The phase shifts of acute systemic inflammation appear linear and involve innate and adaptive immunity. As discussed previously, this contrasts with chronic inflammation of diseases, such as obesity and atherosclerosis, which remain in a proinflammatory phase, where M1 proinflammatory macrophages and Teffs predominate over M2 adaptation-phase-like macrophages and T cell-derived suppressor cells. Under these conditions, HIF-1α induces increased glycolysis in M1 cells and Teffs, and PGC-1 increases in fatty acid oxidation in M2 adaptation phase and Tregs. Another important distinction between the proinflammatory-phase and adaptation-phase phenotypes is seen during chronic inflammation associated with obesity. M1 proinflammatory macrophages have repressed levels of AMPK, Nampt, NAD+, SirT1, and PCG-1, whereas the adaptation-phase M2 macrophages have enhanced levels of these gene products [58, 83, 84]. In other words, the critical bioenergy sensors that support the switch from the proinflammatory phase to the adaptation phase during acute inflammation apparently are unavailable to the M1 macrophage and Teffs of chronic inflammation, although they are available to generate M2 macrophages and Tregs in different areas of inflamed adipose tissue. Thus, the bioenergetics of chronic inflammation is complex and varies within different tissue regions. The arrested proinflammatory phase in M1 and Teffs associated with chronic inflammation is depicted in Fig. 6B. This figure does not show the minority population and M2 macrophages and Tregs, which reflect gene expression and metabolic patterns of the adaptation phase.
New Flame 2010 Activation
A wide range of hormones produced by the gonads, fat, pancreas, gastrointestinal tract, and liver modulate ARC neurons (Woods, 2009). E2 modulates energy intake and expenditure and controls glucose homeostasis through actions of ERα in the hypothalamus (Mauvais-Jarvis et al., 2013). ERα knockout (KO) females are phenotypically obese, glucose intolerant, and resistant to the effects of E2 as full-grown adults (Geary et al., 2001; Yasrebi et al., 2017). Leptin and insulin, peripheral hormones from fat and pancreas, differentially depolarize and hyperpolarize POMC and NPY neurons (Baquero et al., 2014; Qiu et al., 2010, 2014). These hormones activate TRPC channels (TRPC5) to excite POMC neurons and activate KATP channels to suppress NPY neurons through their respective receptors, LepR and InsR (Baquero et al., 2014; Elias et al., 1999; Mirshamsi et al., 2004; Qiu et al., 2010, 2014). Ghrelin is secreted by the stomach to drive hunger and increase feeding through the growth hormone secretagogue receptor (GHSR). GHSR is expressed in NPY/AgRP neurons and increases NPY neuronal excitability (Andrews, 2011; Nogueiras et al., 2010;). GHSR is also highly expressed in KNDy neurons and is upregulated by estradiol through ERα (Yang et al., 2016a,b). GHSR stimulation activates a Gq-coupled signaling pathway that inhibits KCNQ channel activity to increase neuronal excitability (Shi et al., 2013; Yasrebi et al., 2016). The KCNQ family of potassium channels produces the neuronal M-current, a noninactivating outward potassium current under the control of E2 in the ARC (Roepke et al., 2011).
We also examined cation channel subunits that are involved in neuroendocrine functions including the potassium channel KCNQ subunits (KCNQ2, -3, -5) (Roepke et al., 2011, 2012), T-type calcium channel subunits (Cav3.1, Cav3.2, Cav3.3) (Bosch et al., 2009; Qiu et al., 2006), and nonselective cation current canonical transient receptor potential 5 (TRPC5) (Qiu et al., 2010, 2014) (see Table 2). Kcnq2 expression was not changed by FR in WT females but was increased by EE2 (p
These effects on neuropeptide gene expression may be partially dependent on ERα, as only Cart was downregulated in KO males similar to WT males. Furthermore, FR (and EE2) treatment suppressed male ARC Esr1 gene expression, which is a similar response to ligand exposure (E2 treatment) in female mice (Yang et al., 2016a,b). However, female Esr1 gene expression was unaffected. It is well established that ovariectomy promotes hyperphagia and body weight gain, which can be prevented by E2 replacement acting through ERα (Asarian and Geary, 2002). Therefore, OPFR may not be acting directly on ERα but via regulation of the Esr1 gene. FR also interact with multiple steroid and nuclear receptors in vitro such as PXR, thyroid receptors, PPARα/γ, androgen receptors (ARs), and mineralocorticoid and glucocorticoid receptors (Belcher et al., 2014; Hu et al., 2014; Kojima et al., 2013). Interestingly, PPARγ expression is elevated by FR in males and females and may mediate, in part, the effects of these compounds on ARC gene expression. PPARγ is a known modulator of POMC neuronal activity and mediates the impact of high-fat diets on the hypothalamus (Long et al., 2014). However, hypothalamic PPARγ activation augments Npy and Agrp expression in the ARC (Garretson et al., 2015), but these findings do not align with our results. Further investigation is required to determine which nuclear or steroid receptors are interacting with FR either directly or indirectly to control ARC gene expression; those studies should utilize global or brain-specific ERα/β, PPARγ, or other nuclear receptor KO models.
Whether interacting with ERα or PPARγ, FR upregulated ARC expression of peptide hormone receptors Ghsr, Insr, and Lepr in males and Insr in females. InsR is a tyrosine kinase receptor activated by insulin to control glucose metabolism and suppress appetite (Hill et al., 2010). ARC insulin signaling activates POMC neurons and inhibits NPY neurons (Qiu et al., 2014). The adipokine leptin also activates POMC neurons and inhibits NPY neurons through its receptor (Qiu et al., 2010). Both insulin and leptin receptor activation targets nonselective canonical transient receptor potential (TRPC5) channels in POMC and KNDy neurons (Qiu et al., 2010, 2014). Activation of these channels causes depolarization in the neurosecretory neurons, leading to suppressed food intake and other physiological outcomes. Therefore, an increase in Insr or Lepr expression in POMC neurons or an increase of Trpc5 expression would increase their sensitivity to insulin and leptin, leading to decreased food intake.
One of these downstream homeostatic functions is glucose homeostasis and, in particular, hepatic glucose production (Lin et al., 2010). Both BDE-47 and OPFR elevated fasting glucose levels in males, indicating an increase in hepatic glucose production either directly by altering liver glucose metabolism or indirectly by altering the neuroendocrine control of glucose production. FR did not have an effect in females, most likely due to the disruptive effects of ovariectomy (loss of E2) on glucose metabolism. Indeed, glucose clearance was augmented by EE2 and BDE-47 in females, recapitulating the effects of E2 replacement in OVX female rodents (Yasrebi et al., 2017). The activation of ERα increases glucose tolerance by regulating the glucose transporter type 4 (GLUT4) expression and activity in skeletal muscle (Gorres et al., 2011). Thus, ERα KO females exhibit impairments to glucose clearance (Yasrebi et al., 2017) and were not examined in this study.
FR, especially PBDE, can induce xenobiotic receptor signaling in the liver. In our in vivo study, BDE-47 activated farnesoid X receptor (FXR), PXR, and CAR target genes in males and females and OPFR activated PXR and CAR only in males. In human hepatic cells, BDE-47 enhances PXR and CAR activation (Hu et al., 2014; Sueyoshi et al., 2014;). In fact, in vivo, PBDE (BDE-47, -09, and -209) induce Cyp3a11 and Cyp2b10 gene expression by activating PXR in rat livers (Pacyniak et al., 2007). Whether BDE-47 is a FXR modulator needs detailed study in the future. Little is known about the impacts of in vivo OPFR exposure on xenobiotics receptors and their targets genes in the liver. In transfected human liver cells, TPP activates mouse and human PXR and CAR (Honkakoski et al., 2004). Surprisingly, in the ERα KO, there were no significant effects on target gene expression except for an increase in Cd36 by BDE-47, indicating activation of PPARα (Gao et al., 2013). The lack of target gene regulation in the KO suggests that these mechanisms are dependent on interaction with ERα or that the loss of ERα in the liver disrupts normal xenobiotic receptor activity or expression.
In the condensed phase, the phosphorus-containing flame retardants are selectively active with the host polymers containing oxygen (i.e., polyesters, polyamides, cellulose, etc.) during heating or combustion [7]. With most of the phosphorus-containing flame retardants, thermal decomposition leads to the production of phosphoric acid, which condenses readily to produce pyrophosphate structures and release water vapor (see Scheme 1). The water released can dilute the oxidizing and combustible gas phases. In addition, phosphoric acid and pyrophosphoric acid can catalyze the dehydration reaction of the alcohol groups, leading to the formation of carbocations and carbon-carbon double bonds (see Scheme 2), and consequently to the aromatization at high temperature. At high temperature, ortho- and pyrophosphoric acids are turned into metaphosphoric acid [(O)P(O)(OH)] and their corresponding polymers [(PO3H)n]. The phosphate anions (i.e., pyro- and polyphosphates) then participate with the carbonized residues in char formation. This carbonized layer (char residues) can isolate and protect the polymer from the flames, limit the volatilization of fuel, prevent the formation of new free-radicals, confine the oxygen diffusion to reduce combustion, and insulate the polymer underneath from the heat. 2ff7e9595c
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