Physiological responses are modulated by multiple endocrine signaling pathways. As NAD+, endocrine pathways are affected by environmental cues and nutritional factors, suggesting that NAD+ might eventually mediate some endocrine responses and/or vice versa. The possible regulation of longevity by SIRT1 has spurred research into possible interactions of NAD+ signaling and endocrine pathways. Findings in several species have linked endocrine signaling to life span. For example, mutations in many genes of the insulin/IGF-I signaling pathway affect life span in lower eukaryotic organisms (186). Similarly, decreases in IGF-I and insulin signaling prolong life span in mice (187). Interestingly, NAD+-dependent enzymes such as sirtuins are known to influence insulin and IGF-I signaling. The activity of SIRT1 orthologs in different species influences the insulin/IGF signaling pathway at diverse steps (63, 188). In addition, SIRT1 might participate in the regulation of insulin and IGF release (36, 110). Of note, SIRT1 knockout mice are rarely born, but when they are, they overexpress IGF-binding protein-1, which decreases the free levels of IGF-I, rendering a dwarf phenotype. Remarkably, another sirtuin, SIRT6, may also determine serum IGF-I levels (124), although the molecular link between these observations is not clear. It must be mentioned that SIRT1 and SIRT6 knockout mice present multiple abnormalities, which can explain their reduced life span and why reduced IGF-I levels do not promote longevity in this model. In general, the effects of SIRT1 activation have a tendency to oppose those of IGF on longevity, although in the long term or in insulin-resistant states, they might both favor insulin sensitivity through repression of PTP1b (189). It is particularly relevant that sirtuin activity influences FOXO transcriptional activity, which is another evolutionary conserved player in the regulation of life span (190). Insulin/IGF-I negatively regulate FOXO activity through Akt-mediated phosphorylation. Deacetylation of FOXO by sirtuins seems to contribute to target-gene specification and may inhibit insulin-stimulated FOXO1 phosphorylation. Interestingly, insulin/IGF-I action generally increases glycolysis in cells, which should theoretically decrease the NAD+/NADH ratio and, therefore, shut down sirtuin activity. Consequently, it seems likely that SIRT1 and insulin/IGF-I actions negatively regulate each other. Other NAD+-consuming enzymes, such as those of the PARP family, have also been linked to insulin action and secretion. PARP1 activation in the pancreas leads to NAD+ depletion, which compromises ATP levels and insulin secretion (191). Remarkably, PARP1-deficient mice are resistant to streptozotocin-induced β-cell death and diabetes (192, 193). Conversely, in peripheral tissues, insulin (194) and IGF-I (195) action inhibit PARP activity, probably as a way to preserve NAD+ levels. NAD+-consuming enzymes might also regulate the expression and release of other families of growth factors. Specific SIRT1 activating molecules promote a substantial increase in fibroblast growth factor (FGF) 21 expression in the liver (102), probably as a consequence of increased PPARα action (102, 196). This observation was consolidated recently in a mouse model of mild SIRT1 overexpression (197). FGF21 regulation could as such contribute to the positive metabolic effects of SIRT1 activation (198). Of note, FGF21 and FGF23 action have already been linked to aging phenomena because the Klotho family of transmembrane “anti-aging” proteins was demonstrated to work as a crucial coreceptor for FGF-R signaling (199, 200).
Recent findings evidence that endocrine communication and NAD+-consuming enzymes clearly expand beyond insulin/IGF-I and FGF signaling. For example, SIRT1 directly represses DNA binding and transactivation activity of the estrogen and androgen receptors through NAD+-dependent deacetylation (201, 202), clearly suggesting that metabolism may directly modulate ligand-induced hormone signaling. Similarly, PARP1 can bind at the promoter of SMARCB1, a member of the SWI/SNF complex that modulates steroid sensitivity (203). In addition, PARP1 seems to participate in the regulation of estradiol target genes by forming part of a transcriptional “activation” complex together with TopoIIβ (204). Intracellular lipid signaling also seems to be closely related to NAD+ consuming proteins, through the modulation of PPARγ activity. SIRT1 negatively regulates PPARγ by docking with its cofactors NCoR and SMRT (108). Interestingly, another NAD+-consuming protein, PARP2, positively regulates PPARγ activity (205). These observations suggest a model where NAD+ consumption through competing enzymes (SIRT1 and PARP2) may provide opposite outcomes on commonly regulated targets. Together, these findings imply that we may be at the tip of the iceberg in our understanding of possible cross-regulation between NAD+-consuming enzymes and hormone action, providing potential molecular mechanisms on how metabolism or stress situations can modulate hormone sensitivity.
) I am not a huge bio guy and don't pretend to be but I do trust the opinion of aleksandar and will await his comments after you hear back from you chemist Gunnar.
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