PI3Kα inactivation in leptin receptor cells increases leptin sensitivity but disrupts growth and reproduction

García-Galiano, David; Borges, Beatriz de Carvalho; Donato, José; Allen, Susan J.; Bellefontaine, Nicole; Wang, Mengjie; Zhao, Jean J.; Kozloff, Kenneth M.; Hill, Jennifer W.; Elias, Carol F.

doi:10.1172/jci.insight.96728

Cited by 31 publications

(50 citation statements)

References 75 publications

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“…The experimental group was comprised of mice homozygous for three alleles: LR‐Cre, p110α‐floxed and p110β‐floxed, named LR Δα+β . We used LR‐Cre homozygous mice because, in preliminary studies, we found only partial deletion of PI3K in LR cells of heterozygous LR Cre/+ mice harvested by fluorescence activated cell sorting . This finding is also in agreement with previous studies using a different LR‐Cre mouse line .…”

Section: Effects Of Deletion Of P110α and P110β Subunits In Lr Neuronessupporting

confidence: 88%

“…We used a very similar approach and found that, although control mice had early puberty onset, LR Δα female mice were unresponsive to the effects of leptin on the timing of pubertal development. Another interesting finding from this experiment was the increased leptin sensitivity in metabolic regulation of the mutant mice potentially as a result of the increased basal levels of pAkt and leptin‐induced phosphorylated STAT‐3 and the decreased levels of the PIP3 phosphatase PTEN …”

Section: Effects Of Deletion Of P110α Subunits In Lr Neuronesmentioning

confidence: 83%

“…To assess the direct role of PI3K downstream of leptin, we generated mice with deletion of both p110α and p110β catalytic subunits in LR cells . The experimental group was comprised of mice homozygous for three alleles: LR‐Cre, p110α‐floxed and p110β‐floxed, named LR Δα+β .…”

Section: Effects Of Deletion Of P110α and P110β Subunits In Lr Neuronesmentioning

confidence: 99%

“…To assess whether Cre in homozygosity alters LR function, we performed a systematic evaluation of LR cre/cre mouse phenotype. No ectopic expression of Cre (using reporter genes) and no metabolic, growth or reproductive deficits were observed …”

Section: Effects Of Deletion Of P110α and P110β Subunits In Lr Neuronesmentioning

confidence: 99%

“…They also showed an increased food intake (when normalised by body weight), energy expenditure, locomotor activity and brown adipose tissue Ucp1 expression, suggesting increased thermogenesis. Females (but not males) had delayed puberty determined by late vaginal opening (a sign of puberty onset) and delayed first oestrus (puberty completion) . Whether disruption of the actions of oestradiol as a result of PI3K imbalance in LR cells is the cause of the sexually dimorphic phenotype in reproductive function requires further evaluation.…”

Section: Effects Of Deletion Of P110α and P110β Subunits In Lr Neuronesmentioning

confidence: 99%

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PI3K signalling in leptin receptor cells: Role in growth and reproduction

García-Galiano

Borges

Allen

et al. 2019

J Neuroendocrinology

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Nutrition and growth are important signals for pubertal development, although how they are perceived and integrated in brain circuits has not been well defined. Growth hormones and metabolic cues both recruit phosphatidylinositol 3‐kinase (PI3K) signalling in hypothalamic sites, although whether they converge into the same neuronal population(s) is also not known. In this review, we discuss recent findings from our laboratory showing the role of PI3K subunits in cells directly responsive to the adipocyte‐derived hormone leptin in the coordination of growth, pubertal development and fertility. Mice with deletion of PI3K p110α and p110β catalytic subunits in leptin receptor cells (LRΔα+β) have a lean phenotype associated with increased energy expenditure, locomotor activity and thermogenesis. The LRΔα+β mice also show deficient growth and delayed puberty. Deletion of a single subunit (ie, p110α) in LR cells (LRΔα) causes a similar phenotype of increased energy expenditure, deficient growth and delayed pubertal development, indicating that these functions are preferably controlled by p110α. The LRΔα mice show enhanced leptin sensitivity in metabolic regulation but, remarkably, these mice are unresponsive to the effects of leptin on growth and puberty. PI3K is also recruited by insulin and a subpopulation of LR neurones is responsive to i.c.v. insulin administration. Deletion of insulin receptor in LR cells causes no changes in body weight or linear growth and induces only a mild delay in pubertal completion. Our findings demonstrate that PI3K in LR cells plays an essential role in growth and reproduction. We will also discuss the potential neural pathways underlying these effects.

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Section: Effects Of Deletion Of P110α and P110β Subunits In Lr Neuronessupporting

confidence: 88%

Section: Effects Of Deletion Of P110α Subunits In Lr Neuronesmentioning

confidence: 83%

Section: Effects Of Deletion Of P110α and P110β Subunits In Lr Neuronesmentioning

confidence: 99%

Section: Effects Of Deletion Of P110α and P110β Subunits In Lr Neuronesmentioning

confidence: 99%

Section: Effects Of Deletion Of P110α and P110β Subunits In Lr Neuronesmentioning

confidence: 99%

See 3 more Smart Citations

PI3K signalling in leptin receptor cells: Role in growth and reproduction

García-Galiano

Borges

Allen

et al. 2019

J Neuroendocrinology

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Lin28 gene and mammalian puberty

Cao

Gao

Jiang

et al. 2020

Molecular Reproduction Devel

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Lin28a and Lin28b, homologs of the Caenorhabditis elegans Lin28 gene, play important roles in cell pluripotency, reprogramming, and tumorigenicity. Recently, genomewide association and transgenic studies showed that Lin28a and/or Lin28b gene were involved in the onset of mammalian puberty, the stage representing the attainment of reproduction capacity; however, the detailed mechanism of these genes in mammalian puberty remains largely unknown. The present paper reviews the research progress on the roles of Lin28a/b genes in the onset of mammalian puberty by analyzing the results coming from gene expression patterns, mutations, and transgenic studies, and put forward possible pathways for further studies on their roles in animal reproduction.expression pattern, gene mutation, glucose metabolism, Lin28a, Lin28b, onset of puberty

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