Metformin attenuates hypothalamic inflammation via downregulation of RIPK1-independent microglial necroptosis in diet-induced obese mice
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ABSTRACT:
SUBMITTER: Li X
PROVIDER: S-EPMC8575871 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:As a programmed necrotic cell death, necroptosis has the intrinsic initiators, including receptor-interacting serine/threonine-protein kinase 1 (RIPK1), RIPK3 and mixed-lineage kinase domain-like protein (MLKL), which combine to form necroptotic signaling pathway and mediate necroptosis induced by various necroptotic stimuli, such as tumor necrosis factor (TNF). Although chemical inhibition of RIPK1 blocks TNF-induced necroptosis, genetic elimination of RIPK1 does not suppress but facilitate necroptosis triggered by TNF. Moreover, RIPK3 has been reported to mediate the RIPK1-independent necroptosis, but the involved mechanism is unclear. In this study, we found that TRADD was essential for TNF-induced necroptosis in RIPK1-knockdown L929 and HT-22 cells. Mechanistic study demonstrated that TRADD bound RIPK3 to form new protein complex, which then promoted RIPK3 phosphorylation via facilitating RIPK3 oligomerization, leading to RIPK3-MLKL signaling pathway activation. Therefore, TRADD acted as a partner of RIPK3 to initiate necroptosis in RIPK1-knockdown L929 and HT-22 cells in response to TNF stimulation. In addition, TRADD was critical for the accumulation of reactive oxygen species (ROS), which contributed to RIPK1-independent necroptosis triggered by TNF. Collectively, our data demonstrate that TRADD acts as the new target protein for TNF-induced RIPK3 activation and the subsequent necroptosis in a RIPK1-independent manner.
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Project description:Obesity is closely linked to chronic inflammation in peripheral organs and the hypothalamus. Chronic consumption of a high-fat diet (HFD) induces the differentiation of Ly6chigh monocytes into macrophages in adipose tissue, the liver, and the brain, as well as the secretion of pro-inflammatory cytokines. Although cinnamon improves obesity and related diseases, it is unclear which components of cinnamon can affect macrophages and inflammatory cytokines. We performed in silico analyses using ADME, drug-likeness, and molecular docking simulations to predict the active compounds of cinnamon. Among the 82 active compounds of cinnamon, cinnamic acid (CA) showed the highest score of ADME, blood-brain barrier permeability, drug-likeness, and cytokine binding. We then investigated whether CA modulates obesity-induced metabolic profiles and macrophage-related inflammatory responses in HFD-fed mice. While HFD feeding induced obesity, CA ameliorated obesity and related symptoms, such as epididymal fat gain, insulin resistance, glucose intolerance, and dyslipidemia, without hepatic and renal toxicity. CA also improved HFD-induced tumor necrosis factor-α, fat deposition, and macrophage infiltration in the liver and adipose tissue. CA decreased Ly6chigh monocytes, adipose tissue M1 macrophages, and hypothalamic microglial activation. These results suggest that CA attenuates the peripheral and hypothalamic inflammatory monocytes/macrophage system and treats obesity-related metabolic disorders.
| S-EPMC9413375 | biostudies-literature
Project description:The arcuate nucleus (ARC) of the hypothalamus plays a key role in sensing metabolic feedback and regulating energy homeostasis. Recent studies revealed activation of microglia in mice with high-fat diet (HFD)-induced obesity (DIO), suggesting a potential pathophysiological role for inflammatory processes within the hypothalamus. To further investigate the metabolic causes and molecular underpinnings of such glial activation, we analyzed the microglial activity in wild-type (WT), monogenic obese ob/ob (leptin deficient), db/db (leptin-receptor mutation), and Type-4 melanocortin receptor knockout (MC4R KO) mice on either a HFD or on standardized chow (SC) diet. Following HFD exposure, we observed a significant increase in the total number of ARC microglia, immunoreactivity of ionized calcium binding adaptor molecule 1 (iba1-ir), cluster of differentiation 68 (CD68-ir), and ramification of microglial processes. The ob/ob mice had significantly less iba1-ir and ramifications. Leptin replacement rescued these phenomena. The db/db mice had similar iba1-ir comparable with WT mice but had significantly lower CD68-ir and more ramifications than WT mice. After 2 weeks of HFD, ob/ob mice showed an increase of iba1-ir, and db/db mice showed increase of CD68-ir. Obese MC4R KO mice fed a SC diet had comparable iba1-ir and CD68-ir with WT mice but had significantly more ramifications than WT mice. Intriguingly, treatment of DIO mice with glucagon-like peptide-1 receptor agonists reduced microglial activation independent of body weight. Our results show that diet type, adipokines, and gut signals, but not body weight, affect the presence and activity levels of hypothalamic microglia in obesity.
| S-EPMC4213950 | biostudies-literature
Project description:RIPK1 is a critical mediator of cell death and inflammation downstream of TNFR1 upon stimulation by TNF?, a potent proinflammatory cytokine involved in a multitude of human inflammatory and degenerative diseases. RIPK1 contains an N-terminal kinase domain, an intermediate domain, and a C-terminal death domain (DD). The kinase activity of RIPK1 promotes cell death and inflammation. Here, we investigated the involvement of RIPK1-DD in the regulation of RIPK1 kinase activity. We show that a charge-conserved mutation of a lysine located on the surface of DD (K599R in human RIPK1 or K584R in murine RIPK1) blocks RIPK1 activation in necroptosis and RIPK1-dependent apoptosis and the formation of complex II. Ripk1K584R/K584R knockin mutant cells are resistant to RIPK1 kinase-dependent apoptosis and necroptosis. The resistance of K584R cells, however, can be overcome by forced dimerization of RIPK1. Finally, we show that the K584R RIPK1 knockin mutation protects mice against TNF?-induced systematic inflammatory response syndrome. Our study demonstrates the role of RIPK1-DD in mediating RIPK1 dimerization and activation of its kinase activity during necroptosis and RIPK1-dependent apoptosis.
| S-EPMC5834731 | biostudies-literature
Project description:The arcuate nucleus of the hypothalamus (ARH) is a key component of hypothalamic pathways regulating energy balance, and leptin is required for normal development of ARH projections. Diet-induced obesity (DIO) has a polygenic mode of inheritance, and DIO individuals develop the metabolic syndrome when a moderate amount of fat is added to the diet. Here we demonstrate that rats selectively bred to develop DIO, which are known to be leptin resistant before they become obese, have defective ARH projections that persist into adulthood. Furthermore, the ability of leptin to activate intracellular signaling in ARH neurons in vivo and to promote ARH neurite outgrowth in vitro is significantly reduced in DIO neonates. Thus, animals that are genetically predisposed toward obesity display an abnormal organization of hypothalamic pathways involved in energy homeostasis that may be the result of diminished responsiveness of ARH neurons to the trophic actions of leptin during postnatal development.
| S-EPMC2442478 | biostudies-literature
Project description:Obesity in adolescence increases the risk for early adult cardiovascular disease. We recently showed that 6 months of diet, exercise, and metformin resulted in reductions in adiposity and that diet/exercise alone reduced proinflammatory factors and intrahepatic fat in pubertal children with uncomplicated obesity. The purpose of the present study was to determine whether changes in cardiorespiratory fitness (CRF) after 6 months of structured diet and exercise (DE) or DE plus metformin are related to the previously observed changes in adiposity, markers of inflammation, and intrahepatic fat.Sixteen obese pubertal adolescents between the ages of 10 and 17 were randomized into a structured lifestyle program consisting of DE or DE plus metformin. Subjects performed aerobic and resistance exercise 3 d·wk?¹, 30 min per session. Cycle ergometer maximal oxygen consumption (V?O2max), body composition, blood markers (glucose, insulin, homeostatic model assessment-insulin resistance, interleukin-6, hsCRP), and intrahepatic fat were measured at baseline and 6 months.In the cohort, as whole-body weight decreased by 4.0% (P = 0.009), body mass index decreased by 4.9% (P = 0.003), percent body fat decreased by 8.8% (P < 0.001), and V?O2max improved in 10 of 16 subjects. The addition of metformin provided no further effect on body composition, CRF, or inflammatory factors. More favorable changes in adiposity, adiponectin, and a trend toward blood glucose and interleukin-6 concentrations (P = 0.07) were observed in subjects who increased V?O2max at 6 months (n = 10) compared with no change in these variables in those who did not improve V?O2max.Metformin did not provide benefits above lifestyle modification for improving CRF in obese adolescents. Improvements in V?O2max seem to be associated with more favorable metabolic outcomes.
| S-EPMC3998746 | biostudies-literature
Project description:Apoptosis is crucial for the normal development of the nervous system, whereas neurons in the adult CNS are relatively resistant to this form of cell death. However, under pathological conditions, upregulation of death receptor family ligands, such as tumour necrosis factor (TNF), can sensitize cells in the CNS to apoptosis and a form of regulated necrotic cell death known as necroptosis that is mediated by receptor-interacting protein kinase 1 (RIPK1), RIPK3 and mixed lineage kinase domain-like protein (MLKL). Necroptosis promotes further cell death and neuroinflammation in the pathogenesis of several neurodegenerative diseases, including multiple sclerosis, amyotrophic lateral sclerosis, Parkinson disease and Alzheimer disease. In this Review, we outline the evidence implicating necroptosis in these neurological diseases and suggest that targeting RIPK1 might help to inhibit multiple cell death pathways and ameliorate neuroinflammation.
| S-EPMC6342007 | biostudies-literature
Project description:Receptor-interacting protein kinase 1 (RIPK1) regulates cell death and inflammation through kinase-dependent and -independent functions. RIPK1 kinase activity induces caspase-8-dependent apoptosis and RIPK3 and mixed lineage kinase like (MLKL)-dependent necroptosis. In addition, RIPK1 inhibits apoptosis and necroptosis through kinase-independent functions, which are important for late embryonic development and the prevention of inflammation in epithelial barriers. The mechanism by which RIPK1 counteracts RIPK3-MLKL-mediated necroptosis has remained unknown. Here we show that RIPK1 prevents skin inflammation by inhibiting activation of RIPK3-MLKL-dependent necroptosis mediated by Z-DNA binding protein 1 (ZBP1, also known as DAI or DLM1). ZBP1 deficiency inhibited keratinocyte necroptosis and skin inflammation in mice with epidermis-specific RIPK1 knockout. Moreover, mutation of the conserved RIP homotypic interaction motif (RHIM) of endogenous mouse RIPK1 (RIPK1mRHIM) caused perinatal lethality that was prevented by RIPK3, MLKL or ZBP1 deficiency. Furthermore, mice expressing only RIPK1mRHIM in keratinocytes developed skin inflammation that was abrogated by MLKL or ZBP1 deficiency. Mechanistically, ZBP1 interacted strongly with phosphorylated RIPK3 in cells expressing RIPK1mRHIM, suggesting that the RIPK1 RHIM prevents ZBP1 from binding and activating RIPK3. Collectively, these results show that RIPK1 prevents perinatal death as well as skin inflammation in adult mice by inhibiting ZBP1-induced necroptosis. Furthermore, these findings identify ZBP1 as a critical mediator of inflammation beyond its previously known role in antiviral defence and suggest that ZBP1 might be implicated in the pathogenesis of necroptosis-associated inflammatory diseases.
| S-EPMC5755685 | biostudies-literature
Project description:Background Orexin and its receptors are critical regulating sympathetic vasomotor tone under physiological and pathophysiological conditions. Orexin receptor 1 ( OXR 1) is upregulated in the paraventricular nucleus ( PVN ) in the hypothalamus and contributes to increased sympathetic outflow in obese Zucker rats ( OZR s). We hypothesized that silencing OXR 1 expression in the PVN decreases heightened blood pressure and elevated sympathetic outflow in OZR s. Methods and Results An adeno-associated virus ( AAV ) vector containing a short hairpin RNA (sh RNA ) targeting rat OXR 1 was designed to silence OXR 1 expression in the PVN . The AAV - OXR 1-sh RNA or scrambled sh RNA was injected into the PVN in OZR s. The arterial blood pressure in free-moving OZR s was continuously monitored by using a telemetry approach. The firing activity of spinally projecting PVN neurons in rat brain slices was recorded 3 to 4 weeks after injection of viral vectors. The free-moving OZR s treated with AAV - OXR 1-sh RNA had markedly lower OXR 1 expression and lower mean arterial blood pressure, heart rate, and ratio of low- to high-frequency components of heart rate variability compared with OZR s treated with scrambled sh RNA . Furthermore, AAV - OXR 1-sh RNA treatment markedly reduced renal sympathetic nerve activity and attenuated sympathoexcitatory response induced by microinjection of orexin A into the PVN . In addition, treatment with AAV - OXR 1-sh RNA substantially decreased the basal firing activity of spinally projecting PVN neurons in OZR s and attenuated the excitatory effect of orexin A on the firing activity of these neurons. Conclusions These data suggest that chronic downregulation of OXR 1 expression in the PVN reduces sympathetic vasomotor tone in obesity-related hypertension.
| S-EPMC6662376 | biostudies-literature
Project description:Tumor necrosis happens commonly in advanced solid tumors. We reported that necroptosis plays a major role in tumor necrosis. Although several key necroptosis regulators including receptor interacting protein kinase 1 (RIPK1) have been identified, the regulation of tumor necroptosis during tumor development remains elusive. Here, we report that Z-DNA-binding protein 1 (ZBP1), not RIPK1, mediates tumor necroptosis during tumor development in preclinical cancer models. We found that ZBP1 expression is dramatically elevated in necrotic tumors. Importantly, ZBP1, not RIPK1, deletion blocks tumor necroptosis during tumor development and inhibits metastasis. We showed that glucose deprivation triggers ZBP1-depedent necroptosis in tumor cells. Glucose deprivation causes mitochondrial DNA (mtDNA) release to the cytoplasm and the binding of mtDNA to ZBP1 to activate MLKL in a BCL-2 family protein, NOXA-dependent manner. Therefore, our study reveals ZBP1 as the key regulator of tumor necroptosis and provides a potential drug target for controlling tumor metastasis.
| S-EPMC8113527 | biostudies-literature