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” obesity (MUO), the latter being associated with a range of comorbidities, in-cluding 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, in-creasing evidence suggests the key role of low-grade metabolic inflammation (metaflammation) in patho-genesis of obesity and metabolic dysfunction. This review compares numerous pro-inflammatory media-tors observed in MHO and MUO to identify the role of metaflammation in obesity phenotype. A mechanis-tic model is proposed for the progression from MHO to MUO with the exacerbation of metaflammation and dysfunction of insulin-sensitive organs. MUO is characterized by the excess of visceral adiposity, both local and systemic insulin resistance (IR). Obesity is accompanied by a shift in the immune profile from anti-inflammatory to pro-inflammatory, with its worsening in MUO. However no clinically significant pa-rameter has been identified among soluble factors or leukocyte subtypes in the blood as a predictor of MHO to MUO conversion. Structural and functional changes in adipose tissue are not resolved immediately following bariatric interventions. The persistence of «metabolic memory» in the form of epigenetic modi-fications in macrophages of adipose tissue and the emergence of large numbers of CD4+ and CD8+ effec-tor memory T cells with senescent phenotype, may predispose to weight regain and T2DM relapse post-surgery. The review discusses mechanisms underlying metabolic memory and potential reversibility of metabolic disturbances after bariatric surgery.