Figure 1.

Proposed conceptual model for the adiponectin paradox. Among healthy young and middle-aged adults, obesity and low-grade inflammation are associated with hypoadiponectinemia, and each is associated with reduced insulin sensitivity. In such individuals, low circulating adiponectin portends a greater risk of cardiovascular disease. By contrast, in the setting of prevalent cardiovascular disease, heart failure, chronic kidney disease and advanced age, leanness more generally reflects involuntary weight loss / cachexia – which may be accompanied by smaller, differentiated adipocytes – and this is associated with higher plasma adiponectin. Increased production from non-adipose tissues or through direct stimulation by natriuretic peptides, decreased elimination, or other mechanisms associated with high-grade inflammation, may also contribute to elevation in circulating adiponectin levels. Such increased adiponectin levels, whether as markers of underlying illness severity, decreased signaling efficacy (adiponectin resistance) or, possibly, direct pro-inflammatory or other adverse actions, are related to a heightened risk of cardiovascular complications and mortality. Last, heart and vascular expression of T-cadherin also appears to regulate adiponectin levels, apart from mediating its actions. *In healthy elders, the association has been shown to be bidirectional, that is, both low and high adiponectin levels are associated with increased risk.