Abstract The insulin-like growth factor (IGF) signaling pathway consists of multiple IGF ligands, IGF receptors, and IGF-binding proteins (IGFBPs). Studies in a variety of animal and cellular systems ...suggest that the IGF signaling pathway plays a key role in regulating skeletal muscle growth, differentiation, and in maintaining homeostasis of the adult muscle tissues. Intriguingly, IGFs stimulate both myoblast proliferation and differentiation, which are two mutually exclusive biological events during myogenesis. Both of these actions are mediated through the same IGF-1 receptor. Recent studies have shed new insights into the molecular mechanisms underlying these paradoxical actions of IGFs in muscle cells. In this article, we provide a brief review of our current understanding of the IGF signaling system and discuss recent findings on how local oxygen availability and IGFBPs act to specify IGF actions in muscle cells.
Insulin-like growth factors (IGFs) stimulate myoblast proliferation and differentiation. It remains elusive how these mutually exclusive cellular responses are elicited by the same growth factor. ...Here we report that whereas IGF promotes myoblast differentiation under normoxia, it stimulates proliferation under hypoxia. Hypoxia activates the HIF-1 transcriptional program and knockdown of HIF-1α changes the mitogenic action of IGF into myogenic action under hypoxia. Conversely, overexpression of HIF-1α abolishes the myogenic effect of IGF under normoxia. Under normoxia, IGF activates the Akt-mTOR, p38, and Erk1/2 MAPK pathways. Hypoxia suppresses basal and IGF-induced Akt-mTOR and p38 activity, whereas it enhances and prolongs IGF-induced Erk1/2 activation in a HIF-1-dependent fashion. Activation of Akt-mTOR and p38 promotes myogenesis, and p38 also inhibits proliferation. Activation of Erk stimulates myoblast proliferation but inhibits differentiation. These results suggest that hypoxia converts the myogenic action of IGFs into mitogenic action by differentially regulating multiple signaling pathways via HIF-1-dependent mechanisms. Our findings provide a mechanistic explanation for the paradoxical actions of IGFs during myogenesis and reveal a novel mechanism by which cells sense and integrate growth factor signals and oxygen availability in their microenvironments.
Hirschsprung-associated enterocolitis (HAEC) is a common and life-threatening complication of Hirschsprung's disease (HSCR), which can occur before and after surgery. The aim of this study was to ...identify the risk factors associated with the development of HAEC.
We retrospectively reviewed the medical records of HSCR patients admitted to the Children's Hospital of Shanxi Province, China, between January 2011 and August 2021. Diagnosis of HAEC was made using a scoring system with cutoff values ≥4 and included the patient's history, physical examination, and radiological and laboratory findings. The results are shown as frequency (%). The chi-square test was used to analyze a single factor with a significance level of
< 0.05. Logistic regression analysis was used to analyze multiple factors.
A total of 324 patients were included in this study, with 266 males and 58 females. In total, 34.3% (111/324) of patients had HAEC, including 85 males and 26 females; 18.9% (61/324) of patients had preoperative HAEC; and 15.4% (50/324) of patients had postoperative HAEC within one year after surgery. Gender, age at definitive therapy, and feeding methods were not found to be associated with preoperative HAEC in univariate analysis. Respiratory infection was associated with preoperative HAEC (
= 0.00003). No association was found between gender and age at definitive therapy and postoperative HAEC. Postoperative HAEC was associated with microcytic hypochromic anemia (
= 0.00058), preoperative history of HAEC (
= 0.00120), the creation of a preoperative stoma (
= 0.00097), long segment or total colon HSCR (
= 0.00057), and hypoalbuminemia (
= 0.03225). Regression analysis showed that microcytic hypochromic anemia (OR=2.716, 95% CI = 1.418-5.203,
= 0.003), preoperative history of HAEC (OR=2.814, 95% CI = 1.429-5.542,
= 0.003), the creation of a preoperative stoma (OR=2.332, 95% CI = 1.003-5.420,
= 0.049), and long segment or total colon HSCR (OR=2.167, 95% CI = 1.054-4.456,
= 0.035) were associated with postoperative HAEC.
This study revealed that the incidence of preoperative HAEC at our hospital was associated with respiratory infections. In addition, microcytic hypochromic anemia, preoperative history of HAEC, the creation of a preoperative stoma, and long segment or total colon HSCR were risk factors of postoperative HAEC. The most important finding of this study was that microcytic hypochromic anemia was a risk factor for postoperative HAEC, which has been rarely reported. Further studies with larger sample sizes are necessary to confirm these findings.
IGF-II stimulates both mitogenesis and myogenesis through its binding and activation of the IGF-I receptor (IGF-IR). How this growth factor pathway promotes these two opposite cellular responses is ...not well understood. We investigate whether local IGF binding protein-5 (IGFBP-5) promotes the myogenic action of IGF-II. IGFBP-5 is induced before the elevation of IGF-II expression during myogenesis. Knockdown of IGFBP-5 impairs myogenesis and suppresses IGF-II gene expression. IGF-II up-regulates its own gene expression via the PI3K-Akt signaling pathway. Adding IGF-II or constitutively activating Akt rescues the IGFBP-5 knockdown-caused defects. However, an IGF analogue that binds to the IGF-IR but not IGFBP has only a limited effect. When added with low concentrations of IGF-II, IGFBP-5 restores IGF-II expression and myogenic differentiation, whereas an IGF binding-deficient IGFBP-5 mutant has no effect. These findings suggest that IGFBP-5 promotes muscle cell differentiation by binding to and switching on the IGF-II auto-regulation loop.
G protein-coupled receptors (GPCRs) in the gastrointestinal tract are involved in maintaining glucose and energy homeostasis by regulating the release of gut hormones in response to luminal dietary ...nutrients as well as microbial metabolites. We recently identified that an orphan GPCR, Gpr17, was co-expressed in glucagon-like peptide-1 (GLP-1) -expressing EECs in human and rodent intestinal epithelium. However, it is unknown how Gpr17 ablation in the intestinal epithelium affects feeding behavior and satiety regulation. To address this question, we used genetic knockout approach to generate intestinal Gpr17-deficient mice and analyzed their glucose metabolism and feeding behavior. We showed that intestinal Gpr17-deficient mice had similar growth curve, body composition, and ad libitum food intake compared with littermate controls. We found that acute genetic ablation of Gpr17 in intestinal epithelium (iKO) improved oral glucose tolerance and glucose-stimulated insulin secretion (GSIS) in female and male mice. iKO mice responded to glucose or lipid ingestion with increased secretion of GLP-1, but not the other incretin glucose-dependent insulinotropic polypeptide (GIP) . Intestinal Gpr17-deficient mice responded to fasting-refeeding challenge with reduced fasting locomotor activity and less food intake after refeeding, suggesting increased satiety during the phase of rebound hyperphagia. Furthermore, comprehensive studies including gut morphology, gut epithelium heterogeneity by scRNA-seq, and microbiome analysis were examined but none of them was changed because of intestinal Gpr17 ablation. In addition, male Gpr17 whole body knockout mice have improved intraperitoneal glucose tolerance, and increased insulin sensitivity in hyperinsulinemic-euglycemic clamp studies.
In conclusion, our work showed that ablation of intestinal Gpr17 signaling led to improved neurohormonal regulation to maintain metabolic homeostasis.
Disclosure
H.Ren: None.
Funding
National Institute of Health (R01DK120772)
Hypothalamic neurons expressing Agouti-related peptide (AgRP) are critical for initiating food intake, but druggable biochemical pathways that control this response remain elusive. Thus, genetic ...ablation of insulin or leptin signaling in AgRP neurons is predicted to reduce satiety but fails to do so. FoxO1 is a shared mediator of both pathways, and its inhibition is required to induce satiety. Accordingly, FoxO1 ablation in AgRP neurons of mice results in reduced food intake, leanness, improved glucose homeostasis, and increased sensitivity to insulin and leptin. Expression profiling of flow-sorted FoxO1-deficient AgRP neurons identifies G-protein-coupled receptor Gpr17 as a FoxO1 target whose expression is regulated by nutritional status. Intracerebroventricular injection of Gpr17 agonists induces food intake, whereas Gpr17 antagonist cangrelor curtails it. These effects are absent in Agrp-Foxo1 knockouts, suggesting that pharmacological modulation of this pathway has therapeutic potential to treat obesity.
Display omitted
► FoxO1 knockout in AgRP neurons mimics insulin and leptin action ► FoxO1-deficient AgRP mice are lean and have reduced food intake ► Gpr17 is a FoxO1 target, and its expression promotes food intake ► Agonists of Gpr17 increase food intake, whereas antagonists curtail it
AgRP neurons respond to leptin and insulin, regulating food intake via FoxO1 signaling. Antagonists of a newly identified FoxO1 target, GPR17, promote satiety in mice, which suggests that this pathway can be targeted to treat obesity.
High-fat diet (HFD) has been shown to accelerate Alzheimer's disease (AD) pathology, but the exact molecular and cellular mechanisms remain incompletely understood. Moreover, it is unknown whether AD ...mice are more susceptible to HFD-induced metabolic dysfunctions. To address these questions, we used 5xFAD mice as an Alzheimer's disease model to study the physiological and molecular underpinning between HFD-induced metabolic defects and AD pathology. We systematically profiled the metabolic parameters, the gut microbiome composition, and hippocampal gene expression in 5xFAD and wild type (WT) mice fed normal chow diet and HFD. HFD feeding impaired energy metabolism in male 5xFAD mice, leading to increased locomotor activity, energy expenditure, and food intake. 5xFAD mice on HFD had elevated circulating lipids and worsened glucose intolerance. HFD caused profound changes in gut microbiome compositions, though no difference between genotype was detected. We measured hippocampal mRNAs related to AD neuropathology and neuroinflammation and showed that HFD elevated the expression of apoptotic, microglial, and amyloidogenic genes in 5xFAD mice. Pathway analysis revealed that differentially regulated genes were involved in insulin signaling, cytokine signaling, cellular stress, and neurotransmission. Collectively, our results showed that 5xFAD mice were more susceptible to HFD-induced metabolic dysregulation and suggest that targeting metabolic dysfunctions can ameliorate AD symptoms via effects on insulin signaling and neuroinflammation in the hippocampus.
Aim
We evaluated the demographic of biliary atresia (BA) children from twins family and aimed to investigated what it can add to the twins’ literature and our understanding of the disease.
Methods
...This study contains 11 medical centers in mainland China and the medical record of twins with BA was retrospectively analyzed from January 2012 to December 2018. Follow-up was carried out by out-patient review and questionnaire.
Results
The study included 19 twin pairs in whom there was discordance for BA. Sixteen (84.2%) affected twin underwent Kasai Procedure (KP); median age at KP was 78 (49–168) days. There were ten affected twins that became jaundice-free at 3 months post-KP, and eight occurred with different degrees of cholangitis post-KP. Six affected twins received Liver Transplantation (LT) successfully. The 2 year native liver survival rate and the 2 year overall survival rate of affected twins were 61.1 and 94.4%, respectively. There were three affected monozygotic (MZ) twins and one healthy co-twin with BA-associated congenital malformations, all of which were cardiac malformations. The number of virus infection of affected MZ twins was significantly more (
p
= 0.04) than affected dizygotic (DZ) twin.
Conclusions
Discordance for BA in 19 pairs of twins supported that BA may be related to genetic phenotype or penetrance. The difference in genetic background between MZ and DZ affects the susceptibility of the host to virus infection. High acceptance of KP (84.2%) in our study implied a high motivation for treatment for twins with BA. Delays of KP (78 days) in affected twin may be related to the postnatal gradual onset and the late diagnosis.
PDF
