Adiponectin levels and cardiovascular disease – symptom or a cause?

Adiponectin is a major adipocyte-secreted protein (adipokine) and is also considered a hormone that links excess adiposity with metabolic processes central to the pathophysiology of cardiovascular disease (CVD) 1–3. Circulating levels of adiponectin are inversely proportional to adiposity and low adiponectin levels predict the development of type 2 diabetes and CVD 1,2. Adiponectin concentration is largely determined by adipocyte size and insulin sensitivity 2,3, but is also secreted by cardiomyocytes 4. Thus, there is a strong biological precedent for adiponectin as a biomarker of risk for CVD and rationale for the investigation by Sharma et al.5. So what did they do? Sharma and colleagues utilized the scientifically invaluable Coronary Artery Risk Development in Young Adults (CARDIA) study, a longitudinal, population-based study of young black and white men and women, which has provided extensive insight into the etiology and evolution of cardiometabolic diseases in young adults for nearly 30 years. The investigators capitalized on the ability to examine the relationship between adiponectin levels in the population when their average age in years was ∼40 and cardiac structure as measured by echocardiogram 10 years later. A unique aspect of this study relative to the other literature on the topic was the age of the participants and the black/white men/women composition of the study, and the ability to thoroughly account for a spectrum of cardiovascular risk factors in the analysis. Alternatively, the main limitation, as the authors note, is the lack of repeated measures of both adiponectin and echocardiographic variables at the same time. Both of these aforementioned factors inform the interpretation of the results from the study. Indeed, as one would hypothesize, in normotensive participants, higher levels of adiponectin were associated with a more favorable profile (for CVD risk) of measures of cardiac structure, whereas in hypertensive participants, the investigators observed a U-shaped association between adiponectin and cardiac structure. This latter observation aligns with previous research that suggests that in higher risk populations (such as those with hypertension), the U-shaped association may represent a compensatory mechanism where higher levels of adiponectin are a marker of processes related to poor cardiovascular outcomes rather than the more basic biological function attributed to it 1. The authors rightfully conclude that in a normotensive population, adiponectin may be a useful marker of future cardiac structure, but then expound about the future direction of testing adiponectin receptor agonists for benefit and therapeutic use of adiponectin. It is at this point where readers interested in this study should be reminded of the greater body of research informing this topic. This research has shown by Mendelian randomization analyses that the key hypothesized causal pathway relating adiponectin to CVD in insulin sensitivity is likely not causal and is mediated by adiposity 6,7. Therefore, pharmacologic interventions aimed at raising adiponectin are not likely to impact the progression of cardiometabolic disease risk. However, these results also underscore the importance of a number of factors that do impact adiponectin levels and are also widely accepted as causal factors in the pathophysiology of CVD. For example, healthy diet patterns largely aligning with the recent USA dietary guidelines report 8 are associated with higher levels of adiponectin 9,10, as are physical activity 11 and weight loss 3. Central to the topic of the discussed paper by Sharma and colleagues, physical activity and weight loss are also demonstrated avenues to impact cardiac structure and function 11. Thus, although the findings of Sharma and colleagues indicate the importance of adiponectin as a biomarker in the natural history of CVD, an arguably better use of resources over the proposed drug development/testing to raise adiponectin pharmacologically would be population-level strategies used to improve diet quality, increase physical activity levels, and ultimately shift the distribution of overweight and obesity in the USA to the left as this would theoretically have a much greater impact on cardiovascular health as well as the multitude of chronic diseases related to these common risk factors 12.