Insulin resistance and inflammation -
In the following sub-sections, role of various transcriptional pathways in the pathogenesis of IR has been briefly described. IR leads to the increased production of insulin from β-cells of pancreatic islets and as result, compensatory hyperinsulinemia within the body occurs.
Toll like receptors TLRs are the important modulators of IR and its comorbidities. Chronic inflammation plays a crucial role in variety of insulin resistant states [ 86 , 87 ] in which various signaling pathways are activated that directly interfere with the normal functioning of the key components of insulin signaling pathways [ 88 ].
Among various pathways, activation of TLRs imparts crucial role for the generation of inflammation. There are two main types of TLRs i. TLR2 and TLR4. TLR4 is an extracellular cell surface receptor that is expressed in β-cells of pancreatic islets, brain, liver skeletal muscle and adipose tissues Fig.
In nomal conditions, TLR4 regulates insulin sensitivity in these tissues, but the activation of TLR4 directly dampen the insulin action through the activation of various pro-inflammatory mediators and ROS, indirectly generates the activation of various pro-inflammatory mediators by inducing various signaling cascades and transcriptional factors notably MyD88, TIRAP, TRIF, IKKs and JNKs that causes the activation of innate immune responses which ultimately leads to the development of IR Fig.
TLR4 plays this role primarly in coordination with the phosphorylation of IRS serine. Expression TLR4 in integrated tissues and organ systems of the body that regulate the insulin sensitivity. Toll-like receptor 4 TLR4 present in adipocytes, initiates the inflammatory responses that release various pro-inflammatory mediators.
Once, produced, these mediators are entred into the blood stream and thereby promote IR. TLR4, expressed on Kupffer cells and other liver cell components, regulates the various inflammatory responses in liver.
TLR4, expressed in skeletal muscles, has been shown to regulate the substrate metabolism in muscle, favoring glucose oxidation in the absence of insulin. Hypothalamus and mesolimbic area are important sites that modulate the energy expenditure, pancreatic β-cell function and IR in peripheral tissue.
Expression of TLR4 in hypothalamus potentiates various inflammatory responses that contribute to the pathogenesis of IR. Adopted from Kim and Sears Schematic representation of TLR4 signaling cascades.
Lipopolysaccharide LPS and its endotoxic moiety have been reported to be the potential activators of TLR4 Fig. LPS is composed of oligosaccharides and acylated saturated fatty acids SFAs.
Besides LPS, SFAs have also been reported to be the activator of TLR4. The expression and signaling of TLR4 are regulated mainly by the adiponectins. Several studies have reported that adiponectin can inhibit LPS-induced activation of TLR4 through the involvement of AMPK, IL, and heme oxygenase-1 [ 90 — 92 ].
Other regulators of TLR4 are peroxisome proliferators-activated receptor gamma PPARγ and sex hormones [ 93 , 94 ]. Taking together, TLR4 is a molecular link for pro-inflamatory mediators, different body organs, and several transcriptional pathways and cascades that modulate the innate immune system by regulating the insulin sensitivity.
In the proceeding sub-sections, role of TLR4 expression in various vital organs of the body for the pathogenesis of IR has been described. Despite of having the ability to act as storage depot for excess calories, adipose tissues secrete large number of hormones, pro-inflammatory cytokines and chemokines that directly influence the metabolism Fig.
Adipose tissues consist of adipocytes, preadipocytes, macrophages, lymphocytes and endothelial cells. Only adipocytes and macrophages are known to release various pro-inflammatory cytokines IL-1β, IL-6, and TNF-α and chemokines such as MCP-1 that potentiate inflammation in several tissues after being released into the systemic circulation [ 95 ].
Besides this, adipocytes are also a rich source of two important hormones namely leptin [ 96 , 97 ] and adiponectin [ 98 ]. Adiponectin, having anti-inflammatory properties, promotes insulin sensitivity whereas, leptin having inflammatory properties, impairs insulin sensitivity in adipocytes [ 87 ].
Several factors such as oxidative stress, increased FFAs flux and hypoxia that are associated with inflammation can induce IR in adipose tissues [ 87 ]. TLRs present in adipose tissues are directly activated by the nutrients [ 99 , ] which play a key role for the initiation of inflammatory responses which ultimately promotes IR in these tissues [ — ].
Nutritional fatty acids can activate the expression of TLR4 in adipocytes that play crucial role for the activation of various pro-inflammatory mediators and transcriptional mediated pathways which ultimately lead to the development of IR in adipocytes. Skeletal muscles have marked significance to regulate the normal glucose homeostasis and development of IR as these are the primary site for insulin-induced glucose uptake and utilization in peripheral tissues.
Skeletal muscles contain myocytes and macrophages in which TLR4 receptors are expressed Fig. Signal transduction of TLR receptors is an underlying mechanism for the development of IR and chronic inflammation in skeletal muscles [ ].
TLR4 expression in skeletal muscle is associated with severity of IR and skeletal muscle metabolism. The mechanis in the development of IR in skeletal muscles may include the direct effects of intramyocellular FFAs metabolites in skeletal muscles, macrophages and paracrine effects of adipocytes.
Recently, it has been experimentally confirmed that disruption of TLR4 expression prevents SFA-induced IR in TLR mutant mice and improves IRS-1 tyrosine phosphorylation and insulin-stimulated glucose uptake.
Moreover, disruption of TLR4 expression has also shown to decrease the JNK1 phosphorylation and IRS-1 serine phosphorylation [ , ]. Liver is the major and vital organ of the body which is composed of heterogenous types of cells notably hepatocytes, immune cells, kupffer cells and endothelial cells.
Due to their localization at sinusoids, kupffer cells are in close contact with circulating cytokines, lipids, hormones and postprandial LPS, and hence, kupffer cells are important mediators of inflammation within the liver.
TLR4 expressed on kupffer cells in the liver Fig. It has been found that activated levels of pro-inflammatory AP-1 and NF-κB in liver are directly correlated with IR and oxidative stress [ ].
TLR4 signaling pathway is strongly associated with IR as, it has been found that acute treatment of LPS inhibits the production of hepatic glucose via activation of TLR4 signaling pathway and induces IR in liver [ ]. Several TLRs such as TLR2, TLR3 and TLR4, are also expressed in β-cells of pancreatic islets [ ].
Signal transduction of TLRs in β-cells of pancreatic islets is mainly associated with inflammation in β-cells of pancreatic islets [ — ]. Distruction and malfunctioning of β-cells of pancreatic islets may lead to insufficient secretion of insulin in both types of DM.
Expression of TLR4 in pancreatic islets may lead to impaired insulin secretion and promote β-cell apoptosis [ ]. Brain itself palys a central role to regulate glucose homeostasis and metabolism.
In brain, hypothalamus and mesolimbic sites have been considered as important areas that are actively involved in the regulation of insulin sensitivity in peripheral tissues and β-cells secretory functions of pancreatic islets [ ].
TLR4 expression is widely distributed in the body Fig. Vascular endothelial dysfunction is a major complication for induction of IR and pathogenesis of T2DM.
At molecular level, excess amount of nutrient is interlinked with IR through the activation of transcriptional mediated pathways such as IKKβ and NF-κB [ 83 , ]. Augmented levels of FFAs are associated with generation of inflammation and induction of IR in endothelial cells [ , ].
IKKβ and NF-κB are transcriptional mediators of inflammation and TLR4 is implicated as a mediator of IKKβ and NF-κB [ , ]. TLR4 receptors are also expressed in endothelial cells and expression of TLR4 via LPS-stimulated IKKβ and NF-κB activation contributes the dysfunctioning of endothelial cells [ ].
Activation of TLR4 via FFAs can trigger the cellular inflammatory responses in endothelial cells [ , ] whereas, whole body deletion of TLR4 expression has shown to prevent high-fat diet-induced vascular inflammation and IR in mice [ , ].
Similarly, activation of TLR4-dependent IKK and NF-κB indicated impaired insulin signaling and NO production in endothelial cells [ ]. The growing evidence implicates that TLR4 is the major causative factor to induce IR in endothelial cells via activation of various transcriptional mediated pathways and inflammation in endothelial cells.
AMP-activated protein kinase AMPK is an enzyme that is most commonly known as master regulator of energy metabolism [ ] and its activation is based on the energy level of the body. Upon activation, AMPK resotres the energy levels of the body by stimulating various processes in different body organs Fig.
AMPK plays a crucial role between adipose and peripheral tissues, and interferes various metabolic and secretory functions [ ] that are responsible for normoglycemia and glucose homeostasis Fig. In adipocytes, adipokines exhibit their metabolic effects by activating AMPK which result in the increased β-oxidation in peripheral tissues.
Activation of AMPK in peripheral tissues enables skeletal muscles to cope with elevated levels of FFAs. Keeping in view the active role of AMPK in energy metabolim, it has been found that AMPK activation improves insulin sensitivity and glucose homeostasis.
IR is a major hallmark for the pathogenesis of T2DM however, AMPK activation can prevent the pathogenesis of IR and development of T2DM. Protein kinase C PKC and inhibitor kB kinase IKK are the two main important kinases that play crucial role in pro-inflammatory mediators-induced inflammatory processes in adipocytes and peripheral tissues underlying the development of systemic IR [ — ].
IKK induces IR in peripheral tissues by suppressing the insulin signaling and activating NF-κB [ , ]. Inhibition of IKK activation prevents the secretion of adipokines from adipocytes and improves insulin sensitivity in adipocytes and peripheral tissues [ 81 , , ].
NF-κB is a transcriptional mediated pathway that plays its crucial role in the transcription of signals for te production and release of various pro-inflammatory mediators. Most importantly, NF-κB plays active role to regulate IL-1β Fig. Once activated, NF-κB targets serval genes to potentiate the release of various pro-inflammatory mediators in adipose tissues and liver [ 81 , 83 , ].
These pro-inflammatory mediators that are produced in response to NF-κB activation induce tissue-specific IR. Glucolipotoxicity is a general term which is collectively used for the combination of glucotoxicity and lipotoxicity. These two terms are collectively responsible to activate the release of various pro-inflammatory mediators which lead to the development of tissue-specific IR and impaired insulin secretion from β-cells of pancreatic islets Fig.
Adipocytes are the main sites for the storage of fats and energy supplied to the body, is also regulated by the adipocytes.
When accumulation of lipids exceeds the energy expenditure, then most of the excess amount is stored in the form of FFAs in adipose and other insulin-sensitive tissues. When fat storage and energy supply is impaired in adipose tissues, elevation of FFAs levels in plasma occurs which is converted into the triglycerides and stores in non-adipose tissues [ ].
The ectopic storage of FFAs metabolites mostly triglycerides results in lipotoxic effects in peripheral tissues Fig. In addition to this, elevated levels of FFAs in plasma may also interfere with insulin signaling pathways notably IRS-1 serine phosphorylation in peripheral tissues via activation of PKC and inhibition of IKK and JNK [ ].
Hence, it has been evidenced that glucolipotoxicity is one of the major contributor for the development of tissue-specific IR. Mechanism of hyperglycemia- and dyslipidemia-induced inflammation for the development of IR and T2DM.
Hyperglycemia and dyslipidemia collectively provoke the activation of pro-inflammatory mediators through the involvement of several metabolic pathways. Once, these pro-inflammatory mediators are released, they induce tissue-specific inflammation due to which IR in peripheral tissues and impaired insulin secretion in pancreatic islets occur that ultimately lead to overt T2DM.
Adapted from Akash et al. Development of IR is one of the major hallmark for pathogenesis of T2DM. To control the propagation of IR is one of the most important targeted treatment. For the development of IR, several factors are involved Fig. Several treatment strategies have been used to overcome the development of IR.
The most important ones have been described here in the following sub-sections. Interleukin-1 receptor antagonist IL-1Ra is naturally occurring anti-inflammatory cytokine of interleukin-1 family. It competitively binds with IL-1RI and prevent the binding of IL-1β and antagonizes its effects.
It has been evidenced from several experimental studies that imbalance between IL-1Ra and IL-1β generates inflammation in various parts of the body where IL-1RI is present [ 4 , 12 ]. Moreover, it has also been found that expression of IL-1Ra is strongly correlated with the development of IR, impaired insulin secretion and T2DM [ 4 , ].
Treatment of human recombinant IL-1Ra improves normoglycemia, insulin sensitivity in adipose and peripheral tissues, and insulin secretion from β-cells of pancreatic islets impairs [ 31 , , ]. This is one of the most important treatment strategy that anti-inflammatory agent might indeed prevent the development of IR and improves glycemia.
One of the main shortcoming of IL-1Ra is its short biological half-life and to overcome this problem, high doses with frequent dosing intervals are required to achieve desired therapeutic effects. To overcome this problem, several treatment strategies have been applied to prolong the biological half-life and therapeutic effects of IL-1Ra [ 29 ].
Salicylates are an important class of anti-inflammatory agents. They are used in variety of inflammatory diseases and syndromes. Inflammation plays a crucial role for the development of IR and T2DM, therefore, by using salicylates as an alternate treatment strategy, it has been found that salicylates can imporve insulin sensitivity via inhibition of NF-κB and IKKβ [ 82 ] and glucose tolerance [ , ].
In the above sections, it has been briefly described that TNF-α is one of the most important pro-inflammatory mediator that is responsible to induce IR in adipocytes and peripheral tissues. Inhibition of TNF-α production might be one of the choice to prevent the development of IR and pathogenesis of T2DM [ 4 ].
Recently, infliximab has been demonstrated to improve insulin signaling and inflammation especially in the liver in rodent model of diet-induced IR [ ]. Similarly, using anti-TNF-α antibodies also improve the insulin sensitivity in peripheral tissues [ ].
Lo et al. demonstrated that etanercept therapy can also improve total concentration of adiponectin which is anti-inflammatory adipokine and improved insulin sensitivity [ ].
Keeping in view the decisive role of TNF-α in pathogenesis of IR, several anti-TNF-α treatment strategies have been utilized to prevent the pathogeneis of IR and development of T2DM. Similarly, anti-TNF-α treatment has also shown to prevent the IR in Sprague—Dawley rats [ ] while neutralization of TNF-α also prevented IR in hepatocytes [ ].
Few controversial studies have also demonstrated that using TNF-α blockade has no effect on IR [ ] which indicates that TNF-α blockade is not a treatment of choice as its production is dependent on the generation of IL-1β and activation of various transcriptional mediated pathways.
It has been thought that chemokines activately participate in the development of IR by potentiating the inflammation in adipocytes. Moreover, genetic inactivation of these chemokine signaling [ 52 , 53 , ] or inhibition of their axis [ , ] by pharmacological approaches have been shown to improve the insulin sensitivity in adipocytes and peripheral tissues.
ER stress, as mentioned in the above sections, is a key link between IR and T2DM [ ]. Blockade of ER stress is one of the treatment option to prevent the development of IR and pathogenesis of T2DM.
In the recent years, various pharmaceutical chaperones, notably endogenous bile acids and the derivatives of these bile acids such as ursodeoxycholic acid UDCA , 4-phenyl butyric acid PBA have been investigated that have proven to have the ability to modulate the normal functioning of ER and its folding capacity [ 28 ].
Ozcan et al. The results of this study indicated that UDCA significantly improved insulin sensitivity and normoglycemia. Thiazolidinediones also known as glitazones, are one of the most important insulin sensitisers. They are the agonists of peroxisome proliferator-activated receptors-gamma PPARγ.
It has been found that thaizolidinediones have the ability to improve insulin action and decrease IR [ , ]. Inflammatory responses are induced through the activation of various pro-inflammatory and oxidative stress mediators via involment of various transcriptional mediated pathways.
To stop the inflammatory responses in IR development is one of the key treatment strategy. In this areticle, we have comprehensively highlighted the up-to-date scientific knowlesge of role of inflammatory responses in IR development and its treatment strategies.
IR plays a crucial role for the pathogenesis and development of T2DM and its associated complicaitons. Based on the findings mentioned in above sections, anti-inflammatory treatment strategies are one of the best choice to prevent the the pathogenesis of IR, but the studies conducted to investigate the role of anti-inflammatory strategies for the prevention of IR are still in their beginning stages and need to be focused further in future studies for more better and improved clinical outcomes.
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PeerJ 6, e Liu, J. Front Mol Neurosci 12, They found high levels of the cytokine in the fat tissue of rats with type 2 diabetes, and when they bred obese rats that could not make the cytokine, diabetes did not develop in the animals.
Researchers have since shown that TNF-alpha—and, more generally, inflammation—activates and increases the expression of several proteins that suppress insulin-signaling pathways, making the human body less responsive to insulin and increasing the risk for insulin resistance.
So what causes the inflammation? After fat cells have expanded as a result of weight gain, they sometimes do not get enough oxygen from the blood and start to die, he explains. The cellular death recruits immune cells to the scene.
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Insulin resistance causes inflammation, too. In a study published in the August online version of Diabetes , H. Henry Dong and his colleagues at the University of Pittsburgh showed that a protein called FOXO1 serves as a master switch that turns on the expression of another key inflammatory cytokine, interleukin 1-beta, which also interferes with insulin signaling.
But when a person becomes insulin-resistant and pancreatic cells no longer produce enough insulin to overcome the resistance, activity of FOXO1 increases.
Ijsulin and reeistance diets containing high Inxulin of resistane fat are among the major factors contributing to a low-grade state of inflammation, hyperglycemia and dyslipidemia. Cognitive impairment and decreased neurogenic Insulin resistance and inflammation could OMAD and food choices a resostance Chronic inflammation symptoms rexistance disturbances. In these scenarios, the interplay between inflammation and insulin resistance could represent a potential therapeutic target to prevent or ameliorate neurodegeneration and cognitive impairment. The present review aims to provide an update on the impact of metabolic stress pathways on AD with a focus on inflammation and insulin resistance as risk factors and therapeutic targets. Modern lifestyle is associated with detrimental behavioral and dietary habits such as sedentarism and high dietary intake of saturated fats and refined sugars. Journal of Biomedical Science volume 23Article number: Chronic inflammation symptoms Cite this article. Metrics details. Insulin resistance IR resisatnce one Vegan meal ideas for athletes the Insulin resistance and inflammation hallmark for pathogenesis and etiology of type 2 Chronic inflammation symptoms mellitus T2DM. IR rrsistance directly nIsulin with various inflammafion responses which play crucial role in the development of IR. Inflammatory responses play a crucial role in the pathogenesis and development of IR which is one of the main causative factor for the etiology of T2DM. A comprehensive online English literature was searched using various electronic search databases. Different search terms for pathogenesis of IR, role of various inflammatory responses were used and an advanced search was conducted by combining all the search fields in abstracts, keywords, and titles.Insulin resistance and inflammation -
While there is no concluding information regarding if autophagy impairment is a cause or a consequence for AD, its dysfunction is related to a loss of amyloid degradation capacity and an accumulation of toxic waste that could lead to reduced neuronal viability and neuroinflammation, reinforcing the degenerative character of this pathology.
Chronic activation of autophagy by rapamycin administration is associated with cognitive improvement, decreased amyloid pathology and enhanced autophagy in transgenic mouse models of AD Spilman et al. Neuroinflammation is also associated with this scenario.
Our group has recently shown that microglial autophagy is impaired in AD patients and experimental models Pomilio et al. Interestingly, a recent article by Liu et al. Autophagy in the brain is not independent of peripheral stimuli.
In the last years, several studies showed that gut microbiota is altered in transgenic mouse models of AD, and that restoring microbiota enhances the autophagic flux in the brain, amyloid degradation and cognitive performance Bonfili et al.
Particularly, Bonfili et al. The concept of insulin resistance emerges when insulin levels, whether elevated or within normal range, are associated with a diminished metabolic response or sensitivity Wilcox, Several reports indicate that inflammation affects insulin signaling pathways in insulin-sensitive tissues Kloting and Bluher, ; Parimisetty et al.
Hence, it seems evident that obesity-induced inflammation is closely related to the development of T2D, mainly featured by an inefficient action of insulin or insulin resistance, thus placing insulin in the center of the scene.
Among the candidate molecules involved in this inflammatory response are reactive oxygen species ROS , pro-inflammatory cytokines such as TNF-α, IL-1β, IL-6 and stress kinases as Jun N-terminal kinase JNK , inhibitor of kappaB kinase IKK and protein kinase C PKC Boucher et al.
Regarding IL-1β, there are relevant factors to be considered particularly associated with acute and chronic effects in relation to glycemic control.
It has been shown that postprandial-induced hyperglycemia triggers inflammasome-mediated maturation and secretion of IL-1β in adipose macrophages as an homeostatic mechanism to favor insulin-dependent glucose uptake and protect the organism against potential food microbes Dror et al.
Nonetheless, when the pro-inflammatory cytokine levels together with hyperglycemia-induced ROS are sustained chronically, deleterious effects arise and contribute to the development of insulin resistance Maedler et al. The latter has been proposed not only for IL-1β but other inflammatory cytokines such as TNF-α and IL Hotamisligil et al.
Under physiological conditions, proteins are synthesized at the ER, folded, modified and ultimately targeted to the appropriate cellular compartment.
In the context of metabolic stress, nutrient overload or elevated free fatty acids constitute potential inductors of this response Velloso et al. Another relevant phenomenon underlying inflammation-induced insulin resistance is the activation of TLRs, members of the pattern recognition receptor family responsible for the innate immune response.
Interestingly, different rodent models of TLR4 ablation, either genetically modified by knock-out approaches Poggi et al. As for TLR4 ligands in obesogenic contexts, it has been reported that long chain fatty acids increased in obesity-related contexts are able to stimulate TLR4 signaling leading to the development of insulin resistance Velloso et al.
Regarding lipotoxic stimuli as insulin-resistance inducers, ceramides have also been found to be very relevant. Ceramides are important bioactive lipidic messengers regulating cellular functions such as stress response, inflammation and survival.
Levels are increased in obesogenic and diabetogenic contexts and were found to induce insulin resistance both in vitro and in vivo Holland et al.
Even though ERS and TLRs activation have been originally studied as independent mechanisms in the pathophysiology of metabolic disorders, there is a considerable body of evidence suggesting a constant crosstalk between them in the modulation of metabolic dysfunction and inflammation associated to a decreased insulin sensitivity and downstream actions Guillemot-Legris and Muccioli, During insulin resistance, the activity of Akt -a main effector of the insulin receptor pathway- remains low.
Akt is a multi-substrate kinase that regulates the activity of the AMP-dependent kinase AMPK. Although AMPK is activated by several stimuli, it acts as a master regulator for cellular metabolism and its activation is necessary as a mediator for insulin effects on skeletal muscle and adipose tissue, as it was recently reviewed by Chen et al.
Particularly, AMPK activation directly inhibits de novo lipid synthesis and enhances fatty acid oxidation, linking its activity with insulin resistance and macrophage activation in the context of obesity and T2D Herzig and Shaw, The activation of Akt leads to the activation of mTOR, while AMPK directly inhibits its function.
When activated, mTOR upregulates major anabolic pathways like protein synthesis while inhibiting protein degradation through the downregulation of the autophagic-lysosomal system Herzig and Shaw, Insulin sensitivity, among other factors, is regulated by a number of small insulin-sensitive adipocytes Leonardini et al.
It is highly expressed in adipose tissue, and also in the liver and skeletal muscle Vidal-Puig et al. The endogenous ligands of PPARs are free fatty acids and eicosanoids, favoring lipid storage in adipose tissue while reducing lipotoxicity, promoting an anti-inflammatory response and enhancing insulin sensitivity Varga et al.
It has been hypothesized that PPARγ function is also neuroprotective. It was found to be expressed in the hippocampus, cortex and hypothalamus and is associated with decreased levels of pro-inflammatory mediators, ROS and Aβ in AD models Inestrosa et al.
Mainly known for its role in peripheral glucose homeostasis, insulin also has a significant impact within the brain, functioning as a key neuromodulator in behavioral, cellular, biochemical and molecular studies. Emerging evidence from human and animal studies indicate that insulin influences cerebral bioenergetics and neural functioning Kellar and Craft, The brain is now regarded as an insulin-sensitive organ with widespread, yet selective, expression of the insulin receptor in the olfactory bulb, hypothalamus, hippocampus, cerebellum, amygdala and cerebral cortex.
In the hypothalamus, insulin signaling modulates metabolism, food intake and energy balance Lee and Mattson, , while in extra-hypothalamic structures such as the hippocampus, insulin actions are associated with neurotrophic and neuromodulatory functions.
Insulin receptor signaling in the brain is important for neuronal development, glucose regulation, feeding behavior, body weight, and cognitive processes such as executive functioning, learning and memory Kellar and Craft, Insulin receptors are abundantly expressed in neurons and glial cells Frolich et al.
Consistently, individuals with diabetes or insulin resistance show hippocampal atrophy, alterations in brain connectivity and variable degrees of cognitive impairment, shared phenomena between metabolic and neurodegenerative disorders Beauquis et al.
Insulin signaling has been shown to be impaired in experimental models of AD Chua et al. Brain insulin resistance is a cause for dysregulation of brain bioenergetics, and also leads to enhanced Aβ production, impaired axonal transport, apoptosis and neuroinflammation, as it was recently reviewed by Nguyen et al.
Particularly, impaired hippocampal insulin signaling is associated with impairments in memory and other executive functions, and it is proposed as a mediator between peripheral insulin resistance in T2D and brain dysfunction in AD.
In line with this, Li et al. IDE is an extracellular protease that degrades not only insulin, but also Aβ, in a competitive way. Several authors have proposed that Aβ clearance by IDE could be impaired as IDE is saturated by the high insulin levels in the extracellular space due to insulin resistance, finally leading to Aβ accumulation and aggregation Qiu and Folstein, ; Mayeux and Stern, ; Li et al.
Subsequently, activation of GSK3 would lead to a number of effects among which tau hyperphosphorylation Ishiguro et al. However, there are conflicting results in studies addressing this issue.
While some support this hypothesis Steen et al. late stages of the disease Jimenez et al. It has been shown that insulin resistance, induced by chronic exposure to a HFD promotes short-term memory impairments and decreases brain-derived neurotrophic factor BDNF and phospho-Akt levels in the prefrontal cortex and hippocampus.
Even though there is a solid body of literature supporting a mainly pro-homeostatic role of insulin on brain function, contradicting evidence in relation to aging and neurodegeneration should not be ignored. Particularly, and in conflict with the previously mentioned deleterious effects of insulin resistance, there is evidence from animal models suggesting that the downregulation of insulin signaling may have protective effects in aging and AD.
In Tg mice, a commonly used model of AD, neuronal deletion of insulin receptor substrate 2 IRS2 is associated with decreased Aβ deposition in the brain, improved cognitive performance and increased survival of adult animals Freude et al. However, it should be noted that the expression of Akt and other downstream components of the insulin signaling pathway are unaffected by the deletion of IRS2 in this model.
Similarly, using the nematode Caenorhabditis elegans expressing a minigene for human Aβ 1 — 42 , Cohen et al. Regarding human studies, Harries et al. Thus, these results may suggest that decreased insulin signaling may have a role extending lifespan and modulating amyloid aggregation, in potential conflict with therapeutic strategies aimed at promoting insulin signaling.
However it is not clear yet if the impairment of insulin signaling is a consequence of neurodegeneration or a protective response, stressing the need for more mechanistic and functional studies to clarify this central point. The brain is exposed to a highly dynamic environment and requires concerted mechanisms to exert appropriate responses.
In that sense, brain plasticity represents the CNS intrinsic ability to act upon constantly changing conditions by means of structural and functional processes. Among the phenomena involved in such flexibility, synapse formation, elimination or strength modulation, as well as the promotion of hippocampal neurogenesis are essential mechanisms Kelly et al.
In line with this, alterations of such mechanisms of structural plasticity are associated with cognitive decline and memory dysfunction in aging and neurodegenerative disorders. Hippocampal neurogenesis is a key neuroplastic process that involves the proliferation of neural precursor cells NPCs in the subgranular zone SGZ , differentiation, survival and proper integration into the hippocampal circuit.
It is a thoroughly relevant process underlying emotional behavior and cognitive function mainly associated with memory and learning Clelland et al. Neurogenesis occurs during development and continues throughout life, persisting even in aged adults and AD patients.
Nevertheless, it declines with age and is strongly affected by the environment Klempin and Kempermann, Tobin et al. Animal models of AD show decreased rates of hippocampal neurogenesis Mu and Gage, ; Myhre et al.
Interestingly, overactivation of GSK3β by genetic blockade of the kinase inhibition in NPCs has been associated with diminished neurogenesis together with impaired hippocampus-dependent behavior in mice Eom and Jope, ; Pardo et al.
Taking into account metabolic disturbances as negative modulating factors, the aforementioned conditions associated with obesity and T2D, insulin resistance and sustained inflammation have consistently shown to promote neural connectivity dysfunction.
Several studies from our group and others have reported alterations in hippocampal neurogenesis as a consequence of HFD exposure, occurring in association with impaired cognitive and emotional processing Boitard et al. As regards structural changes in dendritic spines and synaptic plasticity upon metabolic disturbances, HFD exposure for instance has been associated to cause alterations either in the density or the morphology patterns of dendritic spines in the hippocampus.
Hao et al. Moreover, dendritic spine reduction was also detected in pyramidal neurons of the parietal cortex in the context of streptozotocin-induced diabetes in hyperglycemic rats, together with an impaired memory performance assessed by the Morris Water Maze MWM Malone et al. Synaptic failure and loss are key factors underlying cognitive impairment in AD patients Scheff et al.
Progressive dendritic spine alterations were found to correlate with intracellular Tau deposits in postmortem analysis Merino-Serrais et al. Several studies have also shown dendritic spine loss and synaptic dysfunction in animal models of AD, where Aβ toxicity appears to be the main contributor Tu et al.
Apart from Aβ-induced toxicity, dendritic spine and associated synaptic alterations could be associated with reduced levels of BDNF in MCI and AD patients, reinforced by the neuroprotective effects of the neurotrophin reported in experimental AD models Peng et al. BDNF signaling through TRKB receptor and PI3K-Akt-GSK3β pathway are central regulators mediating synaptic plasticity-required dendritic spine turnover and preserving long-term potentiation LTP Peineau et al.
The fact that neurotrophin-induced regulation shares the main components of insulin pathway and is counteracted by proinflammatory mediators such as IL-1β Tong et al. The fact that the mentioned alterations of structural plasticity present in AD are also induced by metabolic pathologies would support a further exacerbation of neuroplasticity decline by interaction of age-related neurodegeneration with obesity and associated disturbances.
Given the relevance of insulin resistance and its close association with inflammation as common pathophysiological mechanisms present in metabolic and neurological disorders, in the following sections we will address the aforementioned phenomena as potential therapeutic targets for CNS dysfunction in AD-related pathology.
The crosstalk between these pathways on the brain is schematized in Figure 2 , showing the main actors involved and identifying with letters A-I the potential targets that will be discussed below, classified as insulin signaling-, inflammation- or lifestyle-based approaches.
Figure 2. Schematic representation of interacting components of the insulin signaling and inflammatory pathways on the brain. Pointed-head arrows depict activation and blunt-end arrows inhibition, while letter circles A-I point the level at which the potential therapeutic approaches discussed in this article would act.
Treatment definition and corresponding reference section are defined in the inferior square. Among the existing treatments that address insulin resistance mainly used in diabetic patients, several clinical and pre-clinical studies have assessed the effect of insulin signaling-based approaches as potential mitigators of brain dysfunction and cognitive impairment.
Nevertheless, regarding potentially positive neurological outcomes, the systemic administration of insulin results in low transport levels to the brain and, on the other hand, may account for undesirable side effects such as hypoglycemia Schmid et al.
In that sense, intranasal IN insulin delivery represents a safe and non-invasive method that has gained increased interest in neurodegeneration research, both in patients and animal models. Intranasal administration of insulin has shown a rapid and widespread distribution through perineural spaces of the trigeminal nerve and the ability to activate the insulin receptor Lochhead et al.
The common doses of IN insulin range from 20 to IU according to different studies, with different outcomes even though there is a growing consensus that IN administration is able to promote changes on CNS as well as peripheral pathways.
There are many positive metabolic effects of IN insulin such as body weight management, food intake and fat composition, with variations according to sex, age and protocol of administration Derkach et al. However, in this review we will focus on cognitive-related outcomes.
Several clinical studies, some of which are explicated in Table 1 , have shown that either IN insulin or its long-lasting analog Detemir were associated with memory improvement both in cognitively intact Benedict et al. Memory amelioration in AD subjects was observed for different doses of IN insulin and treatment duration with APOE-ε4 allele being a strong though controversial moderating factor.
Different trials assessing acute Reger et al. Contrary to these studies, Claxton et al. Additionally, in this cohort of patients a greater degree of insulin resistance at baseline was associated with greater cognitive improvement after the treatment Claxton et al.
Table 1. As regards animal models, IN insulin treatment has been associated with positive results in the behavioral profile, brain metabolic pathways, neuroinflammation and plasticity of several rodent models of AD-like aging.
Moreover, IN insulin treatment has shown beneficial effects in the non-transgenic model SAMP8 AD-like mice. Twelve-month-old AD-like mice exhibited cognitive improvement assessed by spatial memory and object recognition paradigms Salameh et al.
The same insulin dose rendered hippocampal gene expression changes associated with the inflammatory response in young and aged SAMP8 mice Rhea et al. Consistent with this, IN insulin treatment exhibited a positive cognitive, metabolic and histopathological outcome in month-old HFD-induced 3xTG-AD mice Sanguinetti et al.
Furthermore, in the intracerebroventricular i. v streptozotocin-induced model, claimed by several authors to promote an AD-like phenotype, IN insulin has shown to prevent memory impairment, neuroinflammation and insulin resistance in the hippocampus and cortex Rajasekar et al.
Glucagon-like peptide 1 is a peptide hormone mainly synthesized in intestinal L-cells and is one of the incretin hormones promoting glucose-induced insulin secretion by the pancreas after food intake, reducing the release of glucagon and also protecting the pancreas by preventing apoptosis of β-cells Farilla et al.
Apart from these effects, it has been shown that this hormone plays an important role in different organs. For instance, GLP-1 receptors are also present in the liver, heart and brain. GLP-1 function has been associated to the prevention of cardiovascular diseases Bethel et al. As regards T2D and obesity treatment, there are currently approved GLP-1 RAs such as exenatide, liraglutide and lixisenatide which are resistant to the enzymatic cleavage of dipeptidyl peptidase-4 DPP-4 , thus accounting for an increased half-life in comparison to endogenous GLP-1, that have shown positive management of the disease Aroda, Given the pleiotropic character of GLP-1 R and in particular its role in neuromodulation and associated cognitive-related outcome, the use of GLP-1 RAs has been proposed as a potential therapy for neurodegenerative diseases Gejl et al.
Although there is an important research gap regarding clinical evidence in AD given the limitation of sample size or unfinished trials Mullins et al. In that sense, Cai et al. In a previous work, the same group also showed the ability of lixisenatide to ameliorate memory performance assessed by the MWM in intrahippocampal Aβ- injected rats Cai et al.
Regarding exenatide and cognitive outcome in AD rodent models, its use has been associated to memory improvement in i. v streptozotocin STZ -induced rats when treated during 2 weeks Solmaz et al. Despite the lack of cognitive improvement in 3xTg-AD mice, the authors later showed that exenatide promoted an enhanced BDNF signaling and reduced inflammation in HFD-induced 3xTg-AD mice Bomba et al.
Moreover, Batista et al. v-injected with Aβ oligomers AβO but also in non-human primates NHP. Interestingly, the GLP-1 RA was able to revert AβO-induced cognitive impairment as well as to prevent insulin receptor loss in mice hippocampus, the latter also being found in NHP, along with synapse loss prevention and decreased p-Tau levels Batista et al.
Metformin constitutes one of the most common treatments for T2D. It is an oral biguanide and anti-hyperglycemic drug that acts as an insulin sensitizer, lowering blood glucose by increasing its uptake and reducing hepatic gluconeogenesis Zhou et al.
The use of metformin in diabetic patients has been associated not only with blood glucose control but also with an improved lipidic profile and decreased inflammatory markers Lin et al. Concerning the impact of metformin in cognitive decline, either induced in the context of diabetes or among age-related AD patients, there is promising evidence albeit contradictory data should be also taken into account.
For instance, in a pilot study, Koenig et al. Moreover, in non-diabetic patients with amnestic MCI co-occurring with overweight or obesity, metformin appeared to ameliorate systemic inflammation lowering CRP levels and a partial improvement in recall memory Luchsinger et al.
However, in a prospective cohort report with a 1—7. Nonetheless, more longitudinal and larger cohort studies should be assessed since there are confounding factors such as other antidiabetic treatments and lifestyle factors diet and exercise , that may account for the variability and conclusions of such complex studies.
Concerning experimental assessment of metformin in animal models, the use of the anti-hyperglycemic drug has shown to rescue hippocampal plasticity alterations and associated cognitive outcomes in both metabolic dysfunction-induced and AD-like paradigms.
p metformin and several pathophysiological parameters were changed. Interestingly, in a sporadic AD model, month-old SAMP8 mice treated with metformin for 8 weeks, also exhibited an ameliorated behavioral profile with improved learning and memory parameters together with decreased levels of Aβ and p-Tau, even though pGSK3β was found to be slightly increased Farr et al.
Among insulin sensitizing drugs, another relevant category is represented by thiazolidinediones such as rosiglitazone RSG and pioglitazone PIO. Ryan et al. In the metabolic sphere, both drugs were able to improve blood glucose and fasting insulin levels and C-peptide were only reduced in the rosiglitazone group.
Both drugs were associated with improved working memory, even though no differences were registered in learning ability or mood assessment Ryan et al. The effect of RSG in AD patients is rather controversial yet.
Although certain preliminary or explorative analyses showed an association with cognitive improvement Watson et al. In relation to experimental data from animal models and potential mechanisms involved, PPAR agonists have shown positive effects in AD pathophysiology and cognitive status.
For instance, the treatment of 3xTG-AD female mice with PIO was associated with several beneficial effects such as learning improvement, decreased Aβ and Tau deposits in the hippocampus and enhanced hippocampal plasticity shown by increased LTP, along with decreased plasma cholesterol levels Searcy et al.
Neuroprotective outcomes in AD models were also found by combining different PPAR agonists. For example, the use of PPAR-δ and PPAR-γ agonists L, and F-L-Leu, respectively, has shown positive changes in brain slices from i.
v STZ injected rats: decreased inflammation, improved mitochondrial function and reduced Aβ neurotoxicity, although lipid peroxidation and cholinergic function were not rescued Reich et al.
In the same line, a recent report showed that targeting PPAR-α with fenofibrate and PPAR-γ with PIO during 21 days ameliorated memory impairment induced by Aβ 1 — 40 i. v injection.
As mentioned in previous sections, inflammation is a crucial phenomenon in the development of insulin resistance-related pathologies and targeting different components of the inflammatory response has been a promising yet challenging approach in chronic metabolic pathologies such as obesity and diabetes.
Furthermore, taking into consideration that inflammation is a common factor occurring also in a wide variety of neuropsychiatric pathologies, and with microglia being a fundamental element in such response, many authors have undertaken experimental animal approaches to inhibit inflammation and ultimately microglial cells with the aim to reverse cognitive decline.
In the present section, we will analyze available inflammation-based therapies used in diabetes or obesity and the impact as potential treatment for AD. As it was previously described, inflammatory mediators are intimately related to the promotion and propagation of metabolic-induced damage in insulin-resistant contexts both in the periphery and the CNS.
Even though anti-inflammatory therapies are not primary treatments for diabetes, obesity or AD, there is interesting clinical and preclinical evidence that may as well contribute to strengthen the role of inflammation and enable the design of future strategies.
As regards TLR4 direct targeting, neurological available data is scarce and comes mostly from animal models possibly due to its relevance in innate immunity and potential secondary effects.
Moser et al. Consistent with this, the neutralization of HMGB1, a TLR4 ligand has shown to reverse cognitive decline and brain pathology in the 5xFAD mouse model. The subcutaneous administration of HMGB1 monoclonal antibody was able to recover dendritic spine density and decrease DNA damage in 6-month-old 5xFAD cortex Fujita et al.
In the same line, inhibiting obesity-induced microglia activation has shown to ameliorate cognitive decline in two different approaches: pharmacologically with the use of minocycline and genetically by the downregulation of microglial fractalkine receptor Cope et al.
Accordingly, in a very recent report, Melo et al. This was achieved by the use of two different approaches: minocycline or TNFα- neutralizing antibody therapy with infliximab.
The latter also prevented memory impairment in mice exposed to chronic HFD feeding Melo et al. In relation to TLR4 downstream signaling, there is an increasing body of literature addressing NFκB induced-cytokines targeting.
One of the most studied is IL-1β due to its close association with metabolic inflammation and insulin resistance. IL-1β receptor antagonists IL-1β RA have been used in clinical trials focused both on diabetic and AD-like scenarios as it can be seen in Table 1.
For instance, T2D adult patients treated with the IL-1β RA anakinra presented ameliorated glucose levels and pancreatic function with decreased systemic inflammation markers such as CRP and IL6 Larsen et al. As regards the impact of cytokine inhibition in cognitive decline and AD pathology, evidence comes mostly from animal models.
In the same line, LTP analysis in a rat model of amyloidosis McGill-RThy1- APP TG rat showed improved synaptic plasticity when animals were treated with NLRP3 inhibitor Mcc, IL-1β RA anakinra or anti- TNF-α etanercept Qi et al.
TNF-α is also one of the most relevant pro-inflammatory cytokines and its neutralization has been associated with improved cognition and synaptic flexibility in different AD models. XPro anti- TNF-α antibody rescued LTP, Aβ deposition and inflammatory response in 5xFAD MacPherson et al.
Authors have recently found not only an improvement of metabolic parameters associated to dyslipidemia and insulin resistance in the periphery but also central insulin signaling was improved in the hypothalamus and prefrontal cortex, together with behavioral changes in anxiety-like behavior De Sousa Rodrigues et al.
Non-steroidal anti-inflammatory drugs NSAIDs constitute a well-known strategy for targeting both acute and chronic inflammation in diverse contexts. There are different types of compounds in this category with primarily anti-inflammatory and analgesic consequences, associated with the inhibition of cyclooxygenase COX activity and downstream prostaglandin synthesis Rao and Knaus, Given the relevance of the inflammatory response in the pathophysiology and progression of chronic metabolic diseases such as obesity and T2D as well as in the context of AD-like dementia, there has been a genuine interest in preclinical and clinical exploration of NSAIDs as potential therapies.
However, there is controversial or insufficient data as regards their efficacy. In relation to AD risk and progression, there is observational data suggesting a potential benefit of NSAIDs usage in the prevention of the disease Etminan et al.
For instance, in a quite large multicenter RCT, Aisen et al. Additionally, drug-exposed groups reported adverse effects such as dizziness, hypertension and fatigue more frequently than placebo Aisen et al.
Consistent with this work, month exposure to ibuprofen was also unable to slow time-dependent cognitive decline, even though an interestingly favorable different outcome was seen for APOE-ε4 carriers in comparison with non-carriers Pasqualetti et al.
Despite the predominance of disappointing clinic results, animal models of AD have shown positive effects of NSAIDs in the progression of the disease. For example, ibuprofen treatment was associated to decreased Aβ deposition, microglial activation and inflammatory cytokine levels in the APP Tg AD mice model, together with improved signs of degeneration shown by decreased dystrophic neurites Lim et al.
Moreover, and in relation to diabetes and cognitive impairment, Wang et al. As mentioned, cholesterol and its oxidized forms called oxysterols are associated with increased risk for AD, promotion of amyloid pathology and induced inflammation.
Oxysterols are ligands for liver X receptors LXRs , nuclear receptors that function as lipid-activated transcription factors and regulate cholesterol homeostasis Wang and Tontonoz, Besides their role on lipid metabolism, LXRs can regulate inflammation and neuroinflammation.
Evidence from in vitro models showed that LXR agonists inhibit the production of pro-inflammatory mediators from microglia and astroglia at least in part through interfering with the capacity of NFκB to bind DNA and induce transcription Zhang-Gandhi and Drew, Also LXR agonists can interfere with Aβ production and decrease soluble amyloid peptides in the brain of the APP23 mouse model of AD Koldamova et al.
Some drug candidates have been proposed for AD treatment but due to the mixed nature of LXRs effects and adverse effects such as dyslipidemia and hepatic steatosis Grefhorst et al.
Novel agonists overcoming these effects can have potential as AD therapies. A more direct approach has been proposed using statins and cholesterol lowering therapies. First known for their protective effects on cardiovascular disease, statins were then proposed as risk-reducing therapies for AD, with many studies describing protection against the risk of dementia and AD but failing when tested in controlled randomized trials, probably due to the complexity of AD, to the variety of lipids involved HDL cholesterol, LDL-cholesterol, triglycerides and the separate cholesterol pools circulation vs.
brain that coexist reviewed in Reitz, ; Samant and Gupta, Another strategy aims at enhancing CYP46A1 activity, the enzyme that converts cholesterol to 24S-hydroxycholesterol 24S-OHC , the major oxysterol in the brain. This oxysterol, besides its effects on cholesterol metabolism and function as LXR agonist, is an α-secretase activator that hence decreases the rate of Aβ production and plaque formation Bjorkhem et al.
Efavirenz, L -glutamine and dapagliflozin are some of the CYP46A1 activators that showed promising results in experimental models and are being tested in clinical trials Mast et al. As it can be appreciated in the previous sections, on a general basis insulin function-based therapies appear to downregulate inflammation and inflammation-based therapies seem to improve insulin sensitivity, supporting the notion of inflammation and insulin resistance as bidirectionally affecting phenomena.
In that line, in the present section we will discuss non-pharmacological lifestyle approaches mainly associated to diet and physical activity interventions in aged adults either with obesity comorbidity or age-related cognitive impairment. Interestingly, such approaches can be potentially proposed not only as treatments but also as relevant preventive strategies in order to promote a healthier aging and improved quality of life.
Among lifestyle modifiable risk factors associated with AD, great attention has been devoted to physical activity since sedentarism is a crucial risk factor for obesity, cardiovascular disease and is also associated with impaired cognitive function.
Sustained physical activity has shown to ameliorate overall health and particularly maintain cognitive function in disease-free elders even when taken up at late stages Elosua et al.
Moreover, non-demented patients with physical and cognitive frailty exhibited positive results regarding both physical parameters such as muscle strength and speed and also in cognitive flexibility when exposed to a 4 months high-speed resistance exercise training Yoon et al.
Given the lack of successful therapies for age-related dementia, and in particular due to AD, several clinical trials have addressed exercise-based interventions as a potential treatment of AD symptoms, some of which are cited in Table 1.
For instance, a RCT assessing the impact of high-to-moderate exercise in patients diagnosed with probable mild or moderate AD has shown to improve neuropsychiatric symptoms and cognitive status after 16 weeks of continuous attendance to the program Hoffmann et al.
From the same trial, Jensen et al. Although they did not find many significant changes, the exercise group presented increased CSF levels of sTREM2 and IL-6 in plasma and, interestingly, APOE-ε4 non-carriers had reduced levels of IFNγ than APOE-ε4 carriers after exercise intervention Jensen et al.
A subgroup of the patients enrolled in the trial were subjected to cardiorespiratory fitness assessment and an improvement was found in the intervention group, together with a positive association with mood and cognitive outcomes Sobol et al. In close association with the physical activity approach, dance therapy constitutes a non-pharmacological alternative that has exhibited positive outcomes in the amelioration of several symptoms related to AD pathology.
Exposure to different types of dance sessions has shown to promote improvement in diverse domains including physical well-being, mood and cognitive status, irrespective of the practice duration Lazarou et al.
However, it should be noted that this kind of intervention not only entails moderate exercise but also social interaction. Therefore, the improvement assessed would be the result of mixed stimuli resembling an enriched sensory-motor environment, as proposed by Kattenstroth et al.
In reference to the interaction with obesity or insulin resistance in the older population, lifestyle interventions also showed to ameliorate cognitive function. Even though the impact of weight loss in the elderly is controversial, in the case of obese older patients, weight loss associated to diet and exercise has shown positive outcomes in several measures assessing global cognition.
In fact, the combination of both interventions appeared to be better, although for several parameters the combination of diet and exercise was no different than exercise alone Napoli et al.
Additionally, albeit being a rather small sample-sized study, a light exercise intervention promoted mild improvement in executive functioning in non-demented T2D patients with self-reported cognitive impairment Shellington et al. Regarding experimental models, there is an extensive body of literature addressing the impact of exercise paradigms on brain function Ryan and Kelly, Exercise has elicited positive effects on cognition, brain metabolism and plasticity.
Additionally, it promoted enhanced mitochondrial function and increased synaptic density Pang et al. Likewise, it was recently reported that hippocampus-dependent memory and synaptic puncta were positively modulated in month-old mice of the same strain subjected to running during 4 months Zhang et al.
Furthermore, running in the 5xFAD mice promoted beneficial effects in spatial memory and Aβ burden along with increased BDNF levels and enhanced adult neurogenesis.
These effects were not detected when neurogenesis alone was stimulated, suggesting a crucial role for BDNF in the exercise-induced response Choi et al.
Finally, exercise has also promoted pro-cognitive, pro-neuroplastic and anti-inflammatory effects in metabolically challenged contexts such as diabetes or diet-induced obesity Ruegsegger et al. In the same sense that highly processed fat and sugar-enriched western diets negatively affect metabolism, inflammatory status and cognitive function, modulating dietary composition can be a powerful strategy to positively modify the aforementioned health domains.
For instance, Mediterranean diet MD has been associated with general wellbeing and preserved cognitive function in the elderly McGrattan et al. MD is predominantly constituted by fruits, vegetables, wholegrains and legumes, fish and poultry to a lesser extent and a very low intake of red meats and processed food where olive oil is the main source of fat, thereby associated with antioxidant and anti-inflammatory components.
Although MD has exhibited an important adherence among commonly proposed diets, the use of certain supplements addressing some of its components has also been related to beneficial effects. As an example, lycopene is a potent antioxidant carotenoid present in fruits and vegetables that has shown protective effects in several chronic diseases such as cancer, cardiovascular disease and neurodegeneration Saini et al.
As regards dietary interventions, CNS impact of lipid metabolism-based supplements was given attention. Not only approaches to decrease cholesterol levels were studied Chu et al. The most commonly used PUFAs are docosahexaenoic acid DHA , eicosapentaenoic acid EPA , and alpha-linolenic acid ALA , which are reported as relevant precursors of neuronal membrane components, fluidity and signaling Chappus-McCendie et al.
As it can be appreciated in Table 1 , several clinical trials analyzed the impact of DHA and EPA in patients with mild-to-moderate AD and mixed results were obtained. Quinn et al. Nevertheless, when administration of DHA was combined with EPA, other clinical studies found either a subtle cognitive improvement in a subgroup of very-mild AD Freund-Levi et al.
Among dietary interventions, fasting, calorie restriction and ketogenic diets KD have also been widely proposed to reverse obesity and T2D, being able not only to promote weight loss but also to enhance insulin sensitivity and reduce inflammation Harvie et al.
In the present section, we will discuss the impact of these particular dietary approaches on brain plasticity and pathological hallmarks as potential therapies for AD-like neurodegeneration.
Fasting can be defined as a period of food deprivation. It has been associated with different socio-cultural factors from religion to periods of food scarcity and it was later related to increased lifespan in several species Brandhorst et al. There are different fasting protocols described in the literature, mainly due to length and frequency variations.
Essentially, intermittent or periodic fasting and dietary restriction are very similar approaches since the main phenomenon is the time restriction of food intake. At the level of the metabolic response and in a similar fashion as ketogenic diets, these dietary interventions lead to an increase of ketone bodies, producing relevant changes in glucose metabolism Wilhelmi de Toledo et al.
Ketogenic diet is mainly featured by a very high-fat and low-carbohydrate intake and can be difficult to sustain, therefore the increase of ketone bodies can also be achieved by administering medium chain triglycerides MCT without changing the diet Reger et al.
In Table 1 , we can find a selection of relevant clinical studies addressing their impact on cognitive function. As regards experimental studies, KD, intermittent fasting IF or dietary restriction DR have shown to promote improved glucose metabolism together with anti-inflammatory and cognitive amelioration in animal models of AD.
For instance, KD exposed 3xTg-AD mice exhibited enhanced memory and learning ability in addition to decreased hippocampal Aβ deposition Kashiwaya et al.
As for intermittent fasting, it was recently shown that App NL-G-F mice maintained in an IF protocol alternating ad libitum and fasting days for a month, exhibited an adaptive response to acute fasting with improved memory and anxiety-related outcomes.
The behavioral profile amelioration occurred concomitantly with synaptic remodeling dependent of SIRT3 mitochondrial deacetylase Liu et al.
In the same line, our group and others have shown that DR represents a moderate and feasible schedule capable of improving cognitive function in aged wild type Ma et al.
In the latter, we found that three cycles of DR alternated with ad libitum feeding between 6. Moreover, periodic DR prevented microglial activation and promoted a decrease in the levels of hippocampal IL-1β, thus counteracting the neuroinflammatory status.
The inflammatory status in the mentioned structures of the CNS present in the context of metabolic diseases has been associated with a low-grade chronic inflammation response both detected and potentially triggered in the periphery.
One of the possible mechanisms corresponds to alterations of the gut microbiota affecting the microbiome-gut-brain axis. Obesity-related disorders are often reported to co-occur with dysbiosis-associated inflammation and interventions with probiotics and related bioactive compounds have been able to reverse inflammatory parameters and ameliorate cognitive decline and hippocampal plasticity alterations, such as LTP and synaptic activity Solas et al.
Gut microbiome diversity alterations have been associated with the AD-like pathological context, not only in relation to the gut but also BBB dysfunction Vogt et al. Therefore, probiotic supplementation has been proposed as a potentially beneficial strategy to improve AD symptoms by modulating microbiota and ultimately the gut-brain axis.
Probiotics are living microorganisms that have shown to elicit beneficial effects in the host, preventing infections, obesity-related alterations as well as promoting CNS positive modulation Hutchinson et al.
As it can be appreciated in the studies cited in Table 1 , different probiotic formulations have shown to ameliorate cognitive function in patients with MCI or AD.
For instance, Tamtaji et al. acidophilus , B. bifidum , and Bifidobacterium longum co-supplemented with selenium, present in several beneficial probiotic formulations, was able to promote improved cognitive performance as well as an ameliorated metabolic profile.
Peripheral inflammation decreased together with enhanced insulin sensitivity and an ameliorated lipidemic profile Tamtaji et al. Consistently with this data, there is also experimental evidence of positive outcomes in 3x-Tg mice that were given selenium-enriched yeast for 3 months.
Interestingly, spatial memory was improved concomitantly with reduced neuroinflammation, GSK3β-dependent Tau phosphorylation and increased expression of synaptic proteins in the cortex and hippocampus Zhang et al. In the same line, in a pilot study and a larger RCT Kobayashi et al. In both cases, administration of the probiotics resulted in improved scores at neuropsychological tests assessing cognitive and mood status.
Likewise, Bifidobacterium breve A1 administration to mice that were i. v- injected with Aβ elicited an anti-inflammatory response, along with an improvement of cognitive decline Kobayashi et al. Taken together, this experimental and clinical data suggests that probiotic supplementation may constitute a beneficial lifestyle approach to enrich and reshape gut microbiome, thereby exerting an anti-inflammatory and anti-neurodegenerative response to AD pathological context.
The alarming prevalence of both AD and obesity- related metabolic disorders and the consequent implications in public health strongly require the rise of efficient therapeutic solutions. The fact that metabolic alterations are risk factors for the development of age-related dementia not only reinforces the relevance of the problem but also provides useful insight as regards potential research fields to further explore.
Therefore, this review intended to highlight the shared pathways at the interface of these pathologies as potential targets to override AD burden.
Insulin resistance and chronic inflammation are two synergic phenomena underlying the pathogenesis of metabolic diseases as well as the development of the wide variety of associated disorders, including AD-like neurodegeneration. Therapeutic approaches targeting these interacting factors could be proposed as potential AD treatments even though data is variable and there is an important gap between experimental evidence from animal models and replication in clinical trials.
Several factors should be taken into account. Firstly, the specific origin or etiology of the diseased context might differ considerably, with a variable substrate to address mainly according to age but also as regards pre-existing or co-occurring morbidities, namely developmental traits, obesity, diabetes and genetic predisposition.
Secondly, and in association with the lack of etiology certainty in AD patients, the proposed therapies may be targeting either causes or mere symptoms, with an additional factor: the targeted pathways redundancy and compensatory mechanisms.
AV, CP, AG, MnB, JP, MsB, FS, and JB discussed, wrote and reviewed this manuscript. All authors contributed to the article and approved the submitted version. This work was supported by Williams, René Barón and Alberto J.
Roemmers Foundations, ANPCyT PICT Grants , , , and , CONICET PIP Grant , and UBACyT The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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This work is partially supported by NIH grants DK and DK to Jian-ping YE and an NIH COBRE grant 2P20RR and ADA grant JF to Zhan-guo GAO. Antioxidant and Gene Regulation Lab, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, , LA, USA.
You can also search for this author in PubMed Google Scholar. Correspondence to Jian-ping Ye. Reprints and permissions. Gao, Zg. Why do anti-inflammatory therapies fail to improve insulin sensitivity?.
Acta Pharmacol Sin 33 , — Download citation. Received : 01 August Accepted : 06 September Published : 31 October Issue Date : February Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article.
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Why do anti-inflammatory therapies fail to improve insulin sensitivity? Download PDF. Abstract Chronic inflammation occurs in obese conditions in both humans and animals. The role of macrophages in obesity-associated islet inflammation and β-cell abnormalities Article 13 December Trends in insulin resistance: insights into mechanisms and therapeutic strategy Article Open access 06 July Cytokine modulation by etanercept ameliorates metabolic syndrome and its related complications induced in rats administered a high-fat high-fructose diet Article Open access 23 November Introduction For about two decades, it has been known that inflammation contributes to obesity-associated insulin resistance.
Chronic inflammation and insulin resistance At the molecular level, inflammation induces insulin resistance by targeting IRS-1 and PPARγ. Inflammation and IRS-1 insulin receptor substrate 1 In cellular models of insulin resistance, the pro-inflammatory cytokine, TNF-α, is widely used to induce insulin resistance.
Free fatty acids and insulin resistance Elevated plasma free fatty acids FFAs induce insulin resistance in obese and diabetic subjects Inflammation and energy metabolism Inflammation is associated with increased energy expenditure in patients with chronic kidney disease 51 , cachexia 52 , inflammatory bowel disease 53 and Crohn's disease New potential drug candidates for insulin resistance The antidiabetic drug thiazolidinedione TZD restores insulin action by activating PPARγ, thus lowering the levels of FFAs in the blood.
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Obesity is one of the inflamation health burdens of the 21st Chronic inflammation symptoms as it contributes Insulin resistance and inflammation the growing Insulin resistance and inflammation of its related comorbidities, including insulin Insluin Chronic inflammation symptoms type 2 diabetes. Resstance evidence suggests a critical role for overnutrition in the development of appetite control in men inflammation. Specifically, chronic infoammation in adipose tissue is considered a crucial risk factor for the development of insulin resistance and type 2 diabetes in obese individuals. The triggers for adipose tissue inflammation are still poorly defined. However, obesity-induced adipose tissue expansion provides a plethora of intrinsic signals e. Immune dysregulation in adipose tissue of obese subjects results in a chronic low-grade inflammation characterized by increased infiltration and activation of innate and adaptive immune cells. In obesity, adipose tissue macrophages are polarized into pro-inflammatory M1 macrophages and secrete many pro-inflammatory cytokines capable of impairing insulin signaling, therefore promoting the progression of insulin resistance.
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