title: Peroxisome proliferator-activated receptorβ/δ activation is essential for modulating p-Foxo1/Foxo1 status in functional insulin-positive cell differentiation.
abstract: 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 PPARβ/δ activation in determining INS+ cell differentiation and functional maturation. We found PPARβ/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, PPARβ/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 PPARβ/δ downstream PI3K/Akt signaling transduction. The present study reveals the essential role of PPARβ/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 PPARβ/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.
authors: Institute of Pharmacology, Toxicology and Biochemical Pharmaceutics, Key Innovation Team for Stem Cell Translational Medicine of Cardiovascular Disease of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
authors: L
authors: L
authors: Li
authors: Institute of Pharmacology, Toxicology and Biochemical Pharmaceutics, Key Innovation Team for Stem Cell Translational Medicine of Cardiovascular Disease of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
authors: T
authors: T
authors: Li
authors: Institute of Pharmacology, Toxicology and Biochemical Pharmaceutics, Key Innovation Team for Stem Cell Translational Medicine of Cardiovascular Disease of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
authors: Y
authors: Y
authors: Zhang
authors: Institute of Pharmacology, Toxicology and Biochemical Pharmaceutics, Key Innovation Team for Stem Cell Translational Medicine of Cardiovascular Disease of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
authors: Z
authors: Z
authors: Pan
authors: Institute of Pharmacology, Toxicology and Biochemical Pharmaceutics, Key Innovation Team for Stem Cell Translational Medicine of Cardiovascular Disease of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
authors: B
authors: B
authors: Wu
authors: Cardiovascular Key Laboratory of Zhejiang Province, The 2nd Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
authors: X
authors: X
authors: Huang
authors: Institute of Pharmacology, Toxicology and Biochemical Pharmaceutics, Key Innovation Team for Stem Cell Translational Medicine of Cardiovascular Disease of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
authors: Y
authors: Y
authors: Zhang
authors: Institute of Pharmacology, Toxicology and Biochemical Pharmaceutics, Key Innovation Team for Stem Cell Translational Medicine of Cardiovascular Disease of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
authors: Y
authors: Y
authors: Mei
authors: Institute of Pharmacology, Toxicology and Biochemical Pharmaceutics, Key Innovation Team for Stem Cell Translational Medicine of Cardiovascular Disease of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
authors: L
authors: L
authors: Ge
authors: Institute of Pharmacology, Toxicology and Biochemical Pharmaceutics, Key Innovation Team for Stem Cell Translational Medicine of Cardiovascular Disease of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
authors: G
authors: G
authors: Shen
authors: 1] The Population Council at the Rockefeller University, New York, NY 10021, USA [2] Institute of Reproductive Biomedicine, the 2nd Affiliated Hospital, Wenzhou Medical University, Wenzhou, China.
authors: R-s
authors: RS
authors: Ge
authors: Institute of Pharmacology, Toxicology and Biochemical Pharmaceutics, Key Innovation Team for Stem Cell Translational Medicine of Cardiovascular Disease of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
authors: D
authors: D
authors: Zhu
authors: Institute of Pharmacology, Toxicology and Biochemical Pharmaceutics, Key Innovation Team for Stem Cell Translational Medicine of Cardiovascular Disease of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
authors: Y
authors: Y
authors: Lou
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D051379:Mice; D008813:Mice, Inbred ICR; D047494:PPAR delta / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D015854:Up-Regulation
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D007328:Insulin; D047494:PPAR delta