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Open research questions in Adipokines, Inflammation, and Metabolic Diseases

55 unresolved questions extracted from the limitations and future-work sections of 345 Adipokines, Inflammation, and Metabolic Diseases papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • The negative correlations of TNF-α with insulin resistance parameters challenge the widely held assumption that TNF-α is uniformly elevated in pediatric obesity; further research is needed to clarify whether the inflammatory profile of obese children differs from that of adults.

    Evaluation of aquaporin-7, adiponectin, and TNF-α levels in obese children · 2026 · DOI

  • However, whether sex modulates inflammation, including the understanding about specific renal compartments, remains insufficiently characterized, particularly in the BTBR ob/ob model. Despite growing interest in the role of biological sex in DKD progression, evidence remains inconsistent, with reports suggesting sex-dependent differences in renal out- comes but limited mechanistic knowledge.

    Sex-dependent and compartment-specific macrophage accumulation associates with glomerular injury in BTBR ob/ob mice · 2026 · DOI

  • However, the expression, regulation and mechanistic targets of GIPR, and indeed many G protein-coupled receptors (GPCRs), in human adipocytes remains unclear, with adipocyte development being particularly under-studied in this regard.

    Identification and functional assessment of GPCRs across human adipogenesis · 2026 · DOI

  • BackgroundSubcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) differ in their metabolic risk, but whether they retain distinct transcriptional identities and remodeling programs in adult humans remains unclear.

    Complementary remodeling strategies distinguish human subcutaneous and omental adipose tissue · 2026 · DOI

  • Breast cancer survivors (BCS) often exhibit persistent metabolic and hepatic disturbances after cancer treatment; however, cardiorespiratory fitness’s (CRF) underlying molecular signatures and associations of CRF with metabolic and hepatic health remain insufficiently understood.

    Cardiorespiratory fitness, adiposity, and metabolic risk in breast cancer survivors: links with circulating WISP-1 and WISP-3 · 2026 · DOI

  • Third, HCY and AIP were each measured only once; therefore, long-term variability, regression dilution, and dynamic changes over time could not be assessed.

    Association of plasma homocysteine with the atherogenic index of plasma and modification by body mass index: a cross-sectional study · 2026 · DOI

  • Cross-sectional studies have shown an inverse relationship between CRP, IL-6 and total testosterone (TT) levels, yet mixed findings have been reported when individual components of metabolic syndrome are considered.

    Longitudinal Associations Between Endogenous Testosterone, C-Reactive Protein, and Interleukin-6 in Aging Men: Findings from the Baltimore Longitudinal Study of Aging · 2026 · DOI

  • Age-associated inflammation varies across tissues, but whether distinct visceral adipose tissue (VAT) depots undergo inflammatory remodeling in a depot-specific manner remains unclear.

    The anatomical compartment defines distinct immune remodeling within human visceral adipose tissue during aging · 2026 · DOI

  • Several limitations of the present study should be considered when interpreting the findings. First, the sample size was relatively limited, which may restrict the generalizability of the results to broader populations. In addition, the study focused on selected adipokines and specific gene expression markers, whereas a com- plex interplay of metabolic, genetic, and inflammatory pathways governs fetal growth regulation. The absence of stratified analyses based on maternal BMI categories further limits the ability to assess the influence of maternal metabolic status on adipokine regulation. Second, the observational, cross-sectional design of the study precludes establishing causal relationships between altered adipokine levels, gene expression changes, and the development of intrauterine growth restriction. Furthermore, although standard- ized protocols were followed, variability in biological conditions and assay methodologies may influence measured adipokine concentrations. The lack of comprehensive metabolic profiling, including insulin resistance parameters such as fasting insulin, HOMA-IR, and glycated hemoglobin (HbA1c), also limits the interpretation of the metabolic context of adipokine alterations. Finally, the study did not include a detailed assessment of placental morphology, such as placental weight or histopathological features, which could provide important structural correlates to the observed molecular findings. Additionally, while placental gene expression and DNA methylation were analyzed, direct quantification of adipokine protein levels in placental tissue was not performed. Future studies integrating larger cohorts, longitudinal designs, detailed metabolic profiling, and combined molecular and histo- pathological analyses are warranted to provide a more comprehen- sive understanding of the mechanisms underlying IUGR.

    Adiponectin and leptin levels in mothers, fetuses, and neonates with intrauterine growth restriction compared to those with appropriate gestational age · 2026 · DOI

  • Recent advances have established WAT as a metabolically and immunologically active organ, the function of which is shaped by lipid turnover, cellular composition and anatomical context. While these insights have clarified key mechanisms linking adiposity to cardiometabolic disease, they have also exposed important gaps in our understanding of adipose tissue biology. This includes biological diversity related to sex and ethnicity, factors that influence WAT biology in important ways. Adipose tissue distribution differs markedly between men and women, with women generally exhibiting greater subcutaneous storage capacity and relative protection from visceral fat accumulation prior to menopause. Ethnic differences in fat distribution and ectopic lipid deposition are also well documented and influence cardiometabolic risk at comparable BMI levels. How sex, developmental programming and genetic background shape adipocyte turnover, state composition and depot-specific immune interactions remains incompletely understood and represents an important area for future investigation. A major unresolved question concerns the stability and reversibility of adipocyte states in humans. Longitudinal studies tracking individual adipocyte populations across weight gain, weight loss and pharmacological intervention are required to determine whether maladaptive states can be durably reprogrammed or merely transiently suppressed. Similarly, the molecular mechanisms underlying adipose ‘memory’ remain incompletely defined, including how transcriptional, epigenetic and structural features interact to constrain long-term metabolic outcomes. Another critical knowledge gap relates to causality. While associations between adipocyte heterogeneity, lipid turnover and inflammation are now reported across multiple studies, direct evidence linking specific adipocyte states to cardiometabolic endpoints in humans is lacking. Addressing this will require integration of deep tissue phenotyping with prospective clinical studies and mechanistic model systems that preserve human-relevant adipocyte biology. Furthermore, the discovery of depot-specific immunomodulatory adipocytes raises new questions regarding adipose–immune communication at barrier sites. Defining how microbial-derived signals, local inflammation and adipocyte state transitions intersect may provide novel insights into the links between metabolic and inflammatory disease. Together, these challenges point towards a shift from weight-centric to tissuecentric therapeutic strategies. Interventions that restore adipocyte function, normalise lipid turnover and rebalance adipocyte states, rather than focusing exclusively on weight loss, may offer more sustained protection against metabolic disease. Finally, while this review has focused on work from our own group, reflecting the scope of the Camillo Golgi Prize Lecture on which it is based, it is important to emphasise that these findings represent only a small part of a much broader and rapidly advancing field. Major conceptual and technical advances in adipose tissue biology have been driven by the work of many outstanding research groups worldwide. I recognise that important contributors or relevant studies may not be cited as this article is not intended to provide a comprehensive review of the field.

    Perspectives on human adipose tissue: from cellular mechanisms to clinical complications · 2026 · DOI

  • While MetS components such as abdominal obesity, elevated blood pressure, and elevated fasting glucose contribute to the pathophysiology of calcification, further investigation is needed to fully elucidate the mechanisms by which hs-CRP increases the inflammatory milieu and augments the calcification process.

    Metabolic syndrome and high-sensitivity C-reactive protein co-modify the risk of coronary artery calcification · 2026 · DOI

  • A comprehensive evaluation strategy that integrates metabolic and inflammatory markers may increase the precision of CAC risk prediction and help mitigate the cardiovascular risks associated with calcification.

    Metabolic syndrome and high-sensitivity C-reactive protein co-modify the risk of coronary artery calcification · 2026 · DOI

  • However, serological studies present conflicting evidence on resistin's link to obesity, IR, and T2DM and only one salivary study exists, with none in the Indian population.

    Assessment of serum and salivary resistin levels in newly diagnosed type-II diabetes mellitus patients · 2025 · DOI

  • However, changes in the serum level of alpha defensin in MS, with or without type 2 DM and CAD, remain insufficiently studied that determines the feasibility of conducting this study.

    Study of alpha defensin in coronary artery disease and type 2 diabetes mellitus on the background of metabolic syndrome · 2022 · DOI

  • Although many studies have investigated the relationships of several adipokines to metabolic syndrome (MetS), the interrelationships of adiponectin (ADP), adipocyte fatty acid binding protein (A-FABP) and fibroblast growth factor 21 (FGF 21) have not been described in detail.

    Evaluation of Total Adiponectin, Adipocyte Fatty Acid Binding Protein and Fibroblast Growth Factor 21 Levels in Individuals With Metabolic Syndrome · 2014 · DOI

  • Adiponectin, Non-Esterified Fatty Acids and Antiphospholipid Antibodies in Type II Diabetes Mellitus The importance of the association of antiphospholipid antibodies (aPL Abs) with the features of type II diabetes mellitus has not yet been elucidated.

    Adiponectin, Non-Esterified Fatty Acids and Antiphospholipid Antibodies in Type II Diabetes Mellitus · 2012 · DOI

  • However, how endocrine, adipokine, insulin-resistance, and fibrinolysis-related biomarkers vary across early metabolic phenotypes remains incompletely understood.

    Adipokine, endocrine, and fibrinolysis-related alterations across abdominal obesity and metabolic syndrome phenotypes in young adults · 2026 · DOI

  • Exercise may act as an anti-inflammatory modulator, but there is no consensus about the role of the TLR in this tuning.

    Toll like receptor expression induced by exercise in obesity and metabolic syndrome: A systematic review · 2026 · DOI

  • However, the metabolic cues that drive Treg cell subset specialization in the obese VAT niche remain elusive.

    Palmitic acid coordinates impaired visceral adipose ICOShi Treg-mediated immunosuppression and systemic metabolic disturbance during obesity · 2026 · DOI

  • Cardiovascular disease is a leading cause of morbidity and mortality in type 2 diabetes mellitus (T2DM), although optimal biomarker strategies for risk stratification remain incompletely defined.

    Can one composite index capture both inflammatory and metabolic cardiovascular risk in type 2 diabetes? · 2026 · DOI

  • While biologically plausible, its incremental value, methodological robustness, and generalizability across populations remain to be established, particularly in comparison with existing composite indices such as the triglyceride-glucose index.

    Can one composite index capture both inflammatory and metabolic cardiovascular risk in type 2 diabetes? · 2026 · DOI

  • C_LIO_LIThe molecular programmes linking circulating proteomic changes to cellular transcriptional states in patients with exclusively primary antiphospholipid syndrome and a history of thrombosis remain uncertain, as do the associations with high-risk phenotypes associated with poor outcomes.

    Multi-omics and network propagation reveal latent innate immune programmes stratifying high-risk thrombotic primary antiphospholipid syndrome · 2026 · DOI

  • Our findings support the need for further investigation into the mechanistic relationship between androgen status and inflammation and whether addressing testosterone deficiency could influence inflammation and downstream chronic disease risk in older male populations.

    Longitudinal Associations Between Endogenous Testosterone, C-Reactive Protein, and Interleukin-6 in Aging Men: Findings from the Baltimore Longitudinal Study of Aging · 2026 · DOI

  • The observed improvement in C-index, while statistically significant, is modest , and its clinical impact remains to be determined. Caution is warranted when extrapolating these results to women, other ethnic groups, or general Western populations.

    Association of the C-reactive protein-triglyceride glucose index with new-onset myocardial infarction risk: a prospective cohort study · 2026 · DOI

  • During acute myocardial infarction (AMI), adipokine profiles may vary according to body mass index (BMI), yet this association remains underexplored.

    Adipokine-mediated metabolic responses across BMI in acute myocardial infarction · 2026 · DOI

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55 open questions have been extracted from the limitations and future-work passages of 345 Adipokines, Inflammation, and Metabolic Diseases papers in our library. Each one below links back to the study that raised it, so you can read the original claim in context.

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