Can brown fat activity improve cardiovascular function and atherosclerosis risk in humans?

Since the description of brown adipose tissue (BAT) as a distinct thermogenic lineage of adipose tissue by Nedergaard and Cannon^1–3, many researchers have studied the function of BAT energy expenditure in hopes of developing therapies against the excess energy stored in obesity and its subsequent complications of type 2 diabetes and cardiovascular disease. In contrast to this observation, epidemiological evidence associates increased incidence of cardiovascular events in cold weather with coincident brown adipose tissue activation and noradrenergic excess.^{4, 5} Reports by three different groups of BAT activity in humans detected by PET-CT in 2009 instigated a new wave of research aimed at harnessing the energy expenditure of browning for treatment of obesity without the hypothesized cardiovascular risk of adrenergic activation.^6–8 Subsequent work highlighted the potential of brown adipose tissue activation by cold exposure⁹ or mirabegron¹⁰ to improve insulin sensitivity. Thus, it remains unclear whether BAT activation as currently available may mitigate human cardiovascular risk associated with insulin resistance and obesity in the short term or worsen cardiovascular risk in the medium to long term from increased adrenergic activation and thermogenesis.

In this issue of ATVB, Raiko and colleagues present a compelling cohort study of subjects undergoing nuclear imaging for brown fat activity coupled with subsequent 5-year followup of anatomic and functional vascular imaging of the carotid arteries as measures of subclinical atherosclerosis in healthy adults.¹¹ The authors extensively characterize their small cohort of mostly lean female subjects with low cardiovascular risk to show that improved cardiovascular functional measurements such as carotid intimal medial thickness, carotid distensibility and flow mediated dilation associates with high BAT volume and activity. This study is unique and novel in likely being the first to correlate functional measures of subclinical atherosclerosis to BAT activity independent of obesity measured by body mass index. The technology used to characterize brown fat activity in the selected subjects makes use of ¹⁵O labeled water, which adds perfusion characteristics to the standard measures of glucose uptake by FDG-PET. The authors observe the expected increase an expected increase in BAT activity in normal weight individuals compared to overweight, and that elements of the metabolic syndrome negatively correlate BAT activity and perfusion at baseline evaluation.

Moreover, characterization of BAT activity by these measures was performed during hyperinsulinemic-euglycemic clamps that allow for quantification of BAT glucose uptake under insulin-stimulated conditions as a measure of sensitivity. The authors appropriately acknowledge limitations of the study in terms of variability of the measured variables (Flow Mediated Dilation, BAT activity), small sample size and corrections for multiple comparisons. The strength of this work relies on the detailed cross sectional characterization of human BAT activity and medium term followup of human carotid vascular outcomes in a well-characterized cohort. Intriguingly, the carotid vascular function and anatomy associations with BAT activity in the human subjects studied could be mediated through paracrine and endocrine effects in addition to increased energy expenditure that could be explored in these or other studies.

Despite the detailed functional characterization of vascular function in subjects with BAT activation, the small sample size of the study limits the generalizability of BAT activity to surrogate measures of cardiovascular risk in intermediate or high-risk groups. Complementary population approaches using electronic medical records may delineate the positive association of BAT activity with improvement in traditional markers of cardiovascular risk such as age, gender and cholesterol levels. The work by Raiko and colleagues adds novel population level evidence that increased BAT activity might potentially decrease the incidence of subclinical atherosclerosis and improve vascular function over conferring risk for cardiovascular disease as highlighted in the Figure. Much work remains in determining the local and systemic mechanisms by which this protection might be conferred, or whether beige adipose tissue might be recruited to influence overall energy expenditure.

Figure:

Activation of human brown adipose tissue correlates with functional improvement in subclinical atherosclerosis. In this issue, Raiko and colleagues identify subjects with high BAT activity through PET-CT which associates with decreased subclinical atherosclerosis by anatomic (intimal medial thickness, IMT) and functional measures (carotid distensibility, Flow Mediated Dilation FMD). This finding adds evidence to the theory that BAT activation would decrease CVD risk independent of increases in circulating metabolites contributing to plaque growth.