The molecular mechanisms of obesity paradox

Clinical observations suggest a complex relationship between human obesity and cardiovascular disease. Whilst abdominal (visceral) adiposity leads to deleterious metabolic disturbances, subcutaneous fat accumulation has a benign effect on cardiometabolic risk. Notably, an accumulating body of evidence paradoxically links increased body mass index with a better prognosis in patients with established cardiovascular disease, a finding that has been termed the 'obesity paradox'. Whilst this is now acknowledged to be an epidemiological finding, a metabolically healthy obese group associated with low cardiovascular risk has also been identified. The current concept of adipose tissue (AT) biology suggests that AT expansion is feasible without accompanying adipocyte dysfunction. A metabolically healthy obese phenotype can be promoted by exercise, but is also linked with intrinsic AT molecular characteristics such as efficient fat storage and lipid droplet formation, high adipogenesis capacity, low extracellular matrix fibrosis, angiogenesis potential, adipocyte browning and low macrophages infiltration/activation. Such features are associated with a secretomic profile of human AT which is protective for the cardiovascular system. In the present review, we summarize the existing knowledge on the molecular mechanisms underlying the 'obesity paradox' and whether fatness can be healthy too.