Adiponectin ameliorates hypoperfusive cognitive deficits by boosting a neuroprotective microglial response

Miao, Wanying; Jiang, Liyuan; Xu, Fei; Lyu, Junxuan; Jiang, Xiaoyan; He, Maxine; Liu, Yaan; Yang, Tuo; Leak, Rehana K.; Stetler, R. Anne; Hu, Xiaoming

doi:10.1016/j.pneurobio.2021.102125

Cited by 26 publications

(14 citation statements)

References 70 publications

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“…Peroxisome proliferator-activated receptor-g (PPARg) is a ligand-activated transcription factor that belongs to the superfamily of nuclear hormone receptors. Activation of PPARg mediated the conversion of microglia phenotype and phagocytic capabilities of peripheral M2 polarized macrophages in various CNS diseases (39,40), including hemorrhagic stroke (21). Flores et al revealed that the PPARg-induced CD36 upregulation in microglia increased M2 microglia polarization and was crucial in enhancing post-GMH hematoma resolution.…”

Section: Discussionmentioning

confidence: 99%

“…PPARg agonists enhanced myelination, reduced inflammation and hydrocephalus, and promoted neurological recovery in newborns with intraventricular hemorrhage (IVH) (41). More recently, studies have shown that activation of adiponectin receptor with adipoRon could boost PPARg expression and inhibit pro-inflammatory microglia responses, therefore ameliorating hyperperfused cognitive deficits (40). Accordingly, we demonstrate that APN promote phenotypic change of microglia from "classically" M1 activated to "alternatively activated" M2 states and enhances hematoma clearance, thereby reducing hydrocephalus by activation of PPARg via AdipoR1 signaling.…”

Section: Discussionmentioning

confidence: 99%

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Adiponectin Ameliorates GMH-Induced Brain Injury by Regulating Microglia M1/M2 Polarization Via AdipoR1/APPL1/AMPK/PPARγ Signaling Pathway in Neonatal Rats

Wei

et al. 2022

Front. Immunol.

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Adiponectin (APN), a fat-derived plasma hormone, is a classic anti-inflammatory agent. Multiple studies have demonstrated the beneficial role of APN in acute brain injury, but the effect of APN in germinal matrix hemorrhage (GMH) is unclear, and the underlying molecular mechanisms remain largely undefined. In the current study, we used a GMH rat model with rh-APN treatment, and we observed that APN demonstrated a protective effect on neurological function and an inhibitory effect on neuroinflammation after GMH. To further explore the underlying mechanisms of these effects, we found that the expression of Adiponectin receptor 1 (AdipoR1) primarily colocalized with microglia and neurons in the brain. Moreover, AdiopR1, but not AdipoR2, was largely increased in GMH rats. Meanwhile, further investigation showed that APN treatment promoted AdipoR1/APPL1-mediated AMPK phosphorylation, further increased peroxisome proliferator-activated receptor gamma (PPARγ) expression, and induced microglial M2 polarization to reduce the neuroinflammation and enhance hematoma resolution in GMH rats. Importantly, either knockdown of AdipoR1, APPL1, or LKB1, or specific inhibition of AMPK/PPARγ signaling in microglia abrogated the protective effect of APN after GMH in rats. In all, we propose that APN works as a potential therapeutic agent to ameliorate the inflammatory response following GMH by enhancing the M2 polarization of microglia via AdipoR1/APPL1/AMPK/PPARγ signaling pathway, ultimately attenuating inflammatory brain injury induced by hemorrhage.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Adiponectin Ameliorates GMH-Induced Brain Injury by Regulating Microglia M1/M2 Polarization Via AdipoR1/APPL1/AMPK/PPARγ Signaling Pathway in Neonatal Rats

Wei

et al. 2022

Front. Immunol.

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“…A Polish study showed that patients with diabetes and mild cognitive impairment have low serum adiponectin levels, suggesting that adiponectin may be involved in cognitive impairment [ 32 ]. Scholars in Pittsburgh found that adiponectin inhibits the activation of microglia in a PPAR γ -dependent manner to improve the cognitive function of vascular dementia [ 33 ]. However, the role of adiponectin in the cognitive maintenance of SCI patients has not been reported yet.…”

Section: Discussionmentioning

confidence: 99%

Decreased Adiponectin Levels Are a Risk Factor for Cognitive Decline in Spinal Cord Injury

et al. 2022

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Objective. Spinal cord injury (SCI) has become popular in recent years, and cognitive decline is a common complication. Adiponectin is a common protein hormone involved in the course of many diseases, but its relationship with SCI has not yet been elucidated. The purpose of our prospective study is to explore whether adiponectin can be used as a biomarker of cognitive decline in SCI. Methods. A total of 64 healthy volunteers and 92 patients with acute SCI were recruited by us. Serum adiponectin levels, demographic data (age and gender), lifestyle (smoking and drinking), medical history (diabetes and hypertension), and clinical baseline data (low-density lipoprotein, high-density lipoprotein, and fasting blood glucose) were recorded. Three months after enrollment, we used the Montreal Cognitive Assessment (MoCA) to evaluate cognitive function. Based on a quarter of the serum adiponectin levels, SCI patients were divided into 4 groups, and the differences in their MoCA scores were compared. In addition, we used multivariate linear regression to predict the risk factors of the MoCA score. Results. The serum adiponectin level ( 6.1 ± 1.1 μ g / ml ) of SCI patients was significantly lower than that of the healthy control group ( 6.7 ± 0.9 μ g / ml ), and there was a significant difference between the two ( p < 0.001 ). The group with higher serum adiponectin levels after 3 months of spinal cord injury had higher MoCA scores. Multivariate regression analysis showed that serum adiponectin level is a protective factor for cognitive function after SCI ( β = 0.210 , p = 0.043 ). Conclusions. Serum adiponectin levels can be used as an independent predictor of cognitive function in patients with acute SCI.

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“…AdipoR1 selectively activates the AMP-activated kinase (AMPK) pathway, while AdipoR2 exerts its biological effects by activating the PPARα pathway [ 25 ]. AdipoRon, a small molecule agonist of APN receptors, can selectively activate both AdipoR1 and AdipoR2 [ 26 , 27 ], which can readily penetrate the blood-brain barrier (BBB) and exert the same effects as those of APN in the CNS [ 26 , 28 ]. This provides a promising prospective towards clinical translation of the mechanism involved in APN-associated anti-oxidative stress and opens up opportunities for clinical applications in CNS diseases.…”

Section: Introductionmentioning

confidence: 99%

Adiponectin/AdiopR1 signaling prevents mitochondrial dysfunction and oxidative injury after traumatic brain injury in a SIRT3 dependent manner

Zhang

Wang

et al. 2022

Redox Biology

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Adiponectin ameliorates hypoperfusive cognitive deficits by boosting a neuroprotective microglial response

Cited by 26 publications

References 70 publications

Adiponectin Ameliorates GMH-Induced Brain Injury by Regulating Microglia M1/M2 Polarization Via AdipoR1/APPL1/AMPK/PPARγ Signaling Pathway in Neonatal Rats

Adiponectin Ameliorates GMH-Induced Brain Injury by Regulating Microglia M1/M2 Polarization Via AdipoR1/APPL1/AMPK/PPARγ Signaling Pathway in Neonatal Rats

Decreased Adiponectin Levels Are a Risk Factor for Cognitive Decline in Spinal Cord Injury

Adiponectin/AdiopR1 signaling prevents mitochondrial dysfunction and oxidative injury after traumatic brain injury in a SIRT3 dependent manner

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