The global obesity pandemic has unveiled adipose tissue as a pivotal, active modulator of neurological health, intricately linking metabolic dysfunction to chronic pain and cognitive decline. This review synthesizes current evidence to propose a unified “neuro-metabo-inflammatory” model of the adipose-central nervous system (CNS) axis. We articulate a framework where, in pathological states such as obesity, dysfunctional adipose tissue releases a milieu of factors—including adipokines, lipids, and extracellular vesicles—that propagate peripheral and central neuroinflammation, disrupt blood–brain barrier integrity, and impair synaptic plasticity. These processes converge to drive pain sensitization and cognitive deficits. Critically, we evaluate the clinical evidence linking visceral adiposity to multisite chronic pain and accelerated cognitive impairment, while highlighting sexually dimorphic pathways. The review moves beyond cataloging findings to prioritize the most robust mechanisms, assess evidence quality, and identify key translational gaps. We conclude by discussing emerging therapeutic strategies targeting this axis and proposing precise directions for future research to disentangle the complex temporal and spatial dynamics of adipose–CNS communication.

Depression presents sexual dimorphism, and one important factor that increases the frequency of depression and contributes to sex-specific variations in its presentation is obesity. The conventional use of Body Mass Index (BMI) as an indicator of obesity is inherently limited due to its inability to distinguish between fat and lean mass, which limits its predictive utility for depression risk. Implementation of dual-energy X-ray absorptiometry (DXA) investigated sex-specific associations between body composition (fat mass, appendicular lean mass) and depression. Data from the NHANES cycles between 2011 and 2018 were analyzed, including 3,637 participants (1,788 males and 1,849 females). Four body composition profiles were identified in the subjects: low adiposity-low muscle (LA-LM), low adiposity-high muscle (LA-HM), high adiposity-low muscle (HA-LM) and high adiposity-high muscle (HA-HM). After accounting for confounding variables, the associations between fat mass index (FMI), appendicular skeletal muscle mass index (ASMI), body fat percentage (BFP), body composition phenotypes, and depression risk were assessed using restricted cubic spline (RCS) curves and multivariable logistic regression models. We further conducted interaction analyses for ASMI and FMI in females. RCS curves indicated a U-shaped relationship between ASMI and the risk of depression in males. Logistic regression analysis revealed that in males, the second (OR = 0.43, 95%CI:0.22–0.85) and third (OR = 0.35, 95%CI:0.14–0.86) quartile levels of ASMI were significantly negatively associated with depression risk. In females, increases in BFP (OR = 1.06, 95%CI:1.03–1.09) and FMI (OR = 1.08, 95% CI:1.04–1.12) were significantly associated with an increased risk of depression. Additionally, compared to females with a low-fat high-muscle phenotype, those with LA-LM (OR = 3.97, 95%CI:2.16–7.30), HA-LM (OR = 5.40, 95%CI:2.34–12.46), and HA-HM (OR = 6.36, 95%CI:3.26–12.37) phenotypes were more likely to develop depression. Interestingly, further interaction analysis of ASMI and FMI in females revealed an interplay between height-adjusted fat mass and muscle mass (OR = 4.67, 95%CI: 2.04–10.71). The findings demonstrate how important it is to consider body composition when estimating the risk of depression, particularly in females. There is a substantial correlation between the LA-LM, HA-LM, and HA-HM phenotypes in females with a higher prevalence of depression. It is advised to use a preventative approach that involves gaining muscle mass and losing fat.

Introduction: Neuropathic pain (NP) conditions arising from injuries to the nervous system due to trauma, disease, or neurotoxins are chronic, severe, debilitating, and exceedingly difficult to treat. However, the mechanisms of NP are not yet clear. Here we explored the role of Dock4, an atypical Rac1 GEF, in the development of NP.Methods: Mechanical allodynia was assessed as paw withdrawal threshold by a dynamic plantar aesthesiometer. Immunofluorescence staining was conducted to investigate the expression and localization of Dock4, Rac1 and GluN2B. Quantitative analysis of Dock4, Rac1 and GluN2B were determined by qRT-PCR and Western blot assay. Spontaneous excitatory and inhibitory postsynaptic currents in spinal cord slices were examined using whole cell patch clam. Dendritic spine remodeling and synaptogenesis were detected in cultured dorsal spinal neurons.Results and discussion: We found that SNL caused markedly mechanical allodynia accompanied by increase of Dock4, GTP-Rac1and GluN2B, which was prevented by knockdown of Dock4. Electrophysiological tests showed that SNL facilitated excitatory synaptic transmission, however, this was also inhibited by Dock RNAi-LV. Moreover, knockdown of Dock4 prevented dendritic growth and synaptogenesis.Conclusion: In summary, our data indicated that Dock4 facilitated excitatory synaptic transmission by promoting the expression of GluN2B at the synaptic site and synaptogenesis, leading to the occurrence of NP.