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Sriram Gubbi, Gabriela Farias Quipildor, Nir Barzilai, Derek M Huffman, and Sofiya Milman

The insulin-like growth factor 1 (IGF1) signaling pathway has emerged as a major regulator of the aging process, from rodents to humans. However, given the pleiotropic actions of IGF1, its role in the aging brain remains complex and controversial. While IGF1 is clearly essential for normal development of the central nervous system, conflicting evidence has emerged from preclinical and human studies regarding its relationship to cognitive function, as well as cerebrovascular and neurodegenerative disorders. This review delves into the current state of the evidence examining the role of IGF1 in the aging brain, encompassing preclinical and clinical studies. A broad examination of the data indicates that IGF1 may indeed play opposing roles in the aging brain, depending on the underlying pathology and context. Some evidence suggests that in the setting of neurodegenerative diseases that manifest with abnormal protein deposition in the brain, such as Alzheimer’s disease, reducing IGF1 signaling may serve a protective role by slowing disease progression and augmenting clearance of pathologic proteins to maintain cellular homeostasis. In contrast, inducing IGF1 deficiency has also been implicated in dysregulated function of cognition and the neurovascular system, suggesting that some IGF1 signaling may be necessary for normal brain function. Furthermore, states of acute neuronal injury, which necessitate growth, repair and survival signals to persevere, typically demonstrate salutary effects of IGF1 in that context. Appreciating the dual, at times opposing ‘Dr Jekyll’ and ‘Mr Hyde’ characteristics of IGF1 in the aging brain, will bring us closer to understanding its impact and devising more targeted IGF1-related interventions.

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Shoshana Yakar, Haim Werner, and Clifford J Rosen

The discovery of the growth hormone (GH)-mediated somatic factors (somatomedins), insulin-like growth factor (IGF)-I and -II, has elicited an enormous interest primarily among endocrinologists who study growth and metabolism. The advancement of molecular endocrinology over the past four decades enables investigators to re-examine and refine the established somatomedin hypothesis. Specifically, gene deletions, transgene overexpression or more recently, cell-specific gene-ablations, have enabled investigators to study the effects of the Igf1 and Igf2 genes in temporal and spatial manners. The GH/IGF axis, acting in an endocrine and autocrine/paracrine fashion, is the major axis controlling skeletal growth. Studies in rodents have clearly shown that IGFs regulate bone length of the appendicular skeleton evidenced by changes in chondrocytes of the proliferative and hypertrophic zones of the growth plate. IGFs affect radial bone growth and regulate cortical and trabecular bone properties via their effects on osteoblast, osteocyte and osteoclast function. Interactions of the IGFs with sex steroid hormones and the parathyroid hormone demonstrate the significance and complexity of the IGF axis in the skeleton. Finally, IGFs have been implicated in skeletal aging. Decreases in serum IGFs during aging have been correlated with reductions in bone mineral density and increased fracture risk. This review highlights many of the most relevant studies in the IGF research landscape, focusing in particular on IGFs effects on the skeleton.

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Cheryl A Conover and Claus Oxvig

The zinc metalloproteinase, PAPP-A, enhances local insulin-like growth factor (IGF) action through cleavage of inhibitory IGF-binding proteins, thereby increasing IGF available for IGF receptor-mediated cell proliferation, migration and survival. In many tumors, enhanced IGF receptor signaling is associated with tumor growth, invasion and metastasis. We will first discuss PAPP-A structure and function, and post-translational inhibitors of PAPP-A expression or proteolytic activity. We will then review the evidence supporting an important role for PAPP-A in many cancers, including breast, ovarian and lung cancer, and Ewing sarcoma.

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David R Clemmons

The IGF-binding protein family contains six members that share significant structural homology. Their principal function is to regulate the actions of IGF1 and IGF2. These proteins are present in plasma and extracellular fluids and regulate access of both IGF1 and II to the type I IGF receptor. Additionally, they have functions that are independent of their ability to bind IGFs. Each protein is regulated independently of IGF1 and IGF2, and this provides an important mechanism by which other hormones and physiologic variables can regulate IGF actions indirectly. Several members of the family are sensitive to changes in intermediary metabolism. Specifically the presence of obesity/insulin resistance can significantly alter the expression of these proteins. Similarly changes in nutrition or catabolism can alter their synthesis and degradation. Multiple hormones such as glucocorticoids, androgens, estrogen and insulin regulate IGFBP synthesis and bioavailability. In addition to their ability to regulate IGF access to receptors these proteins can bind to distinct cell surface proteins or proteins in extracellular matrix and several cellular functions are influenced by these interactions. IGFBPs can be transported intracellularly and interact with nuclear proteins to alter cellular physiology. In pathophysiologic states, there is significant dysregulation between the changes in IGFBP synthesis and bioavailability and changes in IGF1 and IGF2. These discordant changes can lead to marked alterations in IGF action. Although binding protein physiology and pathophysiology are complex, experimental results have provided an important avenue for understanding how IGF actions are regulated in a variety of physiologic and pathophysiologic conditions.

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Richard C Lindsey, Charles H Rundle, and Subburaman Mohan

Insulin-like growth factor 1(IGF1) and ephrin ligand (EFN)–receptor (EPH) signaling are both crucial for bone cell function and skeletal development and maintenance. IGF1 signaling is the major mediator of growth hormone-induced bone growth, but a host of different signals and factors regulate IGF1 signaling at the systemic and local levels. Disruption of the Igf1 gene results in reduced peak bone mass in both experimental animal models and humans. Additionally, EFN–EPH signaling is a complex system which, particularly through cell–cell interactions, contributes to the development and differentiation of many bone cell types. Recent evidence has demonstrated several ways in which the IGF1 and EFN–EPH signaling pathways interact with and depend upon each other to regulate bone cell function. While much remains to be elucidated, the interaction between these two signaling pathways opens a vast array of new opportunities for investigation into the mechanisms of and potential therapies for skeletal conditions such as osteoporosis and fracture repair.

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Pierre Poinsot, Martin Schwarzer, Noël Peretti, and François Leulier

In most animal species, postnatal growth is controlled by conserved insulin/insulin-like growth factor (IGF) signaling. In mammals, juvenile growth is characterized by a longitudinal bone growth resulting from the ossification of the growth plate. This ossification is under IGF1 influence through endocrine and paracrine mechanisms. Moreover, the nutritional status has been largely described as an important factor influencing the insulin/insulin-like growth factor signaling. It is now well established that the gut microbiota modulates the nutrient availability of its host. Hence, studies of the interaction between nutritional status, gut microbiota and bone growth have recently emerged. Here, we review recent findings using experimental models about the impact of gut bacteria on the somatotropic axis and its consequence on the bone growth. We also discuss the perspectives of these studies in opening an entire field for clinical interventions.

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Rhonda D Kineman, Mercedes del Rio-Moreno, and André Sarmento-Cabral

It is clear that insulin-like growth factor-1 (IGF1) is important in supporting growth and regulating metabolism. The IGF1 found in the circulation is primarily produced by the liver hepatocytes, but healthy mature hepatocytes do not express appreciable levels of the IGF1 receptor (IGF1R). Therefore, the metabolic actions of IGF1 are thought to be mediated via extra-hepatocyte actions. Given the structural and functional homology between IGF1/IGF1R and insulin receptor (INSR) signaling, and the fact that IGF1, IGF1R and INSR are expressed in most tissues of the body, it is difficult to separate out the tissue-specific contributions of IGF1/IGF1R in maintaining whole body metabolic function. To circumvent this problem, over the last 20 years, investigators have taken advantage of the Cre/loxP system to manipulate IGF1/IGF1R in a tissue-dependent, and more recently, an age-dependent fashion. These studies have revealed that IGF1/IGF1R can alter extra-hepatocyte function to regulate hormonal inputs to the liver and/or alter tissue-specific carbohydrate and lipid metabolism to alter nutrient flux to liver, where these actions are not mutually exclusive, but serve to integrate the function of all tissues to support the metabolic needs of the organism.

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Yanning Li, Yan Zhong, Wenjian Gong, Xuehan Gao, Huanli Qi, Kun Liu, and Jinsheng Qi

Activation of transforming growth factor β1 (TGFB1)/SMAD3 signaling may lead to additional synthesis of collagen type IV (COL4), which is a major contributor to extracellular matrix (ECM) accumulation in diabetic nephropathy (DN). C-peptide can attenuate fibrosis to have unique beneficial effects in DN. However, whether and how C-peptide affects TGFB1/SMAD3-activated COL4 synthesis is unclear. In this study, pathological changes, expression of COL4 a1-a5 chains (Col4a1-a5), COL4 distribution and protein and TGFB1 and SMAD3 protein were first assessed in a rat model of diabetes. Then, rat mesangial cells were treated with high glucose (HG) and/or C-peptide to investigate the underlying mechanism. Col4a1-a5 expression, COL4 protein and secretion, TGFB1 protein, SMAD3 nuclear translocation and binding of SMAD3 to its cognate sites in the promoters of Col4a1a2, Col4a3a4 and Col4a5 were measured. It was found that C-peptide attenuated glomerular pathological changes and suppressed renal Col4a1 -a5 mRNA expression, COL4 protein content and TGFB1 protein content. C-peptide had a dose-dependent effect to inhibit Col4a1-a5 mRNA expression, COL4 protein content and secretion, in HG-stimulated mesangial cells. In addition, the HG-induced increase in TGFB1 protein content was significantly reduced by C-peptide. Although not apparently affecting SMAD3 nuclear translocation, C-peptide prevented SMAD3 from binding to its sites in the Col4a1a2, Col4a3a4 and Col4a5 promoters in HG-stimulated mesangial cells. In conclusion, C-peptide could prevent SMAD3 from binding to its sites in the Col4a1a2, Col4a3a4 and Col4a5 promoters, to inhibit COL4 generation. These results may provide a mechanism for the alleviation of fibrosis in DN by C-peptide.

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Zhiyu Ma, Ying Zhang, Juan Su, Sheng Yang, Wenna Qiao, Xiang Li, Zhihai Lei, Ling Cheng, Na An, Wenshao Wang, Yanyan Feng, and Jinlong Zhang

Neuromedin B (NMB), a mammalian bombesin-related peptide, has numerous physiological functions, including regulating hormone secretions, cell growth, and reproduction, by binding to its receptor (NMBR). In this study, we investigated the effects of NMB on testosterone secretion, steroidogenesis, cell proliferation, and apoptosis in cultured primary porcine Leydig cells. NMBR was mainly expressed in the Leydig cells of porcine testes, and a specific dose of NMB significantly promoted the secretion of testosterone in the primary Leydig cells; moreover, NMB increased the expression of mRNA and/or proteins of NMBR and steroidogenic mediators (steroidogenic acute regulatory (STAR), CYP11A1, and HSD3B1) in the Leydig cells. In addition, specific doses of NMB promoted the proliferation of Leydig cells and increased the expression of proliferating cell nuclear antigen and Cyclin B1 proteins, while suppressing Leydig cell apoptosis and decreasing BAX and Caspase-3 protein expression. These results suggest that the NMB/NMBR system might play an important role in regulating boar reproductive function by modulating steroidogenesis and/or cell growth in porcine Leydig cells.

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Sucharitha Iyer and Sunita K Agarwal

Epigenetic regulation is emerging as a key feature in the molecular characteristics of various human diseases. Epigenetic aberrations can occur from mutations in genes associated with epigenetic regulation, improper deposition, removal or reading of histone modifications, DNA methylation/demethylation and impaired non-coding RNA interactions in chromatin. Menin, the protein product of the gene causative for the multiple endocrine neoplasia type 1 (MEN1) syndrome, interacts with chromatin-associated protein complexes and also regulates some non-coding RNAs, thus participating in epigenetic control mechanisms. Germline inactivating mutations in the MEN1 gene that encodes menin predispose patients to develop endocrine tumors of the parathyroids, anterior pituitary and the duodenopancreatic neuroendocrine tissues. Therefore, functional loss of menin in the various MEN1-associated endocrine cell types can result in epigenetic changes that promote tumorigenesis. Because epigenetic changes are reversible, they can be targeted to develop therapeutics for restoring the tumor epigenome to the normal state. Irrespective of whether epigenetic alterations are the cause or consequence of the tumorigenesis process, targeting the endocrine tumor-associated epigenome offers opportunities for exploring therapeutic options. This review presents epigenetic control mechanisms relevant to the interactions and targets of menin, and the contribution of epigenetics in the tumorigenesis of endocrine cell types from menin loss.