor gamma co-activator 1 (PGC-1α), nuclear respiratory factor 1 (NRF-1), mitochondrial transcription factor A (mtTFA), the protein levels of the mitochondria uncoupling protein 2 (UCP2), mitochondrial morphology, the insulin secretion capacity and ATP/ADP ratio. Our results show that GW501516 treatment promoted generation of mitochondrial ATP, as well as expression levels of PGC-1α, NRF-1 and mtTFA, decreased basal insulin secretion, but had no effect on glucose-stimulated insulin secretion (GSIS), increased amounts of UCP2 and changed ATP-to-ADP ratio, improved mitochondrial morphology in palmitate-treated β-cells. GW501516-induced activation of PPARδ enhanced mitochondrial energy metabolism, but also promoted a concomitant mitochondrial uncoupling and resulted in decreased basal insulin secretion and restricted GSIS; this observation indicated the possible action of a protective mechanism responding to the alleviation of excessive lipid load and basal insulin secretion in lipotoxic β-cells.
Jiang
Li
L
Department of Endocrinology, West China Hospital, Sichuan University, Chengdu, Sichuan, China. jiang_li71@163.com
Wan
Jun
J
Ke
Lin-qiu
LQ
Lü
Qing-guo
QG
Tong
Nan-wei
NW
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D017931:DNA Primers; D004734:Energy Metabolism; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000378:metabolism*; D047494:PPAR delta / Q000378:metabolism*; D019308:Palmitic Acid / Q000494:pharmacology*; D016133:Polymerase Chain Reaction
D017931:DNA Primers; D007328:Insulin; D047494:PPAR delta; D019308:Palmitic Acid