FGF1 and FGF19 reverse diabetes by suppression of the hypothalamic-pituitary-adrenal axis.
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ABSTRACT:
SUBMITTER: Perry RJ
PROVIDER: S-EPMC4413509 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Leptin treatment reverses hyperglycemia in animal models of poorly controlled type 1 diabetes (T1D), spurring great interest in the possibility of treating patients with this hormone. The antidiabetic effect of leptin has been postulated to occur through suppression of glucagon production, suppression of glucagon responsiveness or both; however, there does not appear to be a direct effect of leptin on the pancreatic alpha cell. Thus, the mechanisms responsible for the antidiabetic effect of leptin remain poorly understood. We quantified liver-specific rates of hepatic gluconeogenesis and substrate oxidation in conjunction with rates of whole-body acetate, glycerol and fatty acid turnover in three rat models of poorly controlled diabetes, including a model of diabetic ketoacidosis. We show that the higher rates of hepatic gluconeogenesis in all these models could be attributed to hypoleptinemia-induced activity of the hypothalamic-pituitary-adrenal (HPA) axis, resulting in higher rates of adipocyte lipolysis, hepatic conversion of glycerol to glucose through a substrate push mechanism and conversion of pyruvate to glucose through greater hepatic acetyl-CoA allosteric activation of pyruvate carboxylase flux. Notably, these effects could be dissociated from changes in plasma insulin and glucagon concentrations and hepatic gluconeogenic protein expression. All the altered systemic and hepatic metabolic fluxes could be mimicked by infusing rats with Intralipid or corticosterone and were corrected by leptin replacement. These data demonstrate a critical role for lipolysis and substrate delivery to the liver, secondary to hypoleptinemia and HPA axis activity, in promoting higher hepatic gluconeogenesis and hyperglycemia in poorly controlled diabetes.
| S-EPMC4344321 | biostudies-literature
Project description:Leptin administration restores euglycemia in rodents with severe insulin-deficient diabetes, and recent studies to explain this phenomenon have focused on the ability of leptin to normalize excessive hypothalamic-pituitary-adrenal (HPA) axis activity. Here, we employed a streptozotocin-induced rat model (STZ-DM) of uncontrolled insulin-deficient diabetes mellitus (uDM) to investigate the contribution of HPA axis suppression to leptin-mediated glucose lowering. Specifically, we asked if HPA axis activation is required for diabetic hyperglycemia, whether HPA axis normalization can be achieved using a dose of leptin below that needed to normalize glycemia, and if the ability of leptin to lower plasma glucocorticoid levels is required for its antidiabetic action. In STZ-DM rats, neither adrenalectomy-induced (ADX-induced) glucocorticoid deficiency nor pharmacological glucocorticoid receptor blockade lowered elevated blood glucose levels. Although elevated plasma levels of corticosterone were normalized by i.v. leptin infusion at a dose that raises low plasma levels into the physiological range, diabetic hyperglycemia was not altered. Lastly, the potent glucose-lowering effect of continuous intracerebroventricular leptin infusion was not impacted by systemic administration of corticosterone at a dose that maintained elevated plasma levels characteristic of STZ-DM. We conclude that, although restoring low plasma leptin levels into the physiological range effectively normalizes increased HPA axis activity in rats with uDM, this effect is neither necessary nor sufficient to explain leptin's antidiabetic action.
| S-EPMC4665796 | biostudies-literature
Project description:Background Inhaled or nasal corticosteroids can cause suppression of the hypothalamic-pituitary-adrenal (HPA) axis. Early detection is important because this suppression can be associated with significant morbidity. Objective To explore the adverse effect of hypothalamic-pituitary-adrenal suppression by local corticosteroids in HIV-infected patients. Method Ambulatory HIV-infected patients were selected if they used both antiretroviral treatment and inhaled or nasal corticosteroid. Suppression of hypothalamic-pituitary-adrenal axis was defined as a morning plasma cortisol below 80 nmol/L or a cortisol below 550 nmol/L during a 250 mcg adrenocorticotropic hormone-stimulation test. Results Twelve patients were tested; four of them were taking a CYP3A4 inhibitor. All patients had a normal morning plasma cortisol. Suppression of the hypothalamic-pituitary-adrenal axis during the ACTH stimulation test was identified in three of the twelve patients. None of these three individuals were taking a CYP3A4 inhibitor. Conclusion Hypothalamic-pituitary-adrenal axis suppression is frequently identified in patients on inhaled or nasal corticosteroids. CYP3A4 inhibitors such as ritonavir or cobicistat may increase the chance of this adverse effect. In this study we did not identify HPA axis suppression in patients taking CYP3A4 inhibitors. This may be related to the fact that 2 of these 4 patients used beclomethasone, a corticosteroid not metabolized by CYP3A4.ClinicalTrials.gov Identifier NCT02501486.
| S-EPMC7192878 | biostudies-literature
Project description:The normal function of the hypothalamic-pituitary-adrenal (HPA) axis, and resultant glucocorticoid (GC) secretion, is essential for human health. Disruption of GC regulation is associated with pathologic, psychological, and physiological disease states such as depression, post-traumatic stress disorder, hypertension, diabetes, and osteopenia, among others. As such, understanding the mechanisms by which HPA output is tightly regulated in its responses to environmental stressors and circadian cues has been an active area of investigation for decades. Over the last 20 years, however, advances in gene targeting and genome modification in rodent models have allowed the detailed dissection of roles for key molecular mediators and brain regions responsible for this control in vivo to emerge. Here, we summarize work done to elucidate the function of critical neuropeptide systems, GC-signaling targets, and inflammation-associated pathways in HPA axis regulation and behavior, and highlight areas for future investigation.
| S-EPMC4677126 | biostudies-literature
Project description:Abnormal function of the hypothalamic-pituitary-adrenal (HPA) axis is an important pathological finding in pregnant women exhibiting major depressive disorder. They show high levels of cortisol pro-inflammatory cytokines, hypothalamic-pituitary peptide hormones and catecholamines, along with low dehydroepiandrosterone levels in plasma. During pregnancy, the TH2 balance together with the immune system and placental factors play crucial roles in the development of the fetal allograft to full term. These factors, when altered, may generate a persistent dysfunction of the HPA axis that may lead to an overt transfer of cortisol and toxicity to the fetus at the expense of reduced activity of placental 11β-hydroxysteroid dehydrogenase type 2. Epigenetic modifications also may contribute to the dysregulation of the HPA axis. Affective disorders in pregnant women should be taken seriously, and therapies focused on preventing the deleterious effects of stressors should be implemented to promote the welfare of both mother and baby.
| S-EPMC5563683 | biostudies-other
Project description:ObjectiveTo determine which parameter is the most useful screening test for hypothalamic-pituitary-adrenal suppression in asthmatic children.DesignCross-sectional study.SettingPaediatric allergy clinics in Cape Town, South Africa.Participants143 asthmatic children of mostly mixed ancestry, aged 5-12 years.Outcome measuresPrimary outcome measures included Spearman correlation coefficients (r) calculated between the postmetyrapone (PMTP) serum adrenocorticotropic hormone (ACTH), 11-deoxycortisol (11DOC), 11DOC+ cortisol (C) and height, weight, height velocity, weight velocity, change in systolic blood pressure from supine to standing, early morning urinary free cortisol (UFC), morning C, ACTH and dehydroepiandrosterone sulfate (DHEAS). Secondary outcome measures were the receiver operating characteristics (ROC) curve and the diagnostic statistics for the most promising test.ResultsAll screening variables were weakly correlated with the three PMTP outcomes. Only DHEAS and UFC (nmol/m(2)) were statistically significant-DHEAS for PMTP ACTH and 11DOC (r=0.20, p=0.025 and r=0.21, p=0.017); UFC (nmol/m(2)) for PMTP 11DOC and 11DOC+C (r=0.19, p=0.033 and r=0.20, p=0.022). The area under ROC curve for DHEAS in the 5-year to 9-year age group was 0.69 (95% CI 0.47 to 0.92). At DHEAS cut-off of 0.2 µmol/L: sensitivity=0.88 (CI 0.47 to 1.00), specificity=0.61 (CI 0.42 to 0.78), positive predictive value=0.37 (CI 0.16 to 0.62), negative predictive value=0.95 (CI 0.75 to 1.00), accuracy=0.67 (CI 0.50 to 0.81), positive likelihood ratio=2.26 (CI 1.35 to 3.78), negative likelihood ratio=0.20 (CI 0.03 to 1.30).ConclusionsNo parameter is useful as a universal screening test. DHEAS may be suitable to exclude HPAS before adrenarche. Further research is needed to confirm these findings and identify factors, for example, genetic that may predict or protect against HPAS.
| S-EPMC3733311 | biostudies-literature
Project description:To test the hypothesis that UVB can activate the hypothalamic-pituitary-adrenal (HPA) axis, the shaved back skin of C57BL/6 mice was exposed to 400?mJ?cm(-2) of UVB or was sham irradiated. After 12 and 24?hours of exposure, plasma, skin, brain, and adrenals were collected and processed to measure corticotropin-releasing hormone (CRH), urocortin (Ucn), ?-endorphin (?-END), ACTH, and corticosterone (CORT) or the brain was fixed for immunohistochemical detection of CRH. UVB stimulated plasma levels of CRH, Ucn, ?-END, ACTH, and CORT and increased skin expression of Ucn, ?-END, and CORT at the gene and protein/peptide levels. UVB stimulated CRH gene and protein expression in the brain that was localized to the paraventricular nucleus of the hypothalamus. In adrenal glands, it increased mRNAs of melanocortin receptor type 2, steroidogenic acute regulatory protein (StAR), and gene coding of steroid 11?-hydroxylase (CYP11B1). Hypophysectomy abolished UVB stimulation of plasma, but not of skin CORT levels, and had no effect on UVB stimulation of CRH and Ucn levels in the plasma, demonstrating the requirement of an intact pituitary for the systemic effect. In conclusion, we identify mechanisms regulating body homeostasis by UVB through activation of the HPA axis that originate in the skin and require the pituitary for systemic effects.
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Project description:Photoperiod and diet are factors known to modulate the hypothalamic-pituitary-adrenal (HPA) axis. Specifically, shifts in photoperiod have been previously linked with affective and anxiety disorders. Furthermore, isoflavones have been shown to mediate behavioral outcome in response to the environment of the animal. Here, we investigated the effect of photoperiod alteration on the HPA axis and how the addition of isoflavones might modulate the response to stress. Male C57BL/6J mice were maintained on either a 12:12 or a 16:8 light-dark (LD) cycle for 10 days, and fed a diet of either standard rodent chow or an isoflavone free (IF) chow beginning 3 weeks prior to light alteration. Consistent with previous work, mice in the shorter active period (16:8 LD cycle) showed increased basal corticosterone (CORT) secretion. In the absence of isoflavones, this response was attenuated. Increases in mineralcorticoid (MR) and glucocorticoid (GR) receptor mRNA expression were seen in the pituitary following photoperiod alteration. However, animals fed the standard isoflavone rich chow showed increases in the ratio of MR:GR mRNA in the anterior bed nucleus of the stria terminalis following photoperiod alteration. Decreases in corticotrophin-releasing factor receptor 1 (CRFR1) mRNA expression were seen in animals fed the IF chow in the amygdala, prefrontal cortex and ventral hippocampus. These data suggest that alterations in CORT secretion following photoperiod alteration may be mediated through differences in CRFR1 gene expression or changes in MR:GR mRNA ratios. These findings provide insight into the potential mechanisms by which the HPA axis adapts to photoperiod and diet.
| S-EPMC6511471 | biostudies-literature
Project description:The hypothalamic-pituitary-adrenal (HPA) axis maintains basal and stress-related homeostasis in vertebrates. Skin expresses all elements of the HPA axis including corticotropin-releasing hormone (CRH), proopiomelanocortin (POMC), ACTH, β-endorphin (β-END) with corresponding receptors, the glucocorticoidogenic pathway, and the glucocorticoid receptor (GR). To test the hypothesis that cutaneous responses to environmental stressors follow the organizational structure of the central response to stress, the activity of the "cutaneous HPA" axis homolog was investigated after exposure to ultraviolet radiation (UVR) wavelengths of UVA (320-400 nm), UVB (280-320 nm), and UVC (100-280 nm) in human skin organ culture and in co-cultured keratinocytes/melanocytes. The level of stimulation of CRH, POMC, MC1R, MC2R, CYP11A1, and CYP11B1 genes was dependent on UV wavelengths and doses, with the highest effects observed for highly energetic UVC and UVB. ELISA and Western assays showed significant production of CRH, POMC, ACTH, and CYP11A1 proteins and of cortisol, with a decrease in GR expression only after UVB and UVC. However, β-END expression was also stimulated by UVA. Immunocytochemistry localized the deposition of the aforesaid antigens predominantly to the epidermis with additional accumulation of CRH, β-END, and ACTH in the dermis. UVR-stimulated CYP11A1 expression was seen in the basal layer of the epidermis and cells of adjacent dermis. Thus, the capacity to activate or change the spatial distribution of the cutaneous HPA axis elements is dependent on highly energetic wavelengths (UVC and UVB), implying a dependence of a local stress response on their noxious activity with overlapping or alternative mechanisms activated by UVA.
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Project description:One of the key proposed agents of fetal programming is exposure to maternal glucocorticoids. Experimental animal studies provide evidence that prenatal exposure to elevated maternal glucocorticoids has consequences for hypothalamic-pituitary-adrenal (HPA) axis functioning in the offspring. There are very few direct tests of maternal glucocorticoids, such as cortisol, during human pregnancy and associations with infant cortisol reactivity. The current study examined the link between maternal prenatal cortisol trajectories and infant cortisol reactivity to the pain of inoculation in a sample of 152 mother-infant (47.4% girls) pairs. The results from the current study provide insight into fetal programming of the infant HPA axis, demonstrating that elevated prenatal maternal cortisol is associated with a larger infant cortisol response to challenge at both 6 and 12 months of age.
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