From Metabolically Healthy to Unhealthy Obesity Through Low-Grade Inflammation

Of the many clinical phenotypes of obesity, the most prevalent are metabolically "healthy" (MHO) and metabolically "unhealthy" (MUO) obesities, the latter being associated with a range of comorbidities, including type 2 diabetes mellitus (T2DM). The underlying causes of different obesity phenotypes and the mechanisms of conversion of one phenotype into another have yet to be fully elucidated. However, increasing evidence suggests the key role of low-grade metabolic inflammation (metaflammation) in the pathogenesis of obesity and metabolic dysfunction. The review presents a comprehensive description of changes in immune cell populations and pro-inflammatory mediators, as well as a detailed comparative mapping of the adipose tissue immune landscape during MHO/MUO transition. Based upon a conceptual model for the intensification of metaflammation during MHO progression and conversion to MUO, a pattern of dynamical changes that accompany MHO/MUO transition is described. Though many parameters demonstrate significant differences in multiple cross-sectional and some longitudinal studies, only a few of them (CRP, IL-6, IL-17A, absolute counts of leukocytes and neutrophils) meet the criteria of a validated biomarker in clinical setting. A lack of standardization in MHO definition and heterogeneity in the severity of MUO make the search for predictive biomarkers a challenge. The review also discusses the mechanisms underlying metabolic memory and the incomplete reversibility of metabolic disturbances after bariatric surgery.