Revisiting the Obesity–Anemia Paradox: Inflammation and Iron Homeostasis in the BMI–Hemoglobin Relationship

Background: Obesity and anemia are global epidemics with complex, overlapping pathophysiology. While excess adiposity is known to induce chronic inflammation that disrupts iron homeostasis, multiple population studies paradoxically report higher hemoglobin levels and lower anemia prevalence among obese individuals. The nonlinear and potentially suppressive role of inflammation in this relationship remains understudied. Methods: We analyzed adults aged 18–64 from the 2015–2023 National Health and Nutrition Examination Survey (NHANES). Hemoglobin was modeled as a function of BMI using survey-weighted linear regression with restricted cubic splines. Interactions with log-transformed CRP were assessed, and ferritin was corrected for inflammation using BRINDA regression-residual methods. Causal mediation analysis decomposed the total effect of BMI on hemoglobin into indirect (mediated by CRP) and direct effects. Secondary models examined anemia (Hb <13.0 g/dL in men, <12.0 g/dL in women) using logistic regression. Results: Hemoglobin increased steeply across lower BMI ranges but plateaued above 30 kg/m² (p-nonlinearity < 0.001). The hemoglobin–BMI curve flattened significantly at higher CRP levels, with strong evidence of interaction (p-interaction < 0.001). Mediation analysis showed that CRP significantly suppressed the BMI–hemoglobin relationship (ACME = –0.044 g/dL, p < 0.001; ADE = 0.216 g/dL, p < 0.001). In contrast, BRINDA-adjusted ferritin mediated <2% of the association. Logistic models showed that anemia risk declined sharply with increasing BMI but rose consistently with CRP. Anemia mediation analysis revealed suppression as well (ACME > 0; ADE < 0), precluding interpretation of proportion mediated. Conclusions: BMI is positively associated with hemoglobin in a non-linear, CRP-dependent fashion. Inflammation significantly suppresses the hematologic benefit of excess adiposity, while inflammation-adjusted ferritin plays a minimal mediating role. These findings underscore the importance of modeling nonlinearity and correcting iron biomarkers for inflammation when studying obesity-related anemia.