Open AccessUnexpected severe consequences of Pikfyve deletion by aP 2‐ or Aq‐promoter‐driven Cre expression for glucose homeostasis and mammary gland development
Author(s) -
Ikonomov Ognian C.,
Sbrissa Diego,
Delvecchio Khortnal,
A. Rillema James,
Shisheva Assia
Publication year - 2016
Publication title -
physiological reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.918
H-Index - 39
ISSN - 2051-817X
DOI - 10.14814/phy2.12812
Subject(s) - biology , endocrinology , medicine , adipose tissue , glucose homeostasis , homeostasis , glucose uptake , downregulation and upregulation , insulin resistance , insulin receptor , insulin , microbiology and biotechnology , biochemistry , gene
Abstract Systemic deficiency of PIK fyve, the evolutionarily conserved phosphoinositide kinase synthesizing cellular PtdIns5P and PtdIns(3,5)P 2 and implicated in insulin signaling, causes early embryonic death in mice. In contrast, mice with muscle‐specific Pikfyve disruption have normal lifespan but exhibit early‐age whole‐body glucose intolerance and muscle insulin resistance, thus establishing the key role of muscle PIK fyve in glucose homeostasis. Fat and muscle tissues control postprandial glucose clearance through different mechanisms, raising questions as to whether adipose Pikfyve disruption will also trigger whole‐body metabolic abnormalities, and if so, what the mechanism might be. To clarify these issues, here we have characterized two new mouse models with adipose tissue disruption of Pikfyve through Cre recombinase expression driven by adipose‐specific aP 2‐ or adiponectin (Aq) promoters. Whereas both mouse lines were ostensibly normal until adulthood, their glucose homeostasis and systemic insulin sensitivity were severely dysregulated. These abnormalities stemmed in part from accelerated fat‐cell lipolysis and elevated serum FFA . Intriguingly, aP 2‐Cre‐ PIK fyve fl/fl but not Aq‐Cre‐ PIK fyve fl/fl females had severely impaired pregnancy‐induced mammary gland differentiation and lactogenesis, consistent with aP 2‐Cre‐mediated Pikfyve excision in nonadipogenic tissues underlying this defect. Intriguingly, whereas mammary glands from postpartum control and Aq‐Cre‐ PIK fyve fl/fl mice or ex vivo mammary gland explants showed profound upregulation of PIK fyve protein levels subsequent to prolactin receptor activation, such increases were not apparent in aP 2‐Cre‐ PIK fyve fl/fl females. Collectively, our data identify for the first time that adipose tissue Pikfyve plays a key role in the mechanisms regulating glucose homeostasis and that the PIKfyve pathway is critical in mammary epithelial differentiation during pregnancy and lactogenesis downstream of prolactin receptor signaling.