Abstract
Metabolism & Endocrinology Themed Meeting of the Physiological Society. Brown adipose tissue: a new human organ?
The Royal Society, London, UK, 11–13 December 2012
The prevalence of obesity and overweight is increasing rapidly and functional brown adipose tissue (BAT), with its role in energy expenditure, may provide one solution. However, several key questions remain: what is the role of BAT in body metabolism, does substantial diet-induced thermogenesis exist in BAT and can it have a significant impact on total energy expenditure? Brown adipocytes are present within white adipose depots (BRITE cells) and the transcriptional control of these and classical brown adipocytes, remains an area of immense research interest. In addition, BAT has a role in lipoprotein and glucose metabolism and may play a part in aging. These, and several other burning issues around BAT, were discussed at a meeting of the Physiological Society in London, UK (11–13 December 2012).
In the context of the increasing prevalence of obesity and overweight, brown adipose tissue (BAT) has re-emerged as a potentially vital human organ. The Metabolism and Endocrinology themed meeting of the Physiological Society in London, UK (11–13 December 2012) brought together leading researchers from across the world to discuss the recent advances in BAT research. BAT has a significant role in energy balance in mammals and the potential that it may lead to a solution to the growing problem of obesity and its related morbidities is one driving force behind BAT research.
Brown adipose tissue
BAT is a thermogenic organ. In contrast to white adipose tissue (WAT), the primary function of BAT is to produce heat by the process of nonshivering thermogenesis (NST). This process is enabled by the presence of the unique mitochondrial protein, UCP1, which functions by uncoupling the process of substrate oxidation from ATP production, releasing the oxidized energy as heat Citation[1].
The re-emergence of scientific interest in BAT is fueled by its recent rediscovery in adult humans Citation[2] but it is, by no means, a ‘new human organ’. Historical reports of its presence date back to 1908 when Bonnot described an interscapular gland in adult cadavers Citation[3]. Brown adipocytes mainly use fatty acids as a substrate, and NST is activated by sympathetic stimulation on cold exposure. It is well known that BAT recruitment is enhanced by cold acclimation but the roles of other physiological and pharmacological agents that can recruit BAT and activate NST are less clear Citation[1]. Although studies have revealed the role of pharmacological agents such as novel β3-adrenoceptor agonists in activating BAT to increase energy expenditure Citation[4] their application to humans is as yet not feasible.
Diet-induced thermogenesis
Diet-induced thermogenesis (DIT) is the metabolic cost of processing food. Its obligatory component is the energy spent in digestion and assimilation of food. In addition, there may be a facultative component, possibly mediated by BAT, which generates additional heat and has been described as a special mechanism for extra energy dissipation in response to overnutrition Citation[5].
Although the role of BAT in DIT has been highly controversial, some new findings were presented at the meeting which support the case for BAT involvement. Studies are required to be conducted at thermoneutral temperatures in order to remove the confounding effect of thermogenesis induced by the relatively cool environment for rodents that are maintained in standard animal house temperatures (21–23°C). Studies at thermoneutrality found that mice fed with a high-fat diet recruit BAT, have higher oxygen consumption and enhanced response to norepinephrine. By contrast, UCP1 knockout mice do not demonstrate such changes. These findings, therefore, illustrate that signaling processes triggered by overfeeding can enhance BAT recruitment and activation and induce increased energy expenditure. However, high-fat diets or hyperphagia are not sufficient to recruit BAT by themselves and the role of the type of fat and other nutrients in the diet remains unresolved. It was also suggested that DIT might be ‘obesity induced thermogenesis’, wherein signals from WAT could act to promote the recruitment and thermogenesis in BAT.
Further support for the existence of DIT was presented in studies of imaging BAT in humans. Both thermal imaging and PET-computed tomography (CT) studies in humans have demonstrated some evidence to support the increased activation of BAT in response to meals.
Regulation of BAT
In addition to their presence in discrete BAT depots, brown adipocytes are also found in WAT depots – variously termed as brown-in-white (BRITE) or beige cells. These cells are distinct from classical brown adipocytes Citation[6] and develop from myogenic factor 5 expressing skeletal muscle precursors Citation[7].
NE stimulation, mediated by β3-adrenergic receptors, is the main activator of BAT Citation[1], but the detailed mechanisms and pathways involved in BAT development and regulation remain largely undetermined. The meeting provided a number of new insights in this area, such as the role of cholesterol ester transfer protein, which increases lipolysis and enhances β3-adrenergic receptor and UCP1 expression in transgenic mice, increasing energy expenditure and reducing adiposity. Early B-cell factor 2 expressed in myoblasts and white adipocyte precursor cells was reported to recruit the master transcription factor PPARγ and strongly activate transcription of PRDM16, a key regulator of thermogenic genes Citation[7] to brown-specific binding sites, reprogramming precursor cells to a brown adipocyte fate.
Novel studies involving other regulatory mechanisms were also presented. Prolactin-releasing peptide in the dorsomedial hypothalamic nuclei is an important component of the circuitry involved in sympathetic activation of BAT and the lack of its receptor, the G protein-coupled receptor 10, leads to obesity, reduced energy expenditure and shivering to maintain core body temperature despite adequate BAT thermogenic capacity. LR11, a neuronal apolipoprotein receptor implicated in Alzheimer’s disease, can negatively regulate thermogenesis in BAT and subcutaneous WAT, but only at thermoneutrality, suggesting a regulatory mechanism independent of adrenergic stimulation. Furthermore, shRNA depletion of pyruvate kinase M2 in white adipocytes promotes the development of a brown-like thermogenic program, and that subcutaneous injection of pyruvate kinase M2-deficient preadipocytes into mice gives rise to ectopic BAT depots. BMP8B is expressed in both BAT and the hypothalamus and was reported to regulate thermogenesis in conjunction with hypothalamic adenosine monophosphate-activated protein kinase Citation[8].
Imaging of BAT
BAT was rediscovered in adult humans due to chance findings on PET scan using 18F-fluorodeoxyglucose tracer combined with CT Citation[9].
At present, PET-CT scans remain the gold standard of imaging BAT and recent data using this technique demonstrate that while lean subjects have more cold-induced thermogenesis, this response decreases in the elderly. Further studies using PET-CT show that BAT activity, in adult humans, is enhanced by cold acclimation and significant reduction in BMI following bariatric surgery.
Despite its widespread use, PET-CT using 18F-fluorodeoxyglucose may not be the ideal method for BAT imaging. The main substrate of BAT is fatty acids, so measurement of glucose uptake may present an inaccurate picture and the use of alternative tracers such as 15O-labeled water for perfusion Citation[10], 18F-fluoro-6-thiaheptadecanoic acid for non-esterified fatty acid uptake and 11C-acetate for oxidative metabolism may be more appropriate. In addition, as the dose of radiation involved in PET-CT is high and does not lend itself to dynamic or repeated imaging in different physiological states, there is great interest in developing alternative imaging techniques.
Thermal imaging is one such modality Citation[11] and findings presented illustrated its role in demonstrating the effects of mild cold exposure, diet and BMI on the supraclavicular depot of BAT in humans. Despite the caveats that such superficial imaging may be confounded by blood flow and insulation from subcutaneous fat, thermal imaging has the potential to emerge as a noninvasive and cost-effective technique for dynamic imaging BAT in both humans and animals.
Other imaging modalities discussed included the use of MRI in humans and elegant experiments showing the delivery of lipophilic nutrients to brown and BRITE adipocytes in vivo, using lipoproteins engineered with superparamagnetic or fluorescent nanocrystals Citation[12].
Paracrine & endocrine role of BAT
It is now well recognized that WAT is an active endocrine organ that secretes numerous signaling molecules, such as adipokines Citation[13], which have both endocrine and paracrine effects. The role of BAT as a secretory organ is controversial, although it is being recognized that BAT may have some role as a producer of some hormones. Similar to WAT, BAT secretes retinol binding protein 4 which modulates insulin resistance and glucose metabolism and has a role in diabetes. Brown adipocytes are also a major site for synthesis of triiodothyronine, which may be released for systemic purposes in conditions of high BAT thermogenesis Citation[14]. Other adipokines, such as interleukins and IGF-1, may also be synthesized and secreted by brown adipocytes and it was reported at the meeting that, during active thermogenesis, BAT is a site for the NE-mediated synthesis and release of FGF-21 Citation[15].
The role of BAT in lipoprotein metabolism and brown adipocytes demonstrate a high uptake of triglyceride-rich lipoproteins Citation[12]. Findings presented at the meeting demonstrate the presence of BAT in vital locations such as the epicardial adipose tissue in humans where brown adipocytes may act as lipid clearing mechanisms to protect the myocardium and coronary vessels from hyperlipidemia.
It was proposed that although its exact role remains unclear, BAT may have some endocrine and paracrine influences that could explain the association between BAT activity and systemic metabolism even when amounts of BAT are scarce, as in adult humans. Further studies demonstrating the role of BAT in aging, shown by the increased life span of transgenic mice expressing UCP1 in skeletal muscles particularly when on a high-fat diet Citation[16], revealed new insights into the role of BAT in mammalian physiology.
BAT research is entering a new phase and the meeting highlighted the latest advances in understanding of BAT physiology, thermogenesis, molecular and genetic mechanisms underlying BAT development and activity as well as the application of various techniques to study the presence and activation of BAT in humans. Such studies have boundless potential to produce translational research for the prevention and treatment of obesity and the metabolic conditions with which it is associated.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
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