Immunometabolic crosstalk between dysfunctional adipose tissue and the brain: implications for postoperative cognitive dysfunction in obesity.

Immunometabolic crosstalk between dysfunctional adipose tissue and the brain: implications for postoperative cognitive dysfunction in obesity

Postoperative cognitive dysfunction (POCD) is an important complication after surgery, particularly in patients with pre-existing metabolic and inflammatory vulnerability. Obesity may increase susceptibility to postoperative cognitive decline, but its independent association with POCD and the underlying mechanisms remain uncertain. This review critically examines a proposed adipose–immune–brain pathway linking obesity-associated adipose dysfunction to perioperative neurocognitive outcomes. In obesity, adipocyte hypertrophy, hypoxia, fibrosis, macrophage accumulation, T-cell imbalance, and activation of inflammasome and innate immune signaling pathways promote chronic low-grade inflammation and altered endocrine function. The resulting changes in cytokines, adipokines, free fatty acids, lipid mediators, insulin sensitivity, and glucose and lipid metabolism may establish a systemically primed immunometabolic state. Surgical trauma may then act as a second inflammatory hit, amplifying peripheral immune activation and promoting blood–brain barrier dysfunction, glial activation, oxidative stress, and impaired neuronal function. However, direct clinical evidence linking adipose tissue inflammation to POCD remains limited; current support is derived largely from preclinical studies, indirect biomarker associations, and heterogeneous clinical studies that sometimes combine postoperative delirium with longer-term cognitive outcomes. Accordingly, the adipose–immune–brain axis should be regarded as a biologically plausible framework rather than an established causal pathway. Better phenotyping of visceral adiposity and metabolic dysfunction, standardized neurocognitive outcomes, and integrated assessment of adipose, circulating, and blood–brain barrier biomarkers are needed. Potential interventions include weight and metabolic optimization, incretin-based therapies, modulation of inflammatory and pro-resolving pathways, and perioperative physiological management, although their efficacy for preventing POCD remains to be established.

1Introduction

Postoperative cognitive dysfunction (POCD) refers to a persistent decline in cognitive function following surgery, and its clinical significance has been increasingly recognized in recent years (1–3). With an aging global population, the reported incidence of POCD in individuals over 55 years ranges between 5% and 56%, and the incidence at 3 months post-surgery is approximately 10%–17% (4). Although POCD has been extensively studied after cardiac surgery, The International Study of Post-Operative Cognitive Dysfunction 1 (ISPOCD1) found that among patients 60 years of age or older undergoing noncardiac major surgery, the incidence of POCD is 25.8% at one week and 9.9% at three months after surgery (4, 5). The risk of POCD is multifactorial including age, surgical trauma, anesthesia, hypotension, metabolic disorders, and neurological disorders (4, 6–10). Although the effect of surgery type remains controversial, some studies suggest that major cardiac surgery is associated with higher POCD rates; additional contributors may include longer surgery duration, postoperative complications, heightened stress responses, and prolonged hospitalization (11, 12).

Obesity, a globally prevalent chronic disease, has been identified as a risk factor for cognitive impairment and may be associated with POCD, although the specific link between obesity and POCD is not yet fully elucidated (13–16). Available clinical evidence suggests that postoperative cognitive outcomes are influenced by multiple interrelated systemic factors, including metabolic burden, oxidative stress, malnutrition, and frailty (17–19). Because several of these factors may coexist with obesity, they may contribute to or confound the observed association between obesity and postoperative cognitive vulnerability. However, the current evidence does not establish obesity itself as an independent risk factor for POCD. This review summarizes current evidence on how obesity-induced adipose immune remodeling and immunometabolic dysfunction promote systemic immune activation and neuroinflammation, potentially increasing susceptibility to POCD. Understanding these pathways is critical for identifying high-risk patients, developing early biomarkers, and designing targeted therapeutic and preventive strategies.

This review therefore examines the proposed sequence from obesity-induced adipose immune remodeling to systemic immunometabolic dysfunction, perioperative inflammatory amplification, blood–brain barrier (BBB) disruption, and postoperative cognitive vulnerability (Figure 1).

2Obesity-induced adipose tissue dysfunction and immune remodeling

2.1Structural and functional remodeling of adipose tissue

Adipose tissue is a metabolically and immunologically active organ that regulates energy storage, endocrine signaling, and systemic homeostasis (20, 21). In obesity, particularly within white adipose tissue, sustained energy excess may preferentially drive adipocyte hypertrophy when adipogenic hyperplasia is insufficient (22, 23). Enlarged adipocytes subsequently develop cellular stress, including endoplasmic reticulum stress, mitochondrial dysfunction, extracellular matrix remodeling, and impaired lipid handling (22–24). As adipose tissue continues to expand, adipocyte death increases and macrophages accumulate around damaged or dying adipocytes, forming characteristic crown-like structures (25–27). These structural alterations represent an early link between adipose tissue expansion and the development of chronic local inflammation.

Adipose tissue expansion also exceeds the capacity of its vascular supply, resulting in tissue hypoxia, dysregulated angiogenesis, and extracellular matrix remodeling (25, 28, 29). Hypoxia promotes adipocyte stress and inflammatory signaling, whereas progressive fibrosis reduces tissue flexibility and limits the capacity of adipose tissue to accommodate excess lipids safely (22, 30). Consequently, surplus lipids may be redistributed to non-adipose organs, contributing to ectopic lipid deposition, lipotoxicity, and systemic metabolic dysfunction (23). The combination of adipocyte hypertrophy, hypoxia, fibrosis, and impaired angiogenesis therefore transforms adipose tissue from an adaptive energy-storage organ into a dysfunctional and chronically stressed tissue (22, 30).

These structural abnormalities are accompanied by impaired endocrine and immunological functions. The secretory profile of obese adipose tissue shifts away from anti-inflammatory and insulin-sensitizing mediators, such as adiponectin, toward increased production of pro-inflammatory adipokines, cytokines, chemokines, and lipid-derived signals (24, 31, 32). Physical inactivity, excessive intake of saturated fats, genetic susceptibility, low birth weight, and sympathetic nervous system overactivity may further promote adipose tissue dysfunction (33). Together, these changes establish a local microenvironment that favors immune-cell recruitment and activation, providing the basis for extensive immune remodeling within obese adipose tissue.

2.2Macrophage accumulation, metabolic reprogramming, and trained immunity

Macrophages are central components of obesity-induced adipose tissue inflammation. Adipocyte hypertrophy, hypoxia, cellular stress, and adipocyte death increase the release of damage-associated molecular patterns and chemotactic mediators (34). In particular, C-C motif chemokine ligand 2, also known as monocyte chemoattractant protein-1 (CCL2/MCP-1), promotes circulating monocyte recruitment through C-C chemokine receptor 2 (35). Recruited monocytes differentiate into adipose tissue macrophages and accumulate around damaged adipocytes, contributing to crown-like structure formation and sustained local inflammation (27, 35, 36).

Obesity also alters the functional phenotype of adipose tissue macrophages. This process has traditionally been described as a shift from an anti-inflammatory M2 phenotype toward a pro-inflammatory M1 phenotype, accompanied by increased production of tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6) (37, 38). However, macrophages within obese adipose tissue display substantial phenotypic and functional heterogeneity that cannot be adequately represented by a binary M1/M2 classification (39–41). Distinct macrophage populations may simultaneously participate in lipid handling, clearance of damaged cells, tissue remodeling, and inflammatory amplification. Therefore, adipose tissue macrophage activation should be understood as a dynamic spectrum shaped by local metabolic and inflammatory signals (42).

In addition to phenotypic changes, adipose tissue macrophages undergo metabolic reprogramming. Obesity-associated macrophage activation is characterized by increased glycolytic activity, altered mitochondrial metabolism, oxidative stress, and sustained hypoxia-inducible factor 1-alpha (HIF-1α)-dependent inflammatory signaling (43). These metabolic adaptations can support prolonged cytokine production and reinforce adipose tissue inflammation. Chronic exposure to fatty acids, hyperglycemia, and inflammatory mediators may also induce persistent epigenetic and metabolic changes resembling trained immunity, in which innate immune cells develop an exaggerated response to subsequent inflammatory stimulation (44, 45). Although this concept provides a plausible explanation for heightened inflammatory responsiveness in obesity, evidence specifically demonstrating trained immunity in human adipose macrophages remains incomplete, and its perioperative relevance requires direct investigation. A recent review further proposed that obesity can induce maladaptive trained immunity in adipose tissue macrophages, thereby sustaining local inflammation and propagating immunometabolic dysfunction to distant organs. However, its contribution to perioperative inflammatory amplification remains untested (46).

2.3T-cell imbalance and adaptive immune dysregulation

Adaptive immune cells are also important regulators of adipose tissue homeostasis. In lean adipose tissue, regulatory T cells (Tregs) contribute to immune tolerance and restrain excessive inflammatory activation (47). Obesity disrupts this protective environment, leading to increased accumulation and activation of pro-inflammatory CD8+ T cells, T helper 1 (Th1) cells, and T helper 17 (Th17) cells, together with reduced abundance or impaired function of adipose-resident Tregs (48). This shift promotes a more inflammatory adaptive immune profile within adipose tissue.

Activated CD8+ T cells may precede and facilitate macrophage recruitment, whereas Th1 cells produce interferon-gamma (IFN-γ) and TNF-α, which further enhance macrophage inflammatory activation and impair insulin signaling (49, 50). Th17 cells and IL-17-associated signaling may promote chemokine production and additional immune-cell recruitment (51). Conversely, loss of Treg-mediated immune regulation weakens anti-inflammatory control and permits sustained activation of macrophages and other immune-cell populations. These reciprocal interactions create a local amplification circuit between innate and adaptive immunity (52).

The relative contribution of individual T-cell subsets varies according to adipose depot, obesity duration, metabolic phenotype, and disease stage. Moreover, much of the mechanistic evidence concerning adipose T-cell dysregulation has been derived from experimental models. Although human studies support obesity-associated changes in adipose immune-cell composition, their functional consequences and relationship to systemic inflammatory responses require further clarification. Nevertheless, the imbalance between pro-inflammatory T-cell subsets and Tregs represents an important component of obesity-associated adipose immune remodeling (52).

2.4NLRP3 Inflammasome and TLR4/NF-κB signaling

The NLR family pyrin domain containing 3 (NLRP3) inflammasome functions as an immunometabolic sensor that links cellular stress to inflammatory cytokine maturation. Obesity-associated stimuli, including saturated fatty acids, ceramide accumulation, mitochondrial dysfunction, excessive reactive oxygen species production, and damage-associated molecular patterns, can provide priming or activation signals for the NLRP3 inflammasome, particularly in adipose tissue macrophages (53, 54). Following inflammasome assembly, NLRP3 activates caspase-1, which cleaves pro-IL-1β and pro-IL-18 into their biologically active forms. IL-1β and context-dependent IL-18 signaling subsequently promote immune-cell activation, adipose tissue inflammation, and impaired insulin signaling (55).

Toll-like receptor 4 (TLR4) signaling represents another important interface between lipid stress and innate immune activation. In dysfunctional adipose tissue, saturated fatty acids, damage-associated molecular patterns, and associated endogenous cofactors can promote or potentiate TLR4 signaling in adipocytes and macrophages. Some lipid-associated effects may occur indirectly through molecules such as fetuin-A rather than through direct binding of fatty acids to TLR4 (56, 57). Predominantly through myeloid differentiation primary response 88 (MyD88)-dependent signaling, TLR4 activates nuclear factor kappa B (NF-κB), thereby increasing the expression of TNF-α, IL-6, CCL2/MCP-1, and other inflammatory mediators (58).

NLRP3 and TLR4/NF-κB signaling are closely interconnected. TLR4-mediated NF-κB activation can provide transcriptional priming for NLRP3 and pro-IL-1β, whereas mitochondrial stress and lipid-derived signals facilitate inflammasome activation (59). Persistent activation of these pathways promotes macrophage recruitment, inflammatory cytokine production, and insulin resistance, reinforcing the interaction between immune dysfunction and metabolic stress (53, 59). Current evidence therefore supports their established roles in obesity-associated adipose inflammation (53). However, whether activation of these pathways specifically within adipose tissue directly determines perioperative neuroinflammatory or cognitive outcomes has not been established and should be regarded as a proposed mechanistic connection requiring further validation.

Collectively, obesity induces coordinated structural, metabolic, and immune remodeling within adipose tissue. Adipocyte hypertrophy, hypoxia, fibrosis, macrophage accumulation, T-cell imbalance, and activation of innate immune pathways transform adipose tissue into a persistent source of inflammatory and metabolic signals (22, 53). The circulating consequences of this dysfunctional adipose microenvironment, including altered adipokines, cytokines, chemokines, free fatty acids, and lipid mediators, are discussed in the following section.

3Circulating immunometabolic mediators and systemic metabolic dysfunction

Dysfunctional adipose tissue releases adipokines, cytokines, chemokines, free fatty acids, and bioactive lipid mediators into the circulation, thereby linking local adipose inflammation with systemic immune and metabolic dysfunction (60–64). These mediators interact rather than act independently: inflammation promotes insulin resistance and abnormal lipid handling, whereas metabolic stress further reinforces immune activation. This circulating immunometabolic environment may increase vulnerability to subsequent perioperative stress, although its direct contribution to POCD remains insufficiently established.

3.1Adipokines, cytokines, and chemokines

Obesity substantially alters the adipokine secretory profile of adipose tissue. Circulating leptin concentrations generally increase with adiposity, whereas leptin resistance may limit its metabolic effects (65). In contrast, adiponectin concentrations commonly decline, reducing anti-inflammatory and insulin-sensitizing activity. Resistin may also contribute to systemic inflammation and metabolic dysfunction, although its cellular sources and biological effects differ between humans and experimental models (60, 64). Beyond their metabolic roles, adipokines can regulate immune-cell activity; for example, leptin can activate circulating monocytes and stimulate TNF-α and IL-6 production (66).

Dysfunctional adipose tissue and infiltrating immune cells also release pro-inflammatory cytokines and chemokines. TNF-α interferes with insulin signaling, IL-6 contributes to systemic low-grade inflammation, and inflammasome-dependent IL-1β can amplify innate immune responses (67–71). Meanwhile, CCL2/MCP-1 promotes continued monocyte recruitment into adipose tissue, sustaining macrophage accumulation and inflammatory signaling (36, 63). Together, these mediators extend obesity-associated immune activation beyond adipose tissue.

However, direct perioperative evidence remains limited. Associations between leptin, adiponectin, resistin, and cognitive impairment have mainly been reported outside the surgical setting (72). Moreover, a recent prospective cohort study found no consistent association between preoperative leptin, soluble leptin receptor, or adiponectin concentrations and perioperative neurocognitive disorders (73). Adipokine and cytokine dysregulation should therefore be regarded as a biologically plausible component of the adipose–immune–brain axis rather than an established cause or validated biomarker of obesity-associated POCD.

3.2Free fatty acids and lipid mediators

Impaired lipid storage in dysfunctional adipose tissue increases the release of free fatty acids (FFAs). When the lipid-buffering capacity of adipose tissue is exceeded, excess FFAs may promote ectopic lipid deposition, mitochondrial stress, impaired insulin signaling, and lipotoxicity (74, 75). However, their inflammatory effects depend on fatty acid composition, concentration, exposure duration, and biological context; circulating FFAs should therefore not be regarded as uniformly pro-inflammatory (76).

Polyunsaturated fatty acids are also precursors of bioactive lipid mediators. Arachidonic acid-derived mediators frequently participate in inflammatory initiation, whereas EPA- and DHA-derived mediators may exert anti-inflammatory or pro-resolving effects (77). Dietary n-3 polyunsaturated fatty acids may shift circulating eicosanoid profiles toward a less inflammatory pattern in individuals with overweight or obesity, although clinical findings remain heterogeneous (78). Specialized pro-resolving mediators (SPMs), including lipoxins, resolvins, protectins, and maresins, actively promote the termination of inflammation and restoration of tissue homeostasis. Altered SPM profiles in severe obesity and after bariatric surgery suggest that obesity may involve both persistent inflammation and insufficient resolution responses (79).

Other lipid classes, including ceramides, sphingosine-1-phosphate, and oxidized phospholipids, can influence insulin signaling, immune-cell activity, and vascular function (80, 81). Lipoxins and resolvins have also been investigated in experimental neurological injury, but their relevance to postoperative neuroinflammation remains uncertain (82). Thus, lipid mediators may either amplify inflammation or promote its resolution, but their roles as biomarkers or mechanistic intermediates in obesity-associated POCD require direct investigation.

3.3Insulin resistance, hyperglycemia, and dyslipidemia

Inflammation and metabolic dysfunction form a self-reinforcing cycle in obesity. Pro-inflammatory cytokines impair insulin signaling in adipose tissue, liver, and skeletal muscle, whereas insulin resistance increases adipose lipolysis, circulating FFAs, and ectopic lipid accumulation. Systemic insulin resistance may also be accompanied by impaired brain insulin signaling, altered glucose utilization, mitochondrial dysfunction, and reduced synaptic plasticity (83, 84). However, most supporting evidence originates from studies of diabetes, aging, and neurodegenerative disease, whereas direct evidence from perioperative settings remains limited (85).

Hyperglycemia can further amplify oxidative stress, mitochondrial dysfunction, advanced glycation-related signaling, and endothelial activation. Experimental evidence indicates that high-glucose conditions enhance microglial inflammatory responses through TLR4-associated signaling (86). Nevertheless, acute perioperative hyperglycemia should be distinguished from chronic poor glycemic control, typically reflected by glycated hemoglobin (HbA1c), and their associations with specific postoperative neurocognitive outcomes are considered separately in the clinical evidence section (87).

Dyslipidemia may contribute to endothelial dysfunction, oxidative stress, and abnormal lipid delivery to the brain. Non-perioperative studies have linked altered lipid profiles with impaired blood–brain barrier integrity, whereas high-fat diet models demonstrate reduced hippocampal neurogenesis, altered brain-derived neurotrophic factor signaling, and synaptic dysfunction (88, 89). These findings provide mechanistic plausibility but do not establish a direct causal pathway in surgical patients. Overall, these interacting abnormalities may establish a state of systemic immunometabolic vulnerability that could amplify the inflammatory response to surgical injury, consistent with a proposed “second-hit” framework.

4Perioperative stress as a second inflammatory hit

Obesity-induced adipose immune remodeling may establish a chronically primed immunometabolic state before surgery. This state is characterized by persistent low-grade inflammation, macrophage and T-cell dysregulation, altered adipokine secretion, and impaired metabolic homeostasis (52). Surgical trauma may then act as a second inflammatory hit, superimposing an acute immune response on this pre-existing condition. Tissue injury, neuroendocrine stress, and perioperative metabolic disturbances can trigger a rapid increase in circulating inflammatory mediators, potentially producing a stronger or more prolonged response in patients with obesity (52, 90).

Surgical injury promotes the release of damage-associated molecular patterns, including high-mobility group box 1 (HMGB1), from damaged tissues. HMGB1 can activate innate immune signaling through receptors such as TLR4 and the receptor for advanced glycation end products, thereby stimulating circulating monocytes and macrophages (91, 92). This response is accompanied by increased production of TNF-α, IL-1β, IL-6, and other inflammatory mediators. Experimental studies indicate that TNF-α can initiate a broader cytokine cascade after surgery, whereas IL-1β contributes to surgery-induced inflammatory responses and cognitive impairment (93, 94). These findings support a mechanistic link between acute surgical inflammation and subsequent neuroimmune dysfunction, although most direct evidence is preclinical.

Obesity-associated innate immune memory may further intensify this response. Chronic exposure to a Western diet, weight cycling, fatty acids, and other metabolic stimuli can induce persistent metabolic and epigenetic reprogramming of innate immune cells, resulting in exaggerated responses to later challenges (44, 45). Adipose tissue macrophages and circulating monocytes in this primed state may therefore respond more strongly to surgery-derived inflammatory signals (95). However, whether adipose macrophage trained immunity directly amplifies perioperative inflammation in humans has not been established and remains a proposed mechanism.

Circulating monocytes and macrophages may serve as an important connection between tissue injury and systemic inflammatory amplification. Preclinical evidence indicates that surgery-derived HMGB1 can activate bone marrow-derived monocytes and macrophages, which subsequently contribute to postoperative inflammatory responses (92). At the same time, obesity-associated activation of c-Jun N-terminal kinase, NF-κB, NLRP3, and related pathways may lower the threshold for cytokine production and prolong the resolution of inflammation (45, 96–98). The resulting systemic response may be shaped not only by obesity but also by age, diabetes, frailty, nutritional status, surgical severity, and perioperative complications (90).

The second-hit model therefore provides a plausible framework in which obesity-related immunometabolic dysfunction increases susceptibility to acute surgical inflammation. Nevertheless, direct clinical evidence that patients with obesity develop a disproportionately amplified perioperative inflammatory response remains limited. Although perioperative increases in inflammatory markers have been observed, these findings neither identify adipose tissue as their source nor establish a causal relationship with POCD (99). Because studies of CRP and IL-6 have assessed different neurocognitive outcomes, their associations with POD and POCD are evaluated separately in Section 5. The amplified peripheral inflammatory response may subsequently affect the brain through BBB and neuroimmune pathways.

5Blood–brain barrier disruption and neuroimmune dysfunction

The blood–brain barrier (BBB) is a key interface through which peripheral immunometabolic disturbances may influence the brain. Obesity-associated inflammation, oxidative stress, insulin resistance, and vascular dysfunction can impair BBB integrity (100). During the perioperative period, acute inflammation caused by surgical injury may further activate brain endothelial signaling and disrupt tight-junction function, thereby increasing BBB permeability and facilitating peripheral-to-central inflammatory communication (101–103). Experimental evidence also indicates that IL-17A contributes to perioperative neurocognitive impairment through BBB disruption in aged mice, although its adipose origin and clinical relevance remain unconfirmed (102). Recent evidence further emphasizes that adipose-derived cytokines, adipokines, lipid mediators, and extracellular vesicles may influence the brain through endothelial, BBB, and glial pathways, although most evidence remains non-perioperative (104).

BBB dysfunction can promote microglial and astrocytic activation. Activated microglia release cytokines and reactive oxygen species, whereas reactive astrocytes may further amplify inflammatory signaling and impair neuronal support and BBB homeostasis (1, 71). Experimental studies have demonstrated an important role for microglia in postoperative hippocampal inflammation and cognitive decline (103, 105). Interactions among activated endothelial cells, microglia, and astrocytes may therefore establish a self-amplifying neuroinflammatory response after surgery.

Persistent neuroinflammation can impair neuronal metabolism, mitochondrial function, synaptic plasticity, and neurogenesis. Experimental and non-perioperative studies link obesity-related metabolic inflammation with mitochondrial dysfunction, oxidative stress, abnormal neuronal lipid handling, and reduced hippocampal neurogenesis (89, 106–109). These changes provide a plausible biological basis for increased cognitive vulnerability but do not establish that adipose inflammation directly causes POCD in humans.

Overall, current evidence supports separate associations between obesity and BBB dysfunction and between surgical stress and postoperative neuroinflammation. However, the integrated pathway in which obesity-related adipose inflammation directly amplifies surgery-induced BBB disruption, glial activation, and cognitive decline remains largely inferential. Existing clinical studies do not identify dysfunctional adipose tissue as the source of perioperative neuroinflammatory abnormalities (110). The proposed interactions among adipose tissue dysfunction, circulating immunometabolic mediators, perioperative inflammatory amplification, BBB disruption, and glial–neuronal injury are summarized in Figure 2. Recent translational evidence has begun to support this integrated pathway. Tropis et al. reported that obesity aggravated postoperative cognitive changes in patients and experimental animals, while interventions targeting adiposity or inflammation attenuated BBB dysfunction and cognitive impairment in mice (111). Nevertheless, the human findings remain observational and require confirmation in larger cohorts.

6Clinical evidence linking obesity-related factors to perioperative neurocognitive outcomes

6.1Obesity and metabolic syndrome

Clinical evidence directly linking obesity to postoperative cognitive dysfunction remains limited and heterogeneous. Although obesity is associated with chronic inflammation, insulin resistance, vascular dysfunction, and cognitive impairment outside the perioperative setting, current studies do not establish obesity itself as an independent risk factor for POCD (15–17). One cohort study found that diabetes, rather than obesity alone, was associated with postoperative cognitive decline, suggesting that metabolic phenotype may be more informative than body mass index (BMI) alone (112). Metabolic syndrome has also been examined in relation to both postoperative delirium (POD) and POCD, but these clinically distinct outcomes should not be interpreted interchangeably (7).

The association between obesity and postoperative cognition is further complicated by age, diabetes, cardiovascular disease, frailty, and malnutrition (17–19). BMI does not distinguish visceral from subcutaneous adiposity or identify differences in insulin resistance, inflammatory burden, and adipose tissue dysfunction. Consequently, patients with a similar BMI may have substantially different perioperative risks. Future clinical studies should characterize obesity using metabolic and inflammatory phenotypes rather than BMI alone (113).

A recent review similarly proposed that metabolic syndrome may prime the perioperative brain through chronic systemic inflammation, BBB vulnerability, central insulin resistance, and mitochondrial dysfunction. This framework supports the importance of metabolic phenotype but does not isolate adipose tissue inflammation as an independent causal factor (114). More recently, Tropis et al. identified obesity as an independent predictor of early postoperative cognitive decline in a mixed cardiac and orthopedic surgical cohort (111). Although this study provides important translational support, its sample size, mixed surgical population, and early assessment period limit extrapolation to longer-term POCD.

6.2Inflammatory and metabolic biomarkers

Inflammatory biomarkers have been investigated in both POD and POCD, but the corresponding evidence must be distinguished. In studies focusing on acute POD, preoperative or early postoperative inflammatory markers, including CRP and IL-6, have been evaluated as potential predictors, although the findings remain variable (115, 116). By contrast, studies of POCD have reported associations between preoperative high-sensitivity CRP and postoperative cognitive impairment after cardiac surgery, as well as associations between postoperative increases in CRP or IL-6 and early or intermediate cognitive decline (117–120). Because POD is an acute fluctuating disturbance of attention and awareness, whereas POCD is identified through decline on neuropsychological testing, biomarker findings from POD studies should not be directly extrapolated to POCD (121).

S100 calcium-binding protein B (S100B) has also been investigated as a marker of astrocytic injury or altered BBB integrity, but its specificity for POCD is limited (110, 122). Evidence for adipokines is less consistent. In a prospective cohort of older surgical patients, preoperative leptin, soluble leptin receptor, and adiponectin concentrations showed no consistent overall associations with either POD or POCD, although exploratory findings suggested possible variation according to obesity status (73). These findings do not support the current use of adipokines as established perioperative cognitive biomarkers.

Metabolic abnormalities may also contribute to postoperative cognitive vulnerability. Perioperative hyperglycemia and diabetes have been associated with adverse neurocognitive outcomes, whereas the influence of obesity alone appears less consistent (112, 123). Lipid-related evidence also differs by outcome: a recent meta-analysis associated hyperlipidemia with acute POD, while a prospective cohort linked hyperlipidemia and total cholesterol with POCD assessed from 7 days to 3 months after surgery (124, 125). A small serum metabolomics study identified a phosphatidylserine species as a potential marker of early POCD, but its sample size limits generalizability (126). These observations support further study of metabolic biomarkers but do not establish causal relationships.

Table 1 summarizes representative clinical studies and evidence syntheses examining obesity-related metabolic factors, adipokines, lipid abnormalities, and perioperative neurocognitive outcomes. To avoid inappropriate comparison, the studies are grouped according to whether they primarily assessed POD, postoperative cognitive decline or POCD, or mixed and heterogeneous perioperative neurocognitive outcomes.

Table 1Representative clinical studies and evidence syntheses examining obesity-related factors and distinct perioperative neurocognitive outcomes.

Study Design and population Metabolic exposure Neurocognitive outcome and timing Main finding and limitation

A. Studies primarily assessing postoperative delirium

Qiu et al., 2025 (124) Systematic review and meta-analysis of 9 studies involving 4,686 surgical patients Hyperlipidemia and lipid profiles POD during the early postoperative period Hyperlipidemia was associated with increased POD risk. Heterogeneity in surgical populations, lipid definitions, and delirium assessments limits generalizability, and the findings should not be extrapolated directly to POCD.

B. Studies primarily assessing postoperative cognitive decline or POCD

Qian and Wang, 2020 (126) Prospective serum metabolomics study of 20 older patients undergoing elective surgery Metabolomic and lipidomic profiles, including PS(17:2/0:0) Early POCD assessed using the ISPOCD battery within 7 postoperative days Several lipid metabolites showed potential diagnostic value for early POCD. The small sample and exploratory design preclude causal interpretation.

Das et al., 2016 (127) Prospective observational study of 60 patients undergoing off-pump coronary artery bypass surgery Preoperative statin therapy Early postoperative memory impairment assessed using a neuropsychological test battery Statin use was associated with less early memory impairment. The nonrandomized design and small sample introduce potential selection bias.

Tropis et al., 2026 (111) Prospective single-center study of 106 adults aged ≥60 years undergoing cardiac or orthopedic surgery Obesity, circulating inflammatory markers, and subcutaneous adipose inflammatory profiles Early PND assessed on postoperative day 5 using the MMSE or TICS; POD assessed separately for 7 days Obesity was independently associated with early PND. The single-center design, mixed surgical populations, different cognitive instruments, and short follow-up limit generalizability.

Shen et al., 2025 (125) Prospective cohort study of 98 patients undergoing laparoscopic gynecological tumor surgery Hyperlipidemia and total cholesterol POCD assessed at 7 days, 1 month, and 3 months using the MoCA and TICS-m Hyperlipidemia was associated with a higher incidence of POCD, and total cholesterol was identified as a possible independent predictor. The modest sample and single-center design are important limitations.

C. Studies assessing mixed or heterogeneous perioperative neurocognitive outcomes

Feinkohl et al., 2024 (73) Prospective BioCog cohort of 768 adults aged ≥65 years undergoing elective surgery Leptin, soluble leptin receptor, free leptin index, and total and high-molecular-weight adiponectin POD assessed until postoperative day 7 or discharge; POCD assessed at 3 months No consistent associations were found between adipokine concentrations and POD or POCD. Obesity-stratified findings were exploratory and require independent validation.

Travica et al., 2023 (17) Umbrella review of meta-analyses of observational studies Glucose regulation, lipid abnormalities, and other metabolic factors Heterogeneous postoperative cognitive outcomes assessed from the early postoperative period to several months Metabolic dysfunction may contribute to postoperative cognitive vulnerability, but heterogeneous definitions, assessment tools, and follow-up periods prevented firm conclusions.

Burns et al., 2023 (15) Narrative review of obesity and postoperative cognitive dysfunction Obesity and related metabolic and inflammatory factors Heterogeneous postoperative cognitive outcomes with variable assessment times The association is biologically plausible, but direct clinical evidence establishing adipose inflammation as a causal driver of POCD remains limited.

ISPOCD, International Study of Postoperative Cognitive Dysfunction; MMSE, Mini-Mental State Examination; MoCA, Montreal Cognitive Assessment; PND, perioperative neurocognitive disorder; POD, postoperative delirium; POCD, postoperative cognitive dysfunction; PS, phosphatidylserine; TICS, Telephone Interview for Cognitive Status; TICS-m, modified Telephone Interview for Cognitive Status.

Outcome terminology is reported according to the original studies. POD is an acute disorder of attention and awareness and is clinically distinct from POCD and other perioperative neurocognitive disorders; these outcomes should not be interpreted interchangeably. Differences in outcome definitions, assessment instruments, and follow-up periods should be considered when comparing studies.

6.3Current limitations of clinical evidence

Interpretation of the current literature is limited by substantial methodological heterogeneity. Studies use different definitions of POD and POCD, cognitive assessment tools, baseline procedures, diagnostic thresholds, and postoperative follow-up periods (121). Some studies assess cognition within days after surgery, whereas others evaluate outcomes after several weeks or months. Small sample sizes and inconsistent adjustment for age, diabetes, frailty, nutritional status, and surgical severity further limit comparisons across studies (116).

Most importantly, few clinical studies simultaneously assess adipose tissue dysfunction, circulating immunometabolic mediators, BBB integrity, and postoperative cognition. Associations between CRP, IL-6, glucose, lipids, or adipokines and neurocognitive outcomes do not demonstrate that these abnormalities originate from adipose tissue (116). The available evidence therefore supports biological plausibility but does not establish a causal adipose–immune–brain pathway in obesity-associated POCD. Prospective studies using standardized neurocognitive definitions, repeated biomarker measurements, and detailed metabolic phenotyping are required to test this proposed pathway (121).

7Therapeutic implications

7.1Weight management and prehabilitation

Weight-loss interventions, including dietary modification, exercise, and bariatric surgery, can improve metabolic status and reduce some obesity-related inflammatory markers. Intentional weight loss has also been associated with modest improvements in selected cognitive domains (128–130). However, these findings were largely obtained outside the perioperative setting, and it remains unknown whether preoperative weight reduction directly reduces POCD risk. Weight management should therefore be considered part of general metabolic optimization rather than an established strategy for POCD prevention (131).

Prehabilitation combining physical activity, dietary optimization, and correction of nutritional deficiencies may improve perioperative resilience. Its timing and intensity should be individualized, particularly in patients with frailty, sarcopenia, or malnutrition, in whom restrictive dietary interventions may further compromise nutritional status (132). Although n-3 polyunsaturated fatty acids can modify some inflammatory and pro-resolving lipid mediators, their effects on adipose inflammation in human obesity remain inconsistent, and their role in preventing POCD is unknown (133, 134).

7.2Metabolic optimization and incretin-based therapies

Perioperative hyperglycemia, insulin resistance, and diabetes are associated with adverse neurocognitive outcomes, supporting careful assessment of metabolic status (112, 123). Nevertheless, the optimal glucose target for POCD prevention has not been established, and intensive glucose lowering may increase the risk of hypoglycemia (87). Future studies should examine glycemic variability, insulin resistance, lipid profiles, and obesity phenotype together rather than using BMI as the sole metabolic measure (113).

Glucagon-like peptide-1 receptor agonists (GLP-1RAs), such as semaglutide, and dual glucose-dependent insulinotropic polypeptide/GLP-1 receptor agonists, such as tirzepatide, provide a potential link between weight reduction, metabolic improvement, and immune modulation (135). GLP-1RAs improve glycemic control, insulin sensitivity, and lipid metabolism and may indirectly reduce adipose inflammation through loss of adiposity (136). Experimental evidence further suggests that tirzepatide can reduce pro-inflammatory adipose tissue macrophage accumulation and cytokine production in obese mice (137). Semaglutide has also been shown to promote resolution of neuroinflammation and modify microglial, endothelial-cell, and pericyte responses in a mouse model of systemic inflammatory challenge (138). However, these findings are preclinical, and direct evidence that GLP-1RAs or dual incretins prevent POCD is currently lacking. Their perioperative neurocognitive effects, optimal timing, and safety require dedicated clinical investigation.

7.3Modulation of inflammation and resolution pathways

Experimental studies implicate TNF-α, IL-1β, TLR4/MyD88/NF-κB signaling, and NLRP3 inflammasome activation in surgery-induced neuroinflammation and cognitive impairment (93, 94, 139, 140). These pathways may represent potential therapeutic targets, particularly in patients with pre-existing metabolic inflammation. Nevertheless, perioperative immune inhibition may interfere with host defense, wound healing, and tissue repair. Current evidence does not support routine cytokine blockade or inflammasome inhibition for POCD prevention (141).

Promoting inflammation resolution may provide a more balanced approach. Specialized pro-resolving mediators, including resolvins, protectins, and maresins, can regulate macrophage phenotype and facilitate resolution of adipose tissue inflammation (142, 143). Restoration of Treg function may also help rebalance pro-inflammatory and regulatory immune responses (52). However, both strategies remain predominantly preclinical, and their perioperative efficacy, optimal delivery, timing, and safety have not been established.

7.4Blood–brain barrier protection and experimental approaches

Preservation of BBB integrity may limit peripheral-to-central inflammatory signaling. Evidence from traumatic brain injury and cerebral ischemia suggests that BBB protection can attenuate neuroinflammation, but these findings represent cross-disease or preclinical extrapolations (144, 145). Adipose-derived stem-cell extracellular vesicles have also shown immunomodulatory and neuroprotective potential in experimental neurological disorders (146). Their active cargo, cellular targets, pharmacokinetics, and long-term safety remain uncertain, and no direct evidence supports their use in obesity-associated POCD.

Additional approaches targeting cerebral lipid handling or the gut–brain axis may be relevant because obesity alters lipid metabolism, microbial metabolites, and systemic inflammation. However, evidence supporting probiotics, microbiota-directed therapies, or specific lipid-targeted treatments for POCD is currently insufficient (147, 148). These approaches should be presented as research priorities rather than clinical recommendations.

7.5Perioperative management

For patients with obesity, perioperative care should prioritize physiological stability, including appropriate anesthetic and analgesic management, avoidance of prolonged hypotension and hypoxemia, and careful control of glucose and temperature (149). No specific anesthetic technique or drug regimen has been proven to prevent obesity-associated POCD (141, 149). Future studies should determine whether treatment effects vary according to visceral adiposity, diabetes status, inflammatory burden, or metabolic phenotype (113).

Clinical trials should use standardized perioperative neurocognitive terminology and distinguish POD, delayed neurocognitive recovery, and longer-term postoperative neurocognitive disorders (121). Multicenter studies should combine neuropsychological testing with repeated measurements of inflammatory, metabolic, and BBB-related biomarkers (121, 141). At present, metabolic optimization, immune modulation, BBB protection, and incretin-based therapies should be considered promising research directions rather than established interventions for POCD prevention (141).

8Limitations and future directions

Current evidence linking obesity-related adipose inflammation to POCD remains predominantly indirect or preclinical (111). Clinical studies vary in neurocognitive definitions, assessment tools, follow-up periods, and adjustment for diabetes, age, frailty, and nutritional status (116, 121). Moreover, few studies directly measure adipose tissue inflammation, and available associations with circulating biomarkers do not establish adipose tissue as their source or confirm causality (111, 116).

Future multicenter prospective studies should use standardized definitions that distinguish POD, delayed neurocognitive recovery, and longer-term postoperative neurocognitive disorders (121). Longitudinal assessment should integrate adipose tissue phenotype, circulating immunometabolic mediators, BBB-related markers, and cognitive outcomes (111, 116). Obesity should also be characterized using visceral adiposity, insulin resistance, and inflammatory phenotype rather than BMI alone (113). Such studies will be essential to validate the proposed adipose–immune–brain pathway and identify clinically relevant therapeutic targets.

9Conclusions

Obesity-induced adipose tissue dysfunction may create a state of chronic immunometabolic vulnerability that is further amplified by surgical stress, potentially promoting BBB disruption, neuroinflammation, and postoperative cognitive decline. Although this adipose–immune–brain axis is biologically plausible, direct clinical evidence remains limited, and a causal relationship between adipose inflammation and POCD has not been established. This framework should therefore guide future mechanistic and prospective clinical studies rather than be interpreted as a confirmed disease pathway.

References

1He L Duan X Li S Zhang R Dai X Lu M .
Unveiling the role of astrocytes in postoperative cognitive dysfunction . Ageing Res Rev . (2024 ) 95 :102223. doi: 10.1016/j.arr.2024.102223 38325753

2Verdonk F Cambriel A Hedou J Ganio E Bellan G Gaudilliere D .
An immune signature of postoperative cognitive decline: A prospective cohort study . Int J Surg . (2024 ) 110 :7749–62. doi: 10.1097/JS9.0000000000002118 39411891
PMC11634152

3Winterer G Androsova G Bender O Boraschi D Borchers F Dschietzig TB .
Personalized risk prediction of postoperative cognitive impairment - rationale for the eu-funded biocog project . Eur Psychiatry . (2018 ) 50 :34–9. doi: 10.1016/j.eurpsy.2017.10.004 29398565

4Bhushan S Li Y Huang X Cheng H Gao K Xiao Z .
Progress of research in postoperative cognitive dysfunction in cardiac surgery patients: A review article . Int J Surg . (2021 ) 95 :106163. doi: 10.1016/j.ijsu.2021.106163 34743049

5Moller JT Cluitmans P Rasmussen LS Houx P Rasmussen H Canet J .
Long-term postoperative cognitive dysfunction in the elderly ispocd1 study. Ispocd investigators. International study of post-operative cognitive dysfunction . Lancet . (1998 ) 351 :857–61. doi: 10.1016/s0140-6736(97)07382-0 9525362

6Zeng K Long J Li Y Hu J .
Preventing postoperative cognitive dysfunction using anesthetic drugs in elderly patients undergoing noncardiac surgery: A systematic review and meta-analysis . Int J Surg . (2023 ) 109 :21 –31 . doi: 10.1097/JS9.0000000000000001 36799783
PMC10389238

7Feinkohl I Janke J Slooter AJC Winterer G Spies C Pischon T .
Metabolic syndrome and the risk of postoperative delirium and postoperative cognitive dysfunction: A multi-centre cohort study . Br J Anaesth . (2023 ) 131 :338–47. doi: 10.1016/j.bja.2023.04.031 37344340

8Yang X Huang X Li M Jiang Y Zhang H .
Identification of individuals at risk for postoperative cognitive dysfunction (pocd) . Ther Adv Neurol Disord . (2022 ) 15 :17562864221114356. doi: 10.1177/17562864221114356 35992893
PMC9386869

9Lai Z Shan W Li J Min J Zeng X Zuo Z .
Appropriate exercise level attenuates gut dysbiosis and valeric acid increase to improve neuroplasticity and cognitive function after surgery in mice . Mol Psychiatry . (2021 ) 26 :7167–87. doi: 10.1038/s41380-021-01291-y 34663905
PMC8873004

10Feng X Hu J Hua F Zhang J Zhang L Xu G .
The correlation of intraoperative hypotension and postoperative cognitive impairment: A meta-analysis of randomized controlled trials . BMC Anesthesiol . (2020 ) 20 :193 . doi: 10.1186/s12871-020-01097-5 32758153
PMC7409718

11Baranov D Bickler PE Crosby GJ Culley DJ Eckenhoff MF Eckenhoff RG .
Consensus statement: First international workshop on anesthetics and alzheimer's disease . Anesth Analg . (2009 ) 108 :1627–30. doi: 10.1213/ane.0b013e318199dc72 19372347
PMC2769511

12Rasmussen LS .
Postoperative cognitive dysfunction: Incidence and prevention . Best Pract Res Clin Anaesthesiol . (2006 ) 20 :315–30. doi: 10.1016/j.bpa.2005.10.011 16850780

13Lazar RM Howard VJ Kernan WN Aparicio HJ Levine DA Viera AJ .
A primary care agenda for brain health: A scientific statement from the american heart association . Stroke . (2021 ) 52 :e295–308. doi: 10.1161/str.0000000000000367 33719523
PMC8995075

14Na M Dou N Ji N Xie D Huang J Tucker KL .
Food insecurity and cognitive function in middle to older adulthood: A systematic review . Adv Nutr . (2020 ) 11 :667–76. doi: 10.1093/advances/nmz122 31711095
PMC7231583

15Burns CI Boghokian A Soti V .
Obesity and postoperative cognitive dysfunction: A curious association . Cureus . (2023 ) 15 :e42436. doi: 10.7759/cureus.42436 37497308
PMC10368079

16Muscat SM Butler MJ Bettes MN DeMarsh JW Scaria EA Deems NP .
Post-operative cognitive dysfunction is exacerbated by high-fat diet via tlr4 and prevented by dietary dha supplementation . Brain Behav Immun . (2024 ) 116 :385 –401 . doi: 10.1016/j.bbi.2023.12.028 38145855
PMC10872288

17Travica N Lotfaliany M Marriott A Safavynia SA Lane MM Gray L .
Peri-operative risk factors associated with post-operative cognitive dysfunction (pocd): An umbrella review of meta-analyses of observational studies . J Clin Med . (2023 ) 12 :1610. doi: 10.3390/jcm12041610 36836145
PMC9965885

18Wu C Gao B Gui Y .
Malondialdehyde on postoperative day 1 predicts postoperative cognitive dysfunction in elderly patients after hip fracture surgery . Biosci Rep . (2019 ) 39 :BSR20190166. doi: 10.1042/bsr20190166 31138765
PMC6616043

19Dammavalam V Murphy J Johnkutty M Elias M Corn R Bergese S .
Perioperative cognition in association with malnutrition and frailty: A narrative review . Front Neurosci . (2023 ) 17 :1275201. doi: 10.3389/fnins.2023.1275201 38027517
PMC10651720

20Kershaw EE Flier JS .
Adipose tissue as an endocrine organ . J Clin Endocrinol Metab . (2004 ) 89 :2548–56. doi: 10.1210/jc.2004-0395 15181022

21Scheja L Heeren J .
The endocrine function of adipose tissues in health and cardiometabolic disease . Nat Rev Endocrinol . (2019 ) 15 :507–24. doi: 10.1038/s41574-019-0230-6 31296970

22Sun K Kusminski CM Scherer PE .
Adipose tissue remodeling and obesity . J Clin Invest . (2011 ) 121 :2094–101. doi: 10.1172/jci45887 21633177
PMC3104761

23Virtue S Vidal-Puig A .
Adipose tissue expandability, lipotoxicity and the metabolic syndrome--an allostatic perspective . Biochim Biophys Acta . (2010 ) 1801 :338–49. doi: 10.1016/j.bbalip.2009.12.006 20056169

24Longo M Zatterale F Naderi J Parrillo L Formisano P Raciti GA .
Adipose tissue dysfunction as determinant of obesity-associated metabolic complications . Int J Mol Sci . (2019 ) 20 :2358. doi: 10.3390/ijms20092358 31085992
PMC6539070

25Crewe C An YA Scherer PE .
The ominous triad of adipose tissue dysfunction: Inflammation, fibrosis, and impaired angiogenesis . J Clin Invest . (2017 ) 127 :74 –82 . doi: 10.1172/jci88883 28045400
PMC5199684

26Weisberg SP McCann D Desai M Rosenbaum M Leibel RL Ferrante AW Jr..
Obesity is associated with macrophage accumulation in adipose tissue . J Clin Invest . (2003 ) 112 :1796–808. doi: 10.1172/jci19246 14679176
PMC296995

27Cinti S Mitchell G Barbatelli G Murano I Ceresi E Faloia E .
Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans . J Lipid Res . (2005 ) 46 :2347–55. doi: 10.1194/jlr.M500294-JLR200 16150820

28Vachharajani V Granger DN .
Adipose tissue: A motor for the inflammation associated with obesity . IUBMB Life . (2009 ) 61 :424–30. doi: 10.1002/iub.169 19319966
PMC2695566

29Disanzo BL You T .
Effects of exercise training on indicators of adipose tissue angiogenesis and hypoxia in obese rats . Metabolism . (2014 ) 63 :452–5. doi: 10.1016/j.metabol.2013.12.004 24412283

30Sun K Li X Scherer PE .
Extracellular matrix (ecm) and fibrosis in adipose tissue: Overview and perspectives . Compr Physiol . (2023 ) 13 :4387–407. doi: 10.1002/cphy.c220020 36715281
PMC9957663

31Ouchi N Parker JL Lugus JJ Walsh K .
Adipokines in inflammation and metabolic disease . Nat Rev Immunol . (2011 ) 11 :85 –97 . doi: 10.1038/nri2921 21252989
PMC3518031

32Kawai T Autieri MV Scalia R .
Adipose tissue inflammation and metabolic dysfunction in obesity . Am J Physiol Cell Physiol . (2021 ) 320 :C375–c91. doi: 10.1152/ajpcell.00379.2020 33356944
PMC8294624

33Schrover IM van der Graaf Y Spiering W Visseren FL .
The relation between body fat distribution, plasma concentrations of adipokines and the metabolic syndrome in patients with clinically manifest vascular disease . Eur J Prev Cardiol . (2018 ) 25 :1548–57. doi: 10.1177/2047487318790722 30052066
PMC6146311

34Ye J Gao Z Yin J He Q .
Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice . Am J Physiol Endocrinol Metab . (2007 ) 293 :E1118–28. doi: 10.1152/ajpendo.00435.2007 17666485

35Weisberg SP Hunter D Huber R Lemieux J Slaymaker S Vaddi K .
Ccr2 modulates inflammatory and metabolic effects of high-fat feeding . J Clin Invest . (2006 ) 116 :115–24. doi: 10.1172/jci24335 16341265
PMC1307559

36Kanda H Tateya S Tamori Y Kotani K Hiasa K Kitazawa R .
Mcp-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity . J Clin Invest . (2006 ) 116 :1494–505. doi: 10.1172/jci26498 16691291
PMC1459069

37Lumeng CN Bodzin JL Saltiel AR .
Obesity induces a phenotypic switch in adipose tissue macrophage polarization . J Clin Invest . (2007 ) 117 :175–84. doi: 10.1172/jci29881 17200717
PMC1716210

38Li X Ren Y Chang K Wu W Griffiths HR Lu S .
Adipose tissue macrophages as potential targets for obesity and metabolic diseases . Front Immunol . (2023 ) 14 :1153915. doi: 10.3389/fimmu.2023.1153915 37153549
PMC10154623

39Kratz M Coats BR Hisert KB Hagman D Mutskov V Peris E .
Metabolic dysfunction drives a mechanistically distinct proinflammatory phenotype in adipose tissue macrophages . Cell Metab . (2014 ) 20 :614–25. doi: 10.1016/j.cmet.2014.08.010 25242226
PMC4192131

40Coats BR Schoenfelt KQ Barbosa-Lorenzi VC Peris E Cui C Hoffman A .
Metabolically activated adipose tissue macrophages perform detrimental and beneficial functions during diet-induced obesity . Cell Rep . (2017 ) 20 :3149–61. doi: 10.1016/j.celrep.2017.08.096 28954231
PMC5646237

41Hildreth AD Ma F Wong YY Sun R Pellegrini M O'Sullivan TE .
Single-cell sequencing of human white adipose tissue identifies new cell states in health and obesity . Nat Immunol . (2021 ) 22 :639–53. doi: 10.1038/s41590-021-00922-4 33907320
PMC8102391

42Chavakis T Alexaki VI Ferrante AW Jr.
Macrophage function in adipose tissue homeostasis and metabolic inflammation . Nat Immunol . (2023 ) 24 :757–66. doi: 10.1038/s41590-023-01479-0 37012544

43Sharma M Boytard L Hadi T Koelwyn G Simon R Ouimet M .
Enhanced glycolysis and hif-1α activation in adipose tissue macrophages sustains local and systemic interleukin-1β production in obesity . Sci Rep . (2020 ) 10 :5555 . doi: 10.1038/s41598-020-62272-9 32221369
PMC7101445

44Caslin HL Cottam MA Piñon JM Boney LY Hasty AH .
Weight cycling induces innate immune memory in adipose tissue macrophages . Front Immunol . (2022 ) 13 :984859. doi: 10.3389/fimmu.2022.984859 36713396
PMC9876596

45Christ A Günther P Lauterbach MAR Duewell P Biswas D Pelka K .
Western diet triggers nlrp3-dependent innate immune reprogramming . Cell . (2018 ) 172 :162 –75.e14 . doi: 10.1016/j.cell.2017.12.013 29328911
PMC6324559

46Chen S Fu J Yan J Zhao R Qian C Yisimayili Z .
Maladaptive trained immunity of adipose tissue macrophages unraveling the link to obesity, t2dm, and beyond . Am J Physiol Endocrinol Metab . (2025 ) 329 :E117–e30. doi: 10.1152/ajpendo.00071.2025 40464356

47Feuerer M Herrero L Cipolletta D Naaz A Wong J Nayer A .
Lean, but not obese, fat is enriched for a unique population of regulatory t cells that affect metabolic parameters . Nat Med . (2009 ) 15 :930–9. doi: 10.1038/nm.2002 19633656
PMC3115752

48Nishimura S Manabe I Nagasaki M Eto K Yamashita H Ohsugi M .
Cd8+ effector t cells contribute to macrophage recruitment and adipose tissue inflammation in obesity . Nat Med . (2009 ) 15 :914–20. doi: 10.1038/nm.1964 19633658

49Winer S Chan Y Paltser G Truong D Tsui H Bahrami J .
Normalization of obesity-associated insulin resistance through immunotherapy . Nat Med . (2009 ) 15 :921–9. doi: 10.1038/nm.2001 19633657
PMC3063199

50Strissel KJ DeFuria J Shaul ME Bennett G Greenberg AS Obin MS .
T-cell recruitment and th1 polarization in adipose tissue during diet-induced obesity in c57bl/6 mice . Obes (Silver Spring) . (2010 ) 18 :1918–25. doi: 10.1038/oby.2010.1 20111012
PMC2894258

51Chehimi M Vidal H Eljaafari A .
Pathogenic role of Il-17-producing immune cells in obesity, and related inflammatory diseases . J Clin Med . (2017 ) 6 :68. doi: 10.3390/jcm6070068 28708082
PMC5532576

52Jacks RD Lumeng CN .
Macrophage and T cell networks in adipose tissue . Nat Rev Endocrinol . (2024 ) 20 :50 –61 . doi: 10.1038/s41574-023-00908-2 37872302

53Vandanmagsar B Youm YH Ravussin A Galgani JE Stadler K Mynatt RL .
The Nlrp3 inflammasome instigates obesity-induced inflammation and insulin resistance . Nat Med . (2011 ) 17 :179–88. doi: 10.1038/nm.2279 21217695
PMC3076025

54Wen H Gris D Lei Y Jha S Zhang L Huang MT .
Fatty acid-induced Nlrp3-Asc inflammasome activation interferes with insulin signaling . Nat Immunol . (2011 ) 12 :408–15. doi: 10.1038/ni.2022 21478880
PMC4090391

55Stienstra R van Diepen JA Tack CJ Zaki MH van de Veerdonk FL Perera D .
Inflammasome is a central player in the induction of obesity and insulin resistance . Proc Natl Acad Sci USA . (2011 ) 108 :15324–9. doi: 10.1073/pnas.1100255108 21876127
PMC3174591

56Shi H Kokoeva MV Inouye K Tzameli I Yin H Flier JS .
Tlr4 links innate immunity and fatty acid-induced insulin resistance . J Clin Invest . (2006 ) 116 :3015–25. doi: 10.1172/jci28898 17053832
PMC1616196

57Orr JS Puglisi MJ Ellacott KL Lumeng CN Wasserman DH Hasty AH .
Toll-like receptor 4 deficiency promotes the alternative activation of adipose tissue macrophages . Diabetes . (2012 ) 61 :2718–27. doi: 10.2337/db11-1595 22751700
PMC3478520

58Griffin C Eter L Lanzetta N Abrishami S Varghese M McKernan K .
Tlr4, Trif, and Myd88 are essential for myelopoiesis and Cd11c(+) adipose tissue macrophage production in obese mice . J Biol Chem . (2018 ) 293 :8775–86. doi: 10.1074/jbc.RA117.001526 29636416
PMC5995515

59Swanson KV Deng M Ting JP .
The Nlrp3 inflammasome: Molecular activation and regulation to therapeutics . Nat Rev Immunol . (2019 ) 19 :477–89. doi: 10.1038/s41577-019-0165-0 31036962
PMC7807242

60Taylor EB .
The complex role of adipokines in obesity, inflammation, and autoimmunity . Clin Sci (Lond) . (2021 ) 135 :731–52. doi: 10.1042/cs20200895 33729498
PMC7969664

61Marcelin G Gautier EL Clément K .
Adipose tissue fibrosis in obesity: Etiology and challenges . Annu Rev Physiol . (2022 ) 84 :135–55. doi: 10.1146/annurev-physiol-060721-092930 34752708

62Revelo XS Ghazarian M Chng MH Luck H Kim JH Zeng K .
Nucleic acid-targeting pathways promote inflammation in obesity-related insulin resistance . Cell Rep . (2016 ) 16 :717–30. doi: 10.1016/j.celrep.2016.06.024 27373163
PMC6354586

63Manka D Chatterjee TK Stoll LL Basford JE Konaniah ES Srinivasan R .
Transplanted perivascular adipose tissue accelerates injury-induced neointimal hyperplasia: Role of monocyte chemoattractant protein-1 . Arterioscler Thromb Vasc Biol . (2014 ) 34 :1723–30. doi: 10.1161/atvbaha.114.303983 24947528
PMC4103955

64Tilg H Moschen AR .
Adipocytokines: Mediators linking adipose tissue, inflammation and immunity . Nat Rev Immunol . (2006 ) 6 :772–83. doi: 10.1038/nri1937 16998510

65Izquierdo AG Crujeiras AB Casanueva FF Carreira MC .
Leptin, obesity, and leptin resistance: Where are we 25 years later ? Nutrients . (2019 ) 11 :2704. doi: 10.3390/nu11112704 31717265
PMC6893721

66Santos-Alvarez J Goberna R Sánchez-Margalet V .
Human leptin stimulates proliferation and activation of human circulating monocytes . Cell Immunol . (1999 ) 194 :6 –11 . doi: 10.1006/cimm.1999.1490 10357875

67Yu H Dong R Lu Y Yang X Chen C Zhang Z .
Short-term postoperative cognitive dysfunction and inflammatory response in patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: A pilot study . Mediators Inflammation . (2017 ) 2017 :3605350. doi: 10.1155/2017/3605350 29249869
PMC5700480

68Stępień M Stępień A Wlazeł RN Paradowski M Banach M Rysz J .
Obesity indices and inflammatory markers in obese non-diabetic normo- and hypertensive patients: A comparative pilot study . Lipids Health Dis . (2014 ) 13 :29. doi: 10.1186/1476-511x-13-29 24507240
PMC3921991

69Eder K Baffy N Falus A Fulop AK .
The major inflammatory mediator interleukin-6 and obesity . Inflammation Res . (2009 ) 58 :727–36. doi: 10.1007/s00011-009-0060-4 19543691

70Feinkohl I Hadzidiakos D Dschietzig TB Janke J Heinrich M Slooter AJC .
Low-grade, systemic inflammation and the risk of perioperative neurocognitive disorders in an observational study of older adults . Sci Rep . (2025 ) 15 :44231 . doi: 10.1038/s41598-025-31986-z 41419753
PMC12722205

71Shaftel SS Griffin WS O'Banion MK .
The role of interleukin-1 in neuroinflammation and Alzheimer disease: An evolving perspective . J Neuroinflamm . (2008 ) 5 :7. doi: 10.1186/1742-2094-5-7 18302763
PMC2335091

72Bednarska-Makaruk M Graban A Wiśniewska A Łojkowska W Bochyńska A Gugała-Iwaniuk M .
Association of adiponectin, leptin and resistin with inflammatory markers and obesity in dementia . Biogerontology . (2017 ) 18 :561–80. doi: 10.1007/s10522-017-9701-0 28421328
PMC5514216

73Feinkohl I Janke J Slooter AJC Winterer G Spies C Pischon T .
The association of plasma leptin, soluble leptin receptor and total and high-molecular weight adiponectin with the risk of perioperative neurocognitive disorders . Am J Geriatr Psychiatry . (2024 ) 32 :1119–29. doi: 10.1016/j.jagp.2024.03.015 38637191

74Li W Zeng H Xu M Huang C Tao L Li J .
Oleanolic acid improves obesity-related inflammation and insulin resistance by regulating macrophages activation . Front Pharmacol . (2021 ) 12 :697483. doi: 10.3389/fphar.2021.697483 34393781
PMC8361479

75Ye R Onodera T Scherer PE .
Lipotoxicity and B cell maintenance in obesity and type 2 diabetes . J Endocr Soc . (2019 ) 3 :617–31. doi: 10.1210/js.2018-00372 30834357
PMC6391718

76Fritsche KL .
The science of fatty acids and inflammation . Adv Nutr . (2015 ) 6 :293s –301s . doi: 10.3945/an.114.006940 25979502
PMC4424767

77Dyall SC Balas L Bazan NG Brenna JT Chiang N da Costa Souza F .
Polyunsaturated fatty acids and fatty acid-derived lipid mediators: Recent advances in the understanding of their biosynthesis, structures, and functions . Prog Lipid Res . (2022 ) 86 :101165. doi: 10.1016/j.plipres.2022.101165 35508275
PMC9346631

78Schweitzer GRB Rios I Gonçalves VSS Magalhães KG Pizato N .
Effect of N-3 long-chain polyunsaturated fatty acid intake on the eicosanoid profile in individuals with obesity and overweight: A systematic review and meta-analysis of clinical trials . J Nutr Sci . (2021 ) 10 :e53. doi: 10.1017/jns.2021.46 34367628
PMC8327393

79Schulte F Asbeutah AA Benotti PN Wood GC Still C Bistrian BR .
The relationship between specialized pro-resolving lipid mediators, morbid obesity and weight loss after bariatric surgery . Sci Rep . (2020 ) 10 :20128 . doi: 10.1038/s41598-020-75353-6 33208757
PMC7674470

80Green CD Maceyka M Cowart LA Spiegel S .
Sphingolipids in metabolic disease: The good, the bad, and the unknown . Cell Metab . (2021 ) 33 :1293–306. doi: 10.1016/j.cmet.2021.06.006 34233172
PMC8269961

81Que X Hung MY Yeang C Gonen A Prohaska TA Sun X .
Oxidized phospholipids are proinflammatory and proatherogenic in hypercholesterolaemic mice . Nature . (2018 ) 558 :301–6. doi: 10.1038/s41586-018-0198-8 29875409
PMC6033669

82Jung JS Kho AR Lee SH Choi BY Kang SH Koh JY .
Changes in plasma lipoxin A4, resolvins and Cd59 levels after ischemic and traumatic brain injuries in rats . Korean J Physiol Pharmacol . (2020 ) 24 :165–71. doi: 10.4196/kjpp.2020.24.2.165 32140040
PMC7043996

83Szablewski L .
Brain glucose transporters: Role in pathogenesis and potential targets for the treatment of Alzheimer's disease . Int J Mol Sci . (2021 ) 22 :8142. doi: 10.3390/ijms22158142 34360906
PMC8348194

84Benedict C Grillo CA .
Insulin resistance as a therapeutic target in the treatment of Alzheimer's disease: A state-of-the-art review . Front Neurosci . (2018 ) 12 :215. doi: 10.3389/fnins.2018.00215 29743868
PMC5932355

85Rhea EM Leclerc M Yassine HN Capuano AW Tong H Petyuk VA .
State of the science on brain insulin resistance and cognitive decline due to Alzheimer's disease . Aging Dis . (2024 ) 15 :1688–725. doi: 10.14336/ad.2023.0814 37611907
PMC11272209

86Zhang X Dong H Zhang S Lu S Sun J Qian Y .
Enhancement of Lps-induced microglial inflammation response via Tlr4 under high glucose conditions . Cell Physiol Biochem . (2015 ) 35 :1571–81. doi: 10.1159/000373972 25790769

87Crowley K Scanaill P Hermanides J Buggy DJ .
Current practice in the perioperative management of patients with diabetes mellitus: A narrative review . Br J Anaesth . (2023 ) 131 :242–52. doi: 10.1016/j.bja.2023.02.039 37061429
PMC10375498

88Bowman GL Kaye JA Quinn JF .
Dyslipidemia and blood-brain barrier integrity in Alzheimer's disease . Curr Gerontol Geriatr Res . (2012 ) 2012 :184042. doi: 10.1155/2012/184042 22654903
PMC3359662

89Park HR Park M Choi J Park KY Chung HY Lee J .
A high-fat diet impairs neurogenesis: Involvement of lipid peroxidation and brain-derived neurotrophic factor . Neurosci Lett . (2010 ) 482 :235–9. doi: 10.1016/j.neulet.2010.07.046 20670674

90Ivascu R Torsin LI Hostiuc L Nitipir C Corneci D Dutu M .
The surgical stress response and anesthesia: A narrative review . J Clin Med . (2024 ) 13 :3017. doi: 10.3390/jcm13103017 38792558
PMC11121777

91Zhang J Zhang L Zhang S Yu Q Xiong F Huang K .
Hmgb1, an innate alarmin, plays a critical role in chronic inflammation of adipose tissue in obesity . Mol Cell Endocrinol . (2017 ) 454 :103–11. doi: 10.1016/j.mce.2017.06.012 28619625

92Vacas S Degos V Tracey KJ Maze M .
High-mobility group box 1 protein initiates postoperative cognitive decline by engaging bone marrow-derived macrophages . Anesthesiology . (2014 ) 120 :1160–7. doi: 10.1097/aln.0000000000000045 24162463
PMC3999217

93Cibelli M Fidalgo AR Terrando N Ma D Monaco C Feldmann M .
Role of interleukin-1beta in postoperative cognitive dysfunction . Ann Neurol . (2010 ) 68 :360–8. doi: 10.1002/ana.22082 20818791
PMC4836445

94Terrando N Monaco C Ma D Foxwell BM Feldmann M Maze M .
Tumor necrosis factor-alpha triggers a cytokine cascade yielding postoperative cognitive decline . Proc Natl Acad Sci USA . (2010 ) 107 :20518–22. doi: 10.1073/pnas.1014557107 21041647
PMC2996666

95Hata M Andriessen E Hata M Diaz-Marin R Fournier F Crespo-Garcia S .
Past history of obesity triggers persistent epigenetic changes in innate immunity and exacerbates neuroinflammation . Science . (2023 ) 379 :45 –62 . doi: 10.1126/science.abj8894 36603072

96Ma G Sun P Chen Y Jiang X Zhang C Qu B .
Nlrp3 inflammasome activation contributes to the cognitive decline after cardiac surgery . Front Surg . (2022 ) 9 :992769. doi: 10.3389/fsurg.2022.992769 36406365
PMC9666730

97Wei P Yang F Zheng Q Tang W Li J .
The potential role of the Nlrp3 inflammasome activation as a link between mitochondria Ros generation and neuroinflammation in postoperative cognitive dysfunction . Front Cell Neurosci . (2019 ) 13 :73. doi: 10.3389/fncel.2019.00073 30873011
PMC6401615

98Han MS Jung DY Morel C Lakhani SA Kim JK Flavell RA .
Jnk expression by macrophages promotes obesity-induced insulin resistance and inflammation . Science . (2013 ) 339 :218–22. doi: 10.1126/science.1227568 23223452
PMC3835653

99Hirsch J Vacas S Terrando N Yuan M Sands LP Kramer J .
Perioperative cerebrospinal fluid and plasma inflammatory markers after orthopedic surgery . J Neuroinflamm . (2016 ) 13 :211 . doi: 10.1186/s12974-016-0681-9 27577265
PMC5006595

100Feng Z Fang C Ma Y Chang J .
Obesity-induced blood-brain barrier dysfunction: Phenotypes and mechanisms . J Neuroinflamm . (2024 ) 21 :110 . doi: 10.1186/s12974-024-03104-9 38678254
PMC11056074

101Huang X Hussain B Chang J .
Peripheral inflammation and blood-brain barrier disruption: Effects and mechanisms . CNS Neurosci Ther . (2021 ) 27 :36 –47 . doi: 10.1111/cns.13569 33381913
PMC7804893

102Ni P Dong H Wang Y Zhou Q Xu M Qian Y .
Il-17a contributes to perioperative neurocognitive disorders through blood-brain barrier disruption in aged mice . J Neuroinflamm . (2018 ) 15 :332 . doi: 10.1186/s12974-018-1374-3 30501622
PMC6267879

103Yang T Velagapudi R Terrando N .
Neuroinflammation after surgery: From mechanisms to therapeutic targets . Nat Immunol . (2020 ) 21 :1319–26. doi: 10.1038/s41590-020-00812-1 33077953
PMC7704062

104Mateus-Gomes S Al-Sayyar A Lobey B Nadjar A Rua R Ahmad R .
Metabolic inflammation at the adipose-brain axis . Front Physiol . (2026 ) 17 :1795058. doi: 10.3389/fphys.2026.1795058 42037991
PMC13107480

105Feng X Valdearcos M Uchida Y Lutrin D Maze M Koliwad SK .
Microglia mediate postoperative hippocampal inflammation and cognitive decline in mice . JCI Insight . (2017 ) 2 :e91229. doi: 10.1172/jci.insight.91229 28405620
PMC5374063

106Crispino M Trinchese G Penna E Cimmino F Catapano A Villano I .
Interplay between peripheral and central inflammation in obesity-promoted disorders: The impact on synaptic mitochondrial functions . Int J Mol Sci . (2020 ) 21 :5964. doi: 10.3390/ijms21175964 32825115
PMC7504224

107Schmitt LO Gaspar JM .
Obesity-induced brain neuroinflammatory and mitochondrial changes . Metabolites . (2023 ) 13 :86. doi: 10.3390/metabo13010086 36677011
PMC9865135

108Luo JS Ning JQ Chen ZY Li WJ Zhou RL Yan RY .
The role of mitochondrial quality control in cognitive dysfunction in diabetes . Neurochem Res . (2022 ) 47 :2158–72. doi: 10.1007/s11064-022-03631-y 35661963
PMC9352619

109Mullins CA Gannaban RB Khan MS Shah H Siddik MAB Hegde VK .
Neural underpinnings of obesity: The role of oxidative stress and inflammation in the brain . Antioxidants (Basel) . (2020 ) 9 :1018. doi: 10.3390/antiox9101018 33092099
PMC7589608

110Danielson M Reinsfelt B Westerlind A Zetterberg H Blennow K Ricksten SE .
Effects of methylprednisolone on blood-brain barrier and cerebral inflammation in cardiac surgery-a randomized trial . J Neuroinflamm . (2018 ) 15 :283 . doi: 10.1186/s12974-018-1318-y 30261896
PMC6158839

111Tropis C Labaste F Sallese M Dortignac A Pereira O Gonidec SL .
Adipose tissue plays a crucial role in obesity-induced postoperative neurocognitive disorders . J Transl Med . (2026 ) 24 :1135. doi: 10.1186/s12967-026-08629-6 42693469
PMC13540911

112Lachmann G Feinkohl I Borchers F Ottens TH Nathoe HM Sauer AM .
Diabetes, but not hypertension and obesity, is associated with postoperative cognitive dysfunction . Dement Geriatr Cognit Disord . (2018 ) 46 :193 –206 . doi: 10.1159/000492962 30326480

113Schulze MB Stefan N .
Metabolically healthy obesity: From epidemiology and mechanisms to clinical implications . Nat Rev Endocrinol . (2024 ) 20 :633–46. doi: 10.1038/s41574-024-01008-5 38937638

114Xie J Yang B Xie J Ji C Zhang B Ma Y .
Metabolic syndrome and perioperative neurocognitive disorders: Epidemiology, mechanisms, and interventions . Front Neurosci . (2026 ) 20 :1836328. doi: 10.3389/fnins.2026.1836328 42325950
PMC13279210

115Noah AM Almghairbi D Evley R Moppett IK .
Preoperative inflammatory mediators and postoperative delirium: Systematic review and meta-analysis . Br J Anaesth . (2021 ) 127 :424–34. doi: 10.1016/j.bja.2021.04.033 34218905

116Liu X Yu Y Zhu S .
Inflammatory markers in postoperative delirium (Pod) and cognitive dysfunction (Pocd): A meta-analysis of observational studies . PloS One . (2018 ) 13 :e0195659. doi: 10.1371/journal.pone.0195659 29641605
PMC5895053

117Zhao A Peng Y Lin L Chen L Lin Y .
Predictive value of preoperative hypersensitive C-reactive protein in the incidence of postoperative cognitive impairment in valvular disease patients: A retrospective study . J Inflammation Res . (2024 ) 17 :11729–39. doi: 10.2147/jir.S499836 39741750
PMC11687280

118Hudetz JA Gandhi SD Iqbal Z Patterson KM Pagel PS .
Elevated postoperative inflammatory biomarkers are associated with short- and medium-term cognitive dysfunction after coronary artery surgery . J Anesth . (2011 ) 25 :1 –9 . doi: 10.1007/s00540-010-1042-y 21061037

119Nurcahyo WI Arifin A Primatika AD Muttaqin Z Elfira Boom C Harahap MS .
An association between C-reactive protein levels and the occurrence of cognitive dysfunction after heart valve replacement . Vasc Health Risk Manag . (2021 ) 17 :713–20. doi: 10.2147/vhrm.S334982 34824534
PMC8610747

120Peng L Xu L Ouyang W .
Role of peripheral inflammatory markers in postoperative cognitive dysfunction (Pocd): A meta-analysis . PloS One . (2013 ) 8 :e79624. doi: 10.1371/journal.pone.0079624 24236147
PMC3827367

121Evered L Silbert B Knopman DS Scott DA DeKosky ST Rasmussen LS .
Recommendations for the nomenclature of cognitive change associated with anaesthesia and surgery-2018 . Br J Anaesth . (2018 ) 121 :1005–12. doi: 10.1016/j.bja.2017.11.087 30336844
PMC7069032

122Tan XX Qiu LL Sun J .
Research progress on the role of inflammatory mechanisms in the development of postoperative cognitive dysfunction . BioMed Res Int . (2021 ) 2021 :3883204. doi: 10.1155/2021/3883204 34869762
PMC8642009

123Zhang X Yan X Gorman J Hoffman SN Zhang L Boscarino JA .
Perioperative hyperglycemia is associated with postoperative neurocognitive disorders after cardiac surgery . Neuropsychiatr Dis Treat . (2014 ) 10 :361–70. doi: 10.2147/ndt.S57761 24570589
PMC3933727

124Qiu LQ Song JL Zhang LC Fan B Li Q Lu B .
Association between hyperlipidemia and postoperative delirium risk: A systematic review and meta-analysis . Front Aging Neurosci . (2025 ) 17 :1544838. doi: 10.3389/fnagi.2025.1544838 40171385
PMC11959067

125Shen H Xiong Y Liang Y Liu Z Guo L Qin Y .
The effects of hyperlipidemia on postoperative cognitive dysfunction in patients undergoing laparoscopic gynecological tumor surgery . Neuropsychiatr Dis Treat . (2025 ) 21 :259–69. doi: 10.2147/ndt.S506570 39963123
PMC11831913

126Qian G Wang Y .
Serum metabolomics of early postoperative cognitive dysfunction in elderly patients using liquid chromatography and Q-Tof mass spectrometry . Oxid Med Cell Longev . (2020 ) 2020 :8957541. doi: 10.1155/2020/8957541 32082482
PMC7007934

127Das S Nanda SK Bisoi AK Wadhawan AN .
Effect of preoperative statin therapy on early postoperative memory impairment after off-pump coronary artery bypass surgery . Ann Card Anaesth . (2016 ) 19 :38 –44 . doi: 10.4103/0971-9784.173018 26750672
PMC4900397

128Veronese N Facchini S Stubbs B Luchini C Solmi M Manzato E .
Weight loss is associated with improvements in cognitive function among overweight and obese people: A systematic review and meta-analysis . Neurosci Biobehav Rev . (2017 ) 72 :87 –94 . doi: 10.1016/j.neubiorev.2016.11.017 27890688

129Liu Y Hong F Lebaka VR Mohammed A Ji L Zhang Y .
Calorie restriction with exercise intervention improves inflammatory response in overweight and obese adults: A systematic review and meta-analysis . Front Physiol . (2021 ) 12 :754731. doi: 10.3389/fphys.2021.754731 34867458
PMC8634604

130Sams VG Blackledge C Wijayatunga N Barlow P Mancini M Mancini G .
Effect of bariatric surgery on systemic and adipose tissue inflammation . Surg Endosc . (2016 ) 30 :3499–504. doi: 10.1007/s00464-015-4638-3 26514136

131Hathaway I Momodu OE Williams DM Beamish AJ Barry J Stephens JW .
Changes in cognitive function following bariatric surgery: An updated systematic review . Obes Surg . (2024 ) 34 :2216–26. doi: 10.1007/s11695-024-07235-z 38668820

132Weimann A Braga M Carli F Higashiguchi T Hübner M Klek S .
Espen practical guideline: Clinical nutrition in surgery . Clin Nutr . (2021 ) 40 :4745–61. doi: 10.1016/j.clnu.2021.03.031 34242915

133Fisk HL Childs CE Miles EA Ayres R Noakes PS Paras-Chavez C .
Modification of subcutaneous white adipose tissue inflammation by omega-3 fatty acids is limited in human obesity-a double blind, randomised clinical trial . EBioMedicine . (2022 ) 77 :103909. doi: 10.1016/j.ebiom.2022.103909 35247847
PMC8894262

134Oakes EG Vlasakov I Kotler G Bubes V Mora S Tatituri R .
Joint effects of one year of marine omega-3 fatty acid supplementation and participant dietary fish intake upon circulating lipid mediators of inflammation resolution in a randomized controlled trial . Nutrition . (2024 ) 123 :112413. doi: 10.1016/j.nut.2024.112413 38518540
PMC11088505

135Drucker DJ .
Glp-1-based therapies for diabetes, obesity and beyond . Nat Rev Drug Discov . (2025 ) 24 :631–50. doi: 10.1038/s41573-025-01183-8 40281304

136Szekeres Z Nagy A Jahner K Szabados E .
Impact of selected glucagon-like peptide-1 receptor agonists on serum lipids, adipose tissue, and muscle metabolism-a narrative review . Int J Mol Sci . (2024 ) 25 :8214. doi: 10.3390/ijms25158214 39125786
PMC11311305

137Xia Y Jin J Sun Y Kong X Shen Z Yan R .
Tirzepatide's role in targeting adipose tissue macrophages to reduce obesity-related inflammation and improve insulin resistance . Int Immunopharmacol . (2024 ) 143 :113499. doi: 10.1016/j.intimp.2024.113499 39471690

138Belmont-Rausch DM Ludwig MQ Bentsen MA Hansen SN Secher A Holst D .
Semaglutide attenuates neuroinflammation in male mice . Nat Commun . (2026 ) 17 :7328. doi: 10.1038/s41467-026-74038-4 42265098
PMC13402617

139Yao Y Lin D Chen Y Liu L Wu Y Zheng X .
Fluoxetine alleviates postoperative cognitive dysfunction by attenuating Tlr4/Myd88/Nf-Kb signaling pathway activation in aged mice . Inflammation Res . (2023 ) 72 :1161–73. doi: 10.1007/s00011-023-01738-8 37188940

140Fu Q Li J Qiu L Ruan J Mao M Li S .
Inhibiting Nlrp3 inflammasome with Mcc950 ameliorates perioperative neurocognitive disorders, suppressing neuroinflammation in the hippocampus in aged mice . Int Immunopharmacol . (2020 ) 82 :106317. doi: 10.1016/j.intimp.2020.106317 32087497

141Mao L Wang L Huang Z Switzer JA Hess DC Zhang Q .
Perioperative neurocognitive disorders: Advances in molecular mechanisms and bioactive molecules . Ageing Res Rev . (2025 ) 112 :102885. doi: 10.1016/j.arr.2025.102885 40914484
PMC12825322

142Titos E Rius B González-Périz A López-Vicario C Morán-Salvador E Martínez-Clemente M .
Resolvin D1 and its precursor docosahexaenoic acid promote resolution of adipose tissue inflammation by eliciting macrophage polarization toward an M2-like phenotype . J Immunol . (2011 ) 187 :5408–18. doi: 10.4049/jimmunol.1100225 22013115

143Serhan CN .
Pro-resolving lipid mediators are leads for resolution physiology . Nature . (2014 ) 510 :92 –101 . doi: 10.1038/nature13479 24899309
PMC4263681

144Lu Y Jin J Zhang H Lu Q Zhang Y Liu C .
Traumatic brain injury: Bridging pathophysiological insights and precision treatment strategies . Neural Regener Res . (2026 ) 21 :887 –907 . doi: 10.4103/nrr.Nrr-d-24-01398 40145994
PMC12296452

145Hou W Yao J Liu J Lin X Wei J Yin X .
Usp14 inhibition promotes recovery by protecting Bbb integrity and attenuating neuroinflammation in Mcao mice . CNS Neurosci Ther . (2023 ) 29 :3612–23. doi: 10.1111/cns.14292 37269080
PMC10580339

146Putthanbut N Lee JY Borlongan CV .
Extracellular vesicle therapy in neurological disorders . J BioMed Sci . (2024 ) 31 :85 . doi: 10.1186/s12929-024-01075-w 39183263
PMC11346291

147Sugita S Tahir P Kinjo S .
The effects of microbiome-targeted therapy on cognitive impairment and postoperative cognitive dysfunction-a systematic review . PloS One . (2023 ) 18 :e0281049. doi: 10.1371/journal.pone.0281049 36749772
PMC9904456

148Feinkohl I Winterer G Pischon T .
Associations of dyslipidaemia and lipid-lowering treatment with risk of postoperative cognitive dysfunction: A systematic review and meta-analysis . J Epidemiol Community Health . (2018 ) 72 :499 –506 . doi: 10.1136/jech-2017-210338 29437865

149Aldecoa C Bettelli G Bilotta F Sanders RD Aceto P Audisio R .
Update of the European Society of Anaesthesiology and Intensive Care Medicine evidence-based and consensus-based guideline on postoperative delirium in adult patients . Eur J Anaesthesiol . (2024 ) 41 :81 –108 . doi: 10.1097/eja.0000000000001876 37599617
PMC10763721