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Essential Role of Pten in Body Size Determination and Pancreatic ß-Cell Homeostasis In Vivo

Department of Medicine, Medical Biophysics, Institute of Medical Science, Ontario Cancer Institute, University of Toronto, Toronto, Ontario, Canada,¹ Department of Physiology, University of Toronto, Toronto, Ontario, Canada,² Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada,³ Department of Medicine, Columbia University, New York, New York,⁴ Department of Molecular Biology, Akita University School of Medicine, Akita, Japan,⁵ The Advanced Medical Discovery Institute and The Campbell Family Institute for Breast Cancer Research, Toronto, Ontario, Canada,⁶ Department of Medicine, St. Michael's Hospital, Toronto, Ontario, Canada⁷

Received 8 February 2006/ Returned for modification 21 March 2006/ Accepted 30 March 2006

PTEN (phosphatase with tensin homology) is a potent negative regulator of phosphoinositide 3-kinase (PI3K)/Akt signaling, an evolutionarily conserved pathway that signals downstream of growth factors, including insulin and insulin-like growth factor 1. In lower organisms, this pathway participates in fuel metabolism and body size regulation and insulin-like proteins are produced primarily by neuronal structures, whereas in mammals, the major source of insulin is the pancreatic ß cells. Recently, rodent insulin transcription was also shown in the brain, particularly the hypothalamus. The specific regulatory elements of the PI3K pathway in these insulin-expressing tissues that contribute to growth and metabolism in higher organisms are unknown. Here, we report PTEN as a critical determinant of body size and glucose metabolism when targeting is driven by the rat insulin promoter in mice. The partial deletion of PTEN in the hypothalamus resulted in significant whole-body growth restriction and increased insulin sensitivity. Efficient PTEN deletion in ß cells led to increased islet mass without compromise of ß-cell function. Parallel enhancement in PI3K signaling was found in PTEN-deficient hypothalamus and ß cells. Together, we have shown that PTEN in insulin-transcribing cells may play an integrative role in regulating growth and metabolism in vivo.

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