Brown Adipose Tissue and the Take (12,13-di)HOME Message to the Heart

Obesity leads to insulin resistance and type 2 diabetes and is a well-established cardiovascular risk factor.¹ Adipose tissue (AT) is a “biochemical factory” in the human body and it plays a crucial role in human metabolism; it secretes a wide range of bioactive adipokines/adipocytokines, with endocrine and paracrine effects on the cardiovascular system.² The location of the AT in the human body is a major determinant of its biological characteristics, with evidence suggesting that visceral AT drives cardiovascular disease, whereas subcutaneous AT has a neutral cardiovascular effect, and gluteal AT is considered to exert cardioprotective effects.² AT biology is largely determined not only by its quantity but also by its quality and function.² To add to the complexity of AT biology, this tissue can be classified as white AT (WAT) or brown AT (BAT) depending on its metabolic, morphologic, and broader biological phenotype. In humans, WAT is the most abundant type and, besides being responsible for energy storage in the form of triglycerides, it has been proven to play a crucial role in regulating cardiovascular function.² WAT can secrete bioactive molecules that affect cardiovascular biology and the diseased cardiovascular system can signal back to AT, modifying its biology and function; this crosstalk plays an important role in cardiovascular disease development.^2–6 BAT, which accounts for only 4.3% of the total fat mass in adults, is located in the interscapular, supraclavicular, mediastinal, paraspinal, and suprarenal area, and is involved in energy expenditure; it is the main site of nonshivering thermogenesis. Recent evidence suggests that BAT has a characteristic secretory profile as it releases “batokines” that contribute to its protective role against obesity and associated metabolic alterations, such as insulin resistance.⁷ It is also able to consume glucose and lipids for thermogenesis.⁷ Although increased BAT activity is believed to play a protective role against cardiovascular disease, there has been very little evidence for meaningful endocrine effects of BAT on either the heart or the vascular wall.^8,9

In this issue of Circulation, Pinckard and colleagues¹⁰ unravel the beneficial effects of BAT on cardiac function and demonstrate the cardioprotective effects of the BAT-secreted lipokine 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME). This oxidized linoleic acid derivative is released from BAT in response to cold temperatures and exercise,^11,12 and previous work from the same group suggested that 12,13-diHOME regulates BAT fuel uptake, supporting its thermogenic function.^11,12 This also increases fatty acid uptake and mitochondrial fatty acid oxidation in skeletal muscle and is inversely correlated with body mass index and insulin resistance.^11,12

Despite the established role of 12,13-diHOME on BAT biology, its potential paracrine/endocrine effects on the heart are unclear.¹³ Pinckard et al¹⁰ observed that 12,13-diHOME plasma levels are lower in patients with heart disease.¹⁰ To understand the biological role of this lipokine, they used a mouse model to demonstrate that 12,13-diHOME counteracts the adverse effects of a high-fat diet on cardiac function and remodeling in mice. 12,13-diHOME treatment also improved cardiac hemodynamics by acting directly on cardiomyocytes’ mitochondrial respiration through a mechanism that involves nitric oxide synthase 1.¹⁰ This important study shows that BAT can exert endocrine effects on the heart and identifies 12,13-diHOME as a potential mediator of these effects. This first discovery calls for further research to better understand the nature of the crosstalk between BAT and the cardiovascular system in humans. Indeed, a thorough analysis of BAT secretome should be carried out to find other putative mediators of the endocrine protective role of BAT on cardiac function and remodeling; it would be interesting to explore the presence of a potential bidirectional communication between BAT and the cardiovascular system, similar to what has been demonstrated in the past for WAT.^2–5

There is also evidence suggesting that 12,13-diHOME exerts similar effects on mitochondrial respiration of both skeletal muscle and cardiomyocytes^10,12; it is therefore essential to understand whether this lipokine can affect mitochondrial function in vascular smooth muscle cells, because that would demonstrate its possible vasoprotective potential.

Concerning the translational implications, the authors observed an improvement in functional cardiac measures after BAT transplantation in mice. BAT was believed to exist only in rodents and human neonates; however, in 2009, multiple retrospective studies using data collected from ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography identified functional BAT in adult humans and this opened the way to consider it as a potential therapeutic tool to treat the metabolic dysregulation observed in obesity. Recent preclinical studies have indeed shown that BAT transplantation improves glucose metabolism, increases insulin sensitivity, and decreases adiposity.¹⁴ The clinical relevance of this animal model was augmented by the demonstration that human beige and brown adipocytes transplanted into mice improve glucose metabolism and reduce adiposity similarly to whole BAT transplantation.¹⁴ Beige or brite (brown-in-white) AT can be found interspersed in WAT depots, whereas WAT browning could be considered a promising alternative therapeutic approach; however, discrepancies between rodents and humans in WAT browning modulation² make this approach challenging.

Could targeting the bioavailability of 12,13-diHOME (eg, by modulating its biosynthesis or its degradation) be a rational therapeutic approach to prevent the cardiovascular complications of obesity? More clinical studies are needed to clarify the upstream and downstream pathways involved in this lipokine synthesis and metabolism. Similarly, imaging of BAT could potentially reveal new imaging biomarkers with prognostic value in human cardiometabolic diseases. However, contrary to the easy assessment of WAT metabolic and inflammatory status using standard computed tomography or positron emission tomography/computed tomography,¹⁵ BAT imaging is challenging given that it is difficult to locate noninvasively and its volume often falls below the detection limits of standard imaging tests such as positron emission tomography/computed tomography.

Overall, the concept of BAT as an endocrine organ is relatively new in humans; the study of Pinckard and colleagues¹⁰ provides the first evidence implying that BAT can exert endocrine effects on the heart. Given the protective role of BAT in cardiometabolic health, the article by Pinckard et al¹⁰ lays the foundation for establishing BAT and its batokines as therapeutic targets or diagnostic tools for cardiovascular diseases.