PDK1-FoxO1 pathway in AgRP neurons of arcuate nucleus promotes bone formation via GHRH-GH-IGF1 axis

Abstract

ObjectiveIn the hypothalamic arcuate nucleus (ARC), orexigenic agouti-related peptide (AgRP) neurons regulate feeding behavior and energy homeostasis, functions connected to bone metabolism. The 3-phosphoinositide-dependent protein kinase-1 (PDK1) serves as a major signaling molecule particularly for leptin and insulin in AgRP neurons. We asked whether PDK1 in AGRP neurons also contributes to bone metabolism.MethodsWe generated AgRP neuron-specific PDK1 knockout (Agrp Pdk1−/−) mice and those with additional AgRP neuron-specific expression of transactivation-defective FoxO1 (Agrp Pdk1−/−Δ256Foxo1). Bone metabolism in KO and WT mice was analyzed by quantitative computed tomography (QCT), bone histomorphometry, measurement of plasma biomarkers, and qPCR analysis of peptides.ResultsIn Agrp Pdk1−/− female mice aged 6 weeks, compared with Agrp Cre mice, both stature and femur length were shorter while body weight was unchanged. Cortical bone mineral density (BMD) and cancellous BMD in the femur decreased, and bone formation was delayed. Furthermore, plasma GH and IGF-1 levels were reduced in parallel with decreased mRNA expressions for GH in pituitary and GHRH in ARC. Osteoblast activity was suppressed and osteoclast activity was enhanced. These changes in stature, BMD and GH level were rescued in Agrp Pdk1−/−Δ256Foxo1 mice, suggesting that the bone abnormalities and impaired GH release were mediated by enhanced Foxo1 due to deletion of PDK1.ConclusionsThis study reveals a novel role of PDK1-Foxo1 pathway of AgRP neurons in controlling bone metabolism primarily via GHRH-GH-IGF-1 axis.

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

“…Because the decreased growth of LR Δα+β and LR Δα mice is only detected following pubertal maturation, IGF1 signaling is not the major player. Rather, our findings indicate that leptin action in growth and bone accrual is mediated by PI3K signaling (42,43). This is in line with the reduced body length of leptin signaling deficient mice and the lack of a growth phenotype following inactivation of STAT signaling in LR cells (23,24).…”

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

“…[84][85][86][87][88] Thus, changes in AgRP levels and/or signalling in LR Δα mice may explain the increased food intake, and the disruption of growth and pubertal development observed in LR Δα mice. 87,89 It is also in agreement with findings showing that PI3K is required for leptin actions on Agrp gene expression. 45 Alternatively, ablation of PI3K may have affected the acute actions of leptin in the ventral premammillary nucleus, a hypothalamic site associated with leptin action in female reproductive function.…”

“…Improved fertility was also observed in LR‐deficient db/db mice with global deletion of Agrp gene, and deletion of LR in AgRP neurones alters fertility . Thus, changes in AgRP levels and/or signalling in LR Δα mice may explain the increased food intake, and the disruption of growth and pubertal development observed in LR Δα mice . It is also in agreement with findings showing that PI3K is required for leptin actions on Agrp gene expression .…”

An evolutionary perspective on immunometabolism

“…NPY/AgRP neurons have also been shown to inhibit Kiss1-expressing neurons (34), which are critical drivers of reproductive maturation and function. AgRP neuron activation may also lead to suppression of the GH-IGF-1 axis (35). Finally, CRH can directly suppress GnRH secretion as well as GHRH-induced GH secretion (36).…”