Peroxisome proliferator-activated receptorβ/δ activation is essential for modulating p-Foxo1/Foxo1 status in functional insulin-positive cell differentiation

• Published in: Cell death & disease Vol. 6; no. 4; p. e1715
• Main Authors: Li, L, Li, T, Zhang, Y, Pan, Z, Wu, B, Huang, X, Mei, Y, Ge, L, Shen, G, Ge, R-s, Zhu, D, Lou, Y
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09-04-2015; Nature Publishing Group
• Subjects: 13/100; 13/31; 13/89; 14/63; 38/77; 631/532/1360; 631/80/86/388; 64/60; 692/308/153; 692/699/2743/137; 82/1; 82/80; Animals; Antibodies; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cell Differentiation - physiology; Forkhead Box Protein O1; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Humans; Immunology; Insulin - metabolism; Life Sciences; Mice; Mice, Inbred ICR; Original; original-article; PPAR delta - metabolism; Signal Transduction; Transfection; Up-Regulation
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2015.88

Peroxisome proliferator-activated receptors (PPARs) participate in energy homeostasis and play essential roles in diabetes therapy through their effects on non-pancreas tissues. Pathological microenvironment may influence the metabolic requirements for the maintenance of stem cell differentiation. Accordingly, understanding the mechanisms of PPARs on pancreatic
β
-cell differentiation may be helpful to find the underlying targets of disrupted energy homeostasis under the pancreatic disease condition. PPARs are involved in stem cell differentiation via mitochondrial oxidative phosphorylation, but the subtype member activation and the downstream regulation in functional insulin-positive (INS
+
) cell differentiation remain unclear. Here, we show a novel role of PPAR
β/
δ
activation in determining INS
+
cell differentiation and functional maturation. We found PPAR
β/δ
expression selectively upregulated in mouse embryonic pancreases or stem cells-derived INS
+
cells at the pancreatic mature stage
in vivo
and
in vitro
. Strikingly, given the inefficiency of generating INS
+
cells
in vitro
, PPAR
β/
δ
activation displayed increasing mouse and human ES cell-derived INS
+
cell numbers and insulin secretion. This phenomenon was closely associated with the forkhead box protein O1 (Foxo1) nuclear shuttling, which was dependent on PPAR
β/
δ
downstream PI3K/Akt signaling transduction. The present study reveals the essential role of PPAR
β/
δ
activation on p-Foxo1/Foxo1 status, and in turn, determining INS
+
cell generation and insulin secretion
via
affecting pancreatic and duodenal homeobox-1 expression. The results demonstrate the underlying mechanism by which PPAR
β/δ
activation promotes functional INS
+
cell differentiation. It also provides potential targets for anti-diabetes drug discovery and hopeful clinical applications in human cell therapy.