Unexpected severe consequences of Pikfyve deletion by aP2‐ or Aq‐promoter‐driven Cre expression for glucose homeostasis and mammary gland development

Systemic deficiency of PIKfyve, 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 PIKfyve 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 aP2‐ 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, aP2‐Cre‐PIKfyve(fl/fl) but not Aq‐Cre‐PIKfyve(fl/fl) females had severely impaired pregnancy‐induced mammary gland differentiation and lactogenesis, consistent with aP2‐Cre‐mediated Pikfyve excision in nonadipogenic tissues underlying this defect. Intriguingly, whereas mammary glands from postpartum control and Aq‐Cre‐PIKfyve(fl/fl) mice or ex vivo mammary gland explants showed profound upregulation of PIKfyve protein levels subsequent to prolactin receptor activation, such increases were not apparent in aP2‐Cre‐PIKfyve(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.