“…Neither body size (Figure 5A) nor elevated plus maze abnormalities (Figure 5B) were rescued after treating WT and Arid1b +/- cohorts with recombinant human IGF1 (rhIGF1). This was not surprising because it is known that exogenous IGF1 is unstable and often does not efficiently reach target tissues responsible for growth (Kletzl et al, 2017). 10.7554/eLife.25730.018Figure 5.GH therapy reverses growth retardation and muscle weakness.( A ) Body weights at p50 (WT + vehicle (n = 12), WT + rhIGF1 (n = 12), Arid1b +/- + vehicle (n = 13) and Arid1b +/- + rhIGF1 (n = 13)).…”
Sequencing studies have implicated haploinsufficiency of ARID1B, a SWI/SNF chromatin-remodeling subunit, in short stature (Yu et al., 2015), autism spectrum disorder (O'Roak et al., 2012), intellectual disability (Deciphering Developmental Disorders Study, 2015), and corpus callosum agenesis (Halgren et al., 2012). In addition, ARID1B is the most common cause of Coffin-Siris syndrome, a developmental delay syndrome characterized by some of the above abnormalities (Santen et al., 2012; Tsurusaki et al., 2012; Wieczorek et al., 2013). We generated Arid1b heterozygous mice, which showed social behavior impairment, altered vocalization, anxiety-like behavior, neuroanatomical abnormalities, and growth impairment. In the brain, Arid1b haploinsufficiency resulted in changes in the expression of SWI/SNF-regulated genes implicated in neuropsychiatric disorders. A focus on reversible mechanisms identified Insulin-like growth factor (IGF1) deficiency with inadequate compensation by Growth hormone-releasing hormone (GHRH) and Growth hormone (GH), underappreciated findings in ARID1B patients. Therapeutically, GH supplementation was able to correct growth retardation and muscle weakness. This model functionally validates the involvement of ARID1B in human disorders, and allows mechanistic dissection of neurodevelopmental diseases linked to chromatin-remodeling.DOI:
http://dx.doi.org/10.7554/eLife.25730.001
“…Neither body size (Figure 5A) nor elevated plus maze abnormalities (Figure 5B) were rescued after treating WT and Arid1b +/- cohorts with recombinant human IGF1 (rhIGF1). This was not surprising because it is known that exogenous IGF1 is unstable and often does not efficiently reach target tissues responsible for growth (Kletzl et al, 2017). 10.7554/eLife.25730.018Figure 5.GH therapy reverses growth retardation and muscle weakness.( A ) Body weights at p50 (WT + vehicle (n = 12), WT + rhIGF1 (n = 12), Arid1b +/- + vehicle (n = 13) and Arid1b +/- + rhIGF1 (n = 13)).…”
Sequencing studies have implicated haploinsufficiency of ARID1B, a SWI/SNF chromatin-remodeling subunit, in short stature (Yu et al., 2015), autism spectrum disorder (O'Roak et al., 2012), intellectual disability (Deciphering Developmental Disorders Study, 2015), and corpus callosum agenesis (Halgren et al., 2012). In addition, ARID1B is the most common cause of Coffin-Siris syndrome, a developmental delay syndrome characterized by some of the above abnormalities (Santen et al., 2012; Tsurusaki et al., 2012; Wieczorek et al., 2013). We generated Arid1b heterozygous mice, which showed social behavior impairment, altered vocalization, anxiety-like behavior, neuroanatomical abnormalities, and growth impairment. In the brain, Arid1b haploinsufficiency resulted in changes in the expression of SWI/SNF-regulated genes implicated in neuropsychiatric disorders. A focus on reversible mechanisms identified Insulin-like growth factor (IGF1) deficiency with inadequate compensation by Growth hormone-releasing hormone (GHRH) and Growth hormone (GH), underappreciated findings in ARID1B patients. Therapeutically, GH supplementation was able to correct growth retardation and muscle weakness. This model functionally validates the involvement of ARID1B in human disorders, and allows mechanistic dissection of neurodevelopmental diseases linked to chromatin-remodeling.DOI:
http://dx.doi.org/10.7554/eLife.25730.001
BackgroundInsulin-like growth factor-1 (IGF-1) improves obesity-induced cognitive impairment, but its mechanism is not fully clari ed. The aim of the study was to reveal whether IGF-1 treated cognitive impairment by improving tau pathology and neuronal pyroptosis in high-fat diet mice, and to further explore its molecular mechanisms involved.
MethodsDuring in vitro experiment, C57BL/6J mice were fed with high-fat diet, and were treated with PEG-IGF-1, IGF-1 receptor blocker AXL1717, HO-1 blocker Znpp IX or their combinations. Cognitive function was evaluated using Morris water maze. Expression of Nrf-2, HO-1, p-tau, NLRP3, Caspase-1 and IL-1β in hippocampus was determined using western blotting. Pyroptosis rate in hippocampus was measured using ow cytometry. During in vivo experiment, HN-h cells were treated with palmic acid, pyroptosis blocker nonecrosulfonamide or their combinations. The expression of the proteins and pyroptosis rate were also measured using western blotting and ow cytometry.
ResultsDuring in vitro experiment, high-fat diet mice showed cognitive impairment, hyperphospharylation of tau protein and signi cant neuronal pyroptosis in hippocampus compared with the sham mice. After exogenous IGF-1 treatment, these abnormalities were reversed, and Nrf-2/HO-1 signaling pathway was activated. Inhibition of such signaling pathway using IGF-1 receptor blocker or HO-1 blocker redeteriorated cognitive function, neuronal pyroptosis and tau pathology in hippocampus. During in vivo experiment, inhibition of pyroptosis using its blocker improved tau pathology in palmic acid-treated HN-h cells.
ConclusionExogenous IGF-1 improved cognitive impairment, tau pathology and neuronal pyroptosis induced by highfat diet through activation of Nrf-2/HO-1 signaling pathway.
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