40 YEARS of IGF1: Understanding the tissue-specific roles of IGF1/IGF1R in regulating metabolism using the Cre/loxP system

Kineman, Rhonda D; Río-Moreno, Mercedes del; Sarmento‐Cabral, André

doi:10.1530/jme-18-0076

Cited by 74 publications

(79 citation statements)

References 86 publications

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“…These mice were also overtly normal. Since both INSR‐SCKO and IGF1R‐SCKO mice were overtly normal, we thought that insulin and IGF1 could be acting in a redundant fashion in SCs as they do in other tissues (Kineman et al, ). So we bred these lines together to generate INSR/IGF1R SCKO mice (heretofore referred to as SCKO mice).…”

Section: Resultsmentioning

confidence: 99%

“…Administration of STZ decreases in nerve conduction and reduces mechanical and thermal sensation (O'Brien et al, 2014). Insulin and insulin-like growth factor (IGF1) both activate the phosphoinositide 3-kinase/PKB, protein kinase b/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway and often act in a redundant fashion (Kineman, del Rio-Moreno, & Sarmento-Cabral, 2018). In accord, IGF1 −/− mice also have neuropathy, including reduced motor and sensory nerve conduction velocities (NCVs; Gao et al, 1999).…”

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confidence: 99%

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Disrupting insulin signaling in Schwann cells impairs myelination and induces a sensory neuropathy

Hackett

Strickland

Milbrandt

2019

Glia

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Although diabetic mice have been studied for decades, little is known about the cell type specific contributions to diabetic neuropathy (DN). Schwann cells (SCs) myelinate and provide trophic support to peripheral nervous system axons. Altered SC metabolism leads to myelin defects, which can be seen both in inherited and DNs. How SC metabolism is altered in DN is not fully understood, but it is clear that insulin resistance underlies impaired lipid metabolism in many cell types throughout the body via the phosphoinositide 3‐kinase/protein kinase b (PKB)/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway. Here, we created an insulin resistant SC by deleting both insulin receptor (INSR) and insulin‐like growth factor receptor 1 (IGF1R), to determine the role of this signaling pathway in development and response to injury in order to understand SC defects in DN. We found that myelin is thinner throughout development and adulthood in INSR/IGF1R Schwann cell specific knock out mice. The nerves of these mutant mice had reduced expression of key genes that mediate fatty acid and cholesterol synthesis due to reduced mTOR–sterol regulatory element‐binding protein signaling. In adulthood, these mice show sensory neuropathy phenotypes reminiscent of diabetic mice. Altogether, these data suggest that SCs may play an important role in DN and targeting their metabolism could lead to new therapies for DN.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Disrupting insulin signaling in Schwann cells impairs myelination and induces a sensory neuropathy

Hackett

Strickland

Milbrandt

2019

Glia

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“…These anti-hypertrophic responses relied on the activation of the physiological cardiac hypertrophy signaling pathway IGFR/PI3K/AKT. IGF-1 signaling regulates cardiac contraction, hypertrophy, aging, metabolism, autophagy, and apoptosis 27 . IGF-1 exerts its function by binding to membrane receptor IGF1R, which activates a 110-kDa lipid kinase PI3K subgroup Iα (p110α), leading to phosphorylation and activation of AKT1 28 .…”

Section: Discussionmentioning

confidence: 99%

A cathelicidin-related antimicrobial peptide suppresses cardiac hypertrophy induced by pressure overload by regulating IGFR1/PI3K/AKT and TLR9/AMPKα

et al. 2020

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Cathelicidin-related antimicrobial peptide (CRAMP), an antimicrobial peptide, was reported to protect against myocardial ischemia/reperfusion injury. However, the effect of CRAMP on pressure overload-induced cardiac hypertrophy was unknown. This study explored the role of CRAMP on cardiac hypertrophy. A cardiac hypertrophy mouse model was induced by aortic banding surgery. Seven days after surgery, mice were given mCRAMP by intraperitoneal injection (8 mg/kg/d) for 7 weeks. Cardiac hypertrophy was evaluated by the hypertrophic response and fibrosis level as well as cardiac function. Mice were also injected with AAV9-shCRAMP to knockdown CRAMP in the mouse heart. CRAMP levels first increased and then reduced in the remodeling heart, as well as in angiotensin IIstimulated endothelial cells but not in cardiomyocytes and fibroblasts. mCRAMP protected against the pressure overload-induced cardiac remodeling process, while CRAMP knockdown accelerated this process. mCRAMP reduced the inflammatory response and oxidative stress in the hypertrophic heart, while mCRAMP deficiency deteriorated the pressure overload-induced inflammatory response and oxidative stress. mCRAMP inhibited the angiotensin IIstimulated hypertrophic response and oxidative stress in neonatal rat cardiomyocytes, but mCRAMP did not help the angiotensin II-induced inflammatory response and oxidative stress in endothelial cells. Mechanistically, we found that mCRAMP suppressed the cardiac hypertrophic response by activating the IGFR1/PI3K/AKT pathway via directly binding to IGFR1. AKT knockout mice completely reversed the anti-hypertrophic effect of mCRAMP but not its anti-oxidative effect. We also found that mCRAMP ameliorated cardiac oxidative stress by activating the TLR9/AMPKa pathway. This was confirmed by a TLR9 knockout mouse experiment, in which a TLR9 knockout partly reversed the anti-hypertrophic effect of mCRAMP and completely counteracted the anti-oxidative effect of mCRAMP. In summary, mCRAMP protected against pressure overload-induced cardiac hypertrophy by activating both the IGFR1/PI3K/AKT and TLR9/ AMPKa pathways in cardiomyocytes.

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“…Females were excluded from this study to reduce confounding factors, as females are intrinsically more variable than males due to their cyclical reproductive hormones, which may interfere in the body condition [ 27 ]. Liver tissue samples were also collected due to the liver’s crucial role in growth and organ development from the fetal stage [ 28 , 29 ]. Then, a more in-depth study was done on this tissue, studying its proteomic signature to find molecular cues related to the phenotypic variations after VET.…”

Section: Methodsmentioning

confidence: 99%

Long-Term Phenotypic and Proteomic Changes Following Vitrified Embryo Transfer in the Rabbit Model

García‐Domínguez

Marco‐Jiménez

Peñaranda

et al. 2020

Animals

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Nowadays, assisted reproductive technologies (ARTs) are considered valuable contributors to our past, but a future without their use is inconceivable. However, in recent years, several studies have evidenced a potential impact of ART on long-term development in mammal species. To date, the long-term follow-up data are still limited. So far, studies have mainly focused on in vitro fertilization or in vitro culture, with information from gametes/embryos cryopreservation field being practically missing. Herein, we report an approach to determine whether a vitrified embryo transfer procedure would have long-term consequences on the offspring. Using the rabbit as a model, we compared animals derived from vitrified-transferred embryos versus those naturally conceived, studying the growth performance, plus the weight throughout life, and the internal organs/tissues phenotype. The healthy status was assessed over the hematological and biochemical parameters in peripheral blood. Additionally, a comparative proteomic analysis was conducted in the liver tissue to investigate molecular cues related to vitrified embryo transfer in an adult tissue. After vitrified embryo transfer, birth weight was increased, and the growth performance was diminished in a sex-specific manner. In addition, vitrified-transferred animals showed significantly lower body, liver and heart weights in adulthood. Molecular analyses revealed that vitrified embryo transfer triggers reprogramming of the liver proteome. Functional analysis of the differentially expressed proteins showed changes in relation to oxidative phosphorylation and dysregulations in the zinc and lipid metabolism, which has been reported as possible causes of a disturbed growth pattern. Therefore, we conclude that vitrified embryo transfer is not a neutral procedure, and it incurs long-term effects in the offspring both at phenotypic and molecular levels. These results described a striking example of the developmental plasticity exhibited by the mammalian embryo.

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40 YEARS of IGF1: Understanding the tissue-specific roles of IGF1/IGF1R in regulating metabolism using the Cre/loxP system

Cited by 74 publications

References 86 publications

Disrupting insulin signaling in Schwann cells impairs myelination and induces a sensory neuropathy

Disrupting insulin signaling in Schwann cells impairs myelination and induces a sensory neuropathy

A cathelicidin-related antimicrobial peptide suppresses cardiac hypertrophy induced by pressure overload by regulating IGFR1/PI3K/AKT and TLR9/AMPKα

Long-Term Phenotypic and Proteomic Changes Following Vitrified Embryo Transfer in the Rabbit Model

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