Findings published this week reveal new insights into the role of fat cells in cognitive decline and neurodegeneration, according to a study that involves the oxidant amplification loop led by Marshall University scientists.
The research, published in iScience, shows that fat cells control the systemic response to brain function, causing impairment in memory and cognition in mice.
The activation of Na,K-ATPase oxidant amplification loop affects the expression of important protein markers in fat cells as well as in the hippocampus, which can worsen brain function and lead to neurodegeneration. Targeting the fat cells to antagonize Na,K-ATPase may improve these outcomes.
“We have aimed to demonstrate that Na,K-ATPase signaling, specifically in adipocytes, play a central role in inducing alterations in specific regions of the brain, most notably in the hippocampus, which is critical to memory and cognitive function,” said senior author Joseph I Shapiro, M.D., professor and dean of the Marshall University Joan C. Edwards School of Medicine.
Researchers used a genetically-modified mouse model that released the peptide NaKtide specifically in adipocytes, or fat cells, to find that NaKtide inhibited the signaling function of Na,K-ATPase.
Inducing oxidative stress through western diet increased production of inflammatory cytokines confined to adipocytes as well as altered protein markers of memory and cognition in the hippocampus.
“Western diet induces oxidant stress and adipocyte alteration through Na,K-ATPase signaling which causes systemic inflammation and affects behavioral and brain biochemical changes,” said Komal Sodhi, M.D., first author and associate professor of surgery and biomedical sciences at the Joan C. Edwards School of Medicine.
“Our study showed that adipocyte-specific NaKtide expression in our murine model ameliorated these changes and improved neurodegenerative phenotype.”
From Inflammation in Adipose Tissue to Impaired Hippocampus Plasticity in Obese and Diabetic Conditions
Obesity induces chronic inflammation in adipose tissues due to infiltration and activation of macrophages [173]. During extreme obesity, it is estimated that these macrophages can take up over 50% of all cells in the adipose tissue [174] and are polarized to the pro-inflammatory phenotype upon activation [175].
Several fat transplantation studies have demonstrated that the inflammatory response in adipose tissue could be linked to obesity and diabetes-impaired hippocampal plasticity and cognitive functions [55,176]. Leptin, a pro-inflammatory cytokine secreted from the adipose tissue, is elevated in obese and diabetic conditions [177,178,179].
Transplantation of epididymal fat from db/db (leptin receptor deficiency) donor to wild-type naïve mice activates microglia and macrophages in the hippocampus, and reduces dendritic spine density in the granule neurons, as well as impairs hippocampal long-term potentiation (LTP) [55]. These structural changes could be linked to spatial memory deficits in the hippocampal-dependent tasks [55].
Conversely, epididymal-lipectomy in db/db donor rescues spatial memory deficits, suppresses neuroinflammatory response, and restores hippocampal plasticity [55]. These findings have suggested that leptin resistance in adipose tissue could be a contributing factor to hippocampal plasticity deficits, and hence cognitive impairment.
The high-fat diet promotes the generation of reactive oxygen species (ROS) in the adipose tissue [180]. ROS can trigger nod-like receptor family, pyrin domain-containing 3 (NLRP3)-containing inflammasome to activate caspase-1 and secrete interleukin 1β (IL-1β) [181]. HFD induces obesity in Nlrp3 global knockout mice but prevents the development of adipose tissue inflammation and insulin resistance [182,183].
Increased circulating IL-1β level is associated with cognitive impairment in diabetes [184]. Visceral adipose tissue transplantation experiment in mice suggests that adipose tissue inflammation has a direct linkage to cognitive impairment with the associated neuroinflammatory response. Transplanting visceral adipose tissue from mice fed with 12-week HFS to wild-type recipient impairs spatial memory, activates microglial and increases hippocampal IL-1β levels [176].
On the contrary, fat transplantations from HFD-fed Nlrp3−/− donors do not trigger neuroinflammatory response and memory deficits in recipients [176]. Other studies have shown that NLRP3-inflammasome/IL-1β signaling contributes to synaptic deficits in the hippocampus. The electrophysiological recording reveals that NLRP3 impairs LTP formation through IL-1 receptors [176].
Conversely, neutralizing IL-1 receptor rescues deficits in structural and synaptic plasticity in the hippocampus of the db/db mice [55]. In sum, these results have suggested that activation of NLRP3-inflammasome/IL-1β signalling could activate neuroinflammatory response and impair synaptic plasticity, leading to cognitive impairment in diet-induced obesity or diabetic condition (Figure 1).
Diet-induced obesity up-regulates the secretion of pro-inflammatory cytokines, whereas inflammatory response in adipose tissue further suppresses the secretion of adipocyte-derived anti-inflammatory cytokines, such as adiponectin [185]. Adiponectin is the most abundant adipokine in the bloodstream, which is secreted by mature adipocytes [186]. Adiponectin is an insulin-sensitizer by promoting glucose and fatty acid metabolism upon feeding [187].
In obese individuals, adiponectin secretion from white visceral adipose tissue decreases as adiposity increases [187]. Reduced insulin sensitivity, together with chronic inflammation, could progressively lead to systemic and central insulin resistance [24,188] (Figure 1). Adiponectin can cross the blood-brain barrier [130,189], suggesting its potential role in promoting insulin sensitivity in the brain. T
he functional role of adiponectin in the brain has recently been found using adiponectin knockout mouse models. Adiponectin activates AMPK to increase insulin sensitization in hippocampal and cortical neurons via suppressing Akt/GSK3β signaling [144]. Conversely, adiponectin deficiency disinhibits GSK3β-mediated cleavage of amyloid precursor protein and promotes plaque deposition [144], which in turn leads to neuroinflammation and hippocampal-dependent learning and memory deficits [144].
Adiponectin also mediates neuroinflammatory response through AdipoR1/NF-κB pathway [190]. Adiponectin deficiency induces microgliosis in the hippocampus and hypothalamus in an association with increased pro-inflammatory cytokine secretion [190]. Adiponectin also promotes hippocampal synaptic [132] and structural plasticity [131], which are abolished in adiponectin-deficient mice.
Both obese and diabetic mice show reductions in adiponectin levels in the hippocampus [58,191]. These studies have collectively suggested that obesity and diabetes alter adiponectin secretion, which could consequently result in neurodegeneration and cognitive deficits.
Metabolic syndromes perturb adipose secretion of pro- and anti-inflammatory cytokines as well as adipose tissue inflammation. These perturbations not only affect the peripheral metabolism, but also trigger microglial activation in the hippocampus, and hence impair hippocampal plasticity. Studies have shown that withdrawal from the high-fat diet is an effective non-pharmacological intervention for improving learning and memory deficits [111,112].
Another study has also demonstrated that a feeding protocol with a 12-week high-fat diet, followed by an 8-week low-fat diet reduces microglial activation and increases spine density in the hippocampus [192]. The beneficial effect of dietary reversal is accompanied by reduced weight gain and fat masses [192]. Little is known about the interplay of microglial activation and adult neurogenesis in the obese and diabetic brain. However, it is shown that aberrant microglial activity may predominate the interplay by internalizing synaptic terminals upon chronic HFD while switching from HFD to a low-fat diet (LFD) attenuates synaptic internalization [192].
A recent study has reported that fractalkine receptor (CX3CR1) is involved in the microglial-mediated synaptic stripping in obese mice [193]. Obesity induces the expression of the phagocytic marker in hippocampal microglia [193], whereas Cx3cr1-haploinsufficiency counteracts spatial learning and memory deficits, microglial activation, and dendritic spine loss in the hippocampus [193]. CX3CR1 mediates microglial motility and activation [194].
Pharmacological blockade of microglial phagocytosis by annexin-V or suppressing microglial activity by minocycline prevents obesity-induced spine lost and cognitive impairment [193]. In sum, these findings have suggested the predominant role of microglia in inducing deficits in hippocampus structural plasticity in obesity (Figure 2).
Intrinsic aberrant microglial activity and apoptotic spines can trigger synaptic stripping. ① HFD-induced hippocampal IL-1β elevation promotes the pro-inflammatory M1 phenotype in microglia. ② The aberrant microglia are attracted by CX3CL1 (Fractalkine) from the dendritic spine, which is recognized by the microglial CX3CR1. On the other hand, ③ reduced adiponectin level induces the accumulation of β-amyloid in the hippocampus. ④ Aβ accumulation causes mitochondrial dysfunction with the reduced mitochondrial membrane potential as well as the increased oxidative stress. The apoptotic mitochondrial releases cytochrome c which can activate flippase activity through caspase 3. ⑤ Phosphatidylserine located at the outer membrane of the phospholipid bilayer are served as an ‘eat-me’ signal, which is recognized by the receptors on the microglia. ⑥ Together, both aberrant microglial activity and malfunctioned neuronal mitochondria can trigger synaptic stripping by the microglia. Created with BioRender.com.
reference link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796248/
More information: Komal Sodhi et al, Role of Adipocyte Na,K-ATPase Oxidant Amplification Loop in Cognitive Decline and Neurodegeneration, iScience (2021). DOI: 10.1016/j.isci.2021.103262
