An essential role for IGF2 in cartilage development and glucose metabolism during postnatal long bone growth

Uchimura, Tomoya; Hollander, Judith M.; Nakamura, Daisy S.; Liu, Zhiyi; Rosen, Clifford J.; Georgakoudi, Irene; Zeng, Li

doi:10.1242/dev.155598

Cited by 51 publications

(42 citation statements)

References 103 publications

(113 reference statements)

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“…In contrast to the HFD, LFD increased circulating levels of IGF2 and this effect was only observed in females. IGF2 participates in bone growth, adipose tissue accumulation and glucose metabolism, stimulating glucose uptake by adipocytes and acting directly at the level of the pancreas ( 57 – 59 ). Thus, it is possible that the high sucrose content of the LFD is involved in stimulating this rise in IGFBP2.…”

Section: Discussionmentioning

confidence: 99%

Short-Term Diet Induced Changes in the Central and Circulating IGF Systems Are Sex Specific

et al. 2020

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Insulin-like growth factor (IGF) 1 exerts a wide range of functions in mammalians participating not only in the control of growth and metabolism, but also in other actions such as neuroprotection. Nutritional status modifies the IGF system, although little is known regarding how diet affects the newest members of this system including pregnancy-associated plasma protein-A (PAPP-A) and PAPP-A2, proteases that liberate IGF from the IGF-binding proteins (IGFBPs), and stanniocalcins (STCs) that inhibit PAPP-A and PAPP-A2 activity. Here we explored if a 1-week dietary change to either a high-fat diet (HFD) or a low-fat diet (LFD) modifies the central and peripheral IGF systems in both male and female Wistar rats. The circulating IGF system showed sex differences in most of its members at baseline. Males had higher levels of both free (p < 0.001) and total IGF1 (p < 0.001), as well as IGFBP3 (p < 0.001), IGFBP5 (p < 0.001), and insulin (p < 0.01). In contrast, females had higher serum levels of PAPP-A2 (p < 0.05) and IGFBP2 (p < 0.001). The responses to a short-term dietary change were both diet and sex specific. Circulating levels of IGF2 increased in response to LFD intake in females (p < 0.001) and decreased in response to HFD intake in males (p < 0.001). In females, LFD intake also decreased circulating IGFBP2 levels (p < 0.001). In the hypothalamus LFD intake increased IGF2 (p < 0.01) and IGFBP2 mRNA (p < 0.001) levels, as well as the expression of NPY (p < 0.001) and AgRP (p < 0.01), but only in males. In conclusion, short-term LFD intake induced more changes in the peripheral and central IGF system than did short-term HFD intake. Moreover, these changes were sex-specific, with IGF2 and IGFBP2 being more highly affected than the other members of the IGF system. One of the main differences between the commercial LFD employed and the HFD or normal rodent chow is that the LFD has a significantly higher sucrose content, suggesting that this nutrient could be involved in the observed responses.

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Section: Discussionmentioning

confidence: 99%

Short-Term Diet Induced Changes in the Central and Circulating IGF Systems Are Sex Specific

et al. 2020

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“…Finally, it is not clear whether and how growth factors modulate glucose metabolism in the developing cartilage. A recent study has indicated that Igf2 deletion leads to elevated and imbalanced glucose metabolism in the growth plate cartilage, but it remains unclear whether such dysregulation is directly due to the loss of Igf2 signaling or secondary to other changes 25 . Overall, further studies are necessary to understand the potential role and mechanism of metabolic regulation in skeletal development.…”

Section: Introductionmentioning

confidence: 99%

Glucose metabolism induced by Bmp signaling is essential for murine skeletal development

2018

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Much of the mammalian skeleton originates from a cartilage template eventually replaced by bone via endochondral ossification. Despite much knowledge about growth factors and nuclear proteins in skeletal development, little is understood about the role of metabolic regulation. Here we report that genetic deletion of the glucose transporter Glut1 (Slc2a1), either before or after the onset of chondrogenesis in the limb, severely impairs chondrocyte proliferation and hypertrophy, resulting in dramatic shortening of the limbs. The cartilage defects are reminiscent to those caused by deficiency in Bmp signaling. Importantly, deletion of Bmpr1a in chondrocytes markedly reduces Glut1 levels in vivo, whereas recombinant BMP2 increases Glut1 mRNA and protein levels, boosting glucose metabolism in primary chondrocytes. Biochemical studies identify a Bmp-mTORC1-Hif1a signaling cascade resulting in upregulation of Glut1 in chondrocytes. The results therefore uncover a hitherto unknown connection between Bmp signaling and glucose metabolism in the regulation of cartilage development.

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“…HC loss is irreversible in adult mammals, whereas HCs can be regenerated from supporting cells (SCs) in the inner ear of birds and fish [1]. Recent studies have shown that in newborn mice, HCs can also be regenerated from SCs, especially from a subset of Lgr5+ progenitor cells [2][3][4][5][6][7][8]. However, this regenerative ability is quickly lost as the mice age [2-4, 9, 10].…”

Section: Introductionmentioning

confidence: 99%

Knockdown of Foxg1 in supporting cells increases the trans-differentiation of supporting cells into hair cells in the neonatal mouse cochlea

Zhang

Dong

et al. 2019

Cell. Mol. Life Sci.

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Foxg1 is one of the forkhead box genes that are involved in morphogenesis, cell fate determination, and proliferation, and Foxg1 was previously reported to be required for morphogenesis of the mammalian inner ear. However, Foxg1 knock-out mice die at birth, and thus the role of Foxg1 in regulating hair cell (HC) regeneration after birth remains unclear. Here we used Sox2 CreER/+ Foxg1 loxp/loxp mice and Lgr5-EGFP CreER/+ Foxg1 loxp/loxp mice to conditionally knock down Foxg1 specifically in Sox2+ SCs and Lgr5+ progenitors, respectively, in neonatal mice. We found that Foxg1 conditional knockdown (cKD) in Sox2+ SCs and Lgr5+ progenitors at postnatal day (P)1 both led to large numbers of extra HCs, especially extra inner HCs (IHCs) at P7, and these extra IHCs with normal hair bundles and synapses could survive at least to P30. The EdU assay failed to detect any EdU+ SCs, while the SC number was significantly decreased in Foxg1 cKD mice, and lineage tracing data showed that much more tdTomato+ HCs originated from Sox2+ SCs in Foxg1 cKD mice compared to the control mice. Moreover, the sphere-forming assay showed that Foxg1 cKD in Lgr5+ progenitors did not significantly change their sphereforming ability. All these results suggest that Foxg1 cKD promotes HC regeneration and leads to large numbers of extra HCs probably by inducing direct trans-differentiation of SCs and progenitors to HCs. Real-time qPCR showed that cell cycle and Notch signaling pathways were significantly down-regulated in Foxg1 cKD mice cochlear SCs. Together, this study provides new evidence for the role of Foxg1 in regulating HC regeneration from SCs and progenitors in the neonatal mouse cochlea.

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An essential role for IGF2 in cartilage development and glucose metabolism during postnatal long bone growth

Cited by 51 publications

References 103 publications

Short-Term Diet Induced Changes in the Central and Circulating IGF Systems Are Sex Specific

Short-Term Diet Induced Changes in the Central and Circulating IGF Systems Are Sex Specific

Glucose metabolism induced by Bmp signaling is essential for murine skeletal development

Knockdown of Foxg1 in supporting cells increases the trans-differentiation of supporting cells into hair cells in the neonatal mouse cochlea

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