Brown adipose tissue and lipid metabolism: New strategies for identification of activators and biomarkers with clinical potential
Introduction
Pharmacological activation of brown adipose tissue (BAT) is an attractive therapeutic strategy which may contribute to the prevention and management of obesity. The underlying physiology relates to the capacity of BAT for non-shivering thermogenesis and the associated energy expenditure that fuels this heat production. BAT thermogenesis is mediated primarily by uncoupling protein-1 (UCP-1), a thermogenic protein unique to BAT, located in the inner mitochondrial membrane (Cannon & Nedergaard, 2004; Cypess et al., 2009).
Key to the therapeutic potential of BAT is its high functional plasticity. BAT is able to vary its heat production and energy expenditure through both acute and adaptive processes, which are primarily driven by environmental temperature cues. In thermoneutral conditions, BAT thermogenic activity is very low due to inhibitory adenine nucleotides bound to UCP-1 within the mitochondrial intermembrane space, and thus the electrochemical gradient generated through cellular respiration is ‘coupled’ to adenosine triphosphate (ATP) synthesis (Fig. 1) (Fedorenko, Lishko, & Kirichok, 2012). Acute, or facultative, BAT thermogenesis in response to cold exposure is initiated by sympathetic nervous system activation targeted to β-adrenoceptors on brown adipocytes. This increases lipolysis and therefore the intracellular concentration of long-chain fatty acids (LCFAs, 14 or more carbons) that competitively displace bound adenine nucleotides and activate UCP-1 (Fedorenko et al., 2012), leading to thermogenesis and energy expenditure as the electrochemical gradient is rapidly dissipated by UCP-1 (Cannon and Nedergaard, 2004, Cannon and Nedergaard, 2017). In parallel, similar sympathetic activity directed to white adipocytes increases rates of lipolysis, causing an increase in plasma LCFAs which can be taken up from the circulation by BAT to activate UCP-1 and fuel BAT thermogenesis (Schreiber et al., 2017; Shin et al., 2017).
The degree of BAT facultative thermogenesis upon acute activation is determined by the prevailing ambient temperature conditions experienced over weeks-to-months, which drives various sympathetic-mediated adaptations that alter the thermogenic potential of brown adipocytes (Fig. 2) (Loh, Kingwell, & Carey, 2017). These adaptive changes occur both at a tissue level (such as changes in vascularity, innervation and mass) and on a cellular level (changes in thermogenic gene expression programs, key signaling intermediates, mitochondrial density and UCP-1 protein content) (Cannon & Nedergaard, 2004; Wang & Seale, 2016). This process is bi-directional (Rosenwald, Perdikari, Rulicke, & Wolfrum, 2013) and in rodents, can occur in virtually all adipose tissues to some degree (Cinti, 2009; Kalinovich, de Jong, Cannon, & Nedergaard, 2017). Human clinical trials have focused predominantly on induction of cold-stimulated pro-thermogenic adaptation of BAT. This adaptation, termed ‘browning’ (Kajimura et al., 2008) increases BAT facultative thermogenesis and energy expenditure to a given stimulus (Fig. 2) (Blondin et al., 2014; Lee et al., 2014; van der Lans et al., 2013; Yoneshiro et al., 2013). In addition to the well-described pro-thermogenic response to cold, preclinical studies have revealed several endogenous molecules which may induce browning and present potential as therapeutic candidates (Fisher et al., 2012; Montanari, Poscic, & Colitti, 2017; Owen et al., 2014; Villarroya, Cereijo, et al., 2017).
Section snippets
Brown adipose tissue energy expenditure and obesity
Obesity is the primary pathology that development of BAT-directed therapeutics aims to address. Combining contemporary estimates of the rates of human BAT energy expenditure (Carey & Kingwell, 2013; Muzik et al., 2013) with a recently expanded approximation of adult human BAT volume (Leitner et al., 2017), thermogenic adaptation and activation of all adult human adipose tissue capable of browning could significantly increase whole body energy expenditure well beyond previous estimates.
Current status of pharmacological BAT activation in humans
A number of objectives must first be achieved before novel pharmacological BAT-directed therapies can be developed. These, include identification of novel molecules associated with BAT activation which can be further explored for therapeutic benefit and development of an accurate method to measure BAT activity and energy expenditure in humans.
To date, all potential BAT-activating agents examined in human trials have demonstrated various limitations which prevent clinical translation (Lee &
Lipidomic strategies to identify BAT activators and biomarkers
The integral relationship between lipids and BAT function (Fig. 3) suggest that they may represent both potential stimulatory agents and novel biomarkers of BAT function which could be harnessed for therapeutic use. Thus, identification and further exploration of lipids associated with BAT represents a promising strategy to address both of the aforementioned objectives.
Advances in metabolomics and specifically lipidomics provides a platform for discovery of novel plasma lipid species associated
Circulating lipids modulating BAT function
The role of LCFAs in activating UCP-1 by competitively displacing inhibitory adenine nucleotides bound to UCP-1 has been known for almost five decades (Fedorenko et al., 2012; Rafael, Ludolph, & Hohorst, 1969). Initially, it was thought that intracellular LCFAs mobilized through β-adrenergically stimulated BAT adipose triglyceride lipase (ATGL) activity would be essential for maximal activation of UCP-1 and the primary substrate for BAT thermogenesis (Cannon and Nedergaard, 2004, Cannon and
BAT-associated lipids and the plasma lipidome
BAT likely influences the plasma lipidome both directly through uptake and secretion of lipid species, but also indirectly via signaling to distant tissues.
Progress in lipidomic assessment of BAT-associated plasma lipids
Lipidomic analysis of 88 lipid species in human serum recently identified 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME) (Fig. 4), a cytochrome P450-derived linoleic acid metabolite (Zimmer et al., 2018), as the sole lipid which increased following cold exposure in all study participants (Lynes et al., 2017). Plasma concentration of 12,13-diHOME was significantly associated with [18F]FDG uptake before and after acute cold challenge in these individuals. Subsequent mouse experiments
Conclusion
BAT has potential as a therapeutic target for obesity and associated metabolic disorders, with human studies demonstrating improvement in disease markers in association with increased BAT function. However, small human trials of agents directed to mimic BAT cold-adaptation have all demonstrated significant limitations. Additionally, whilst impaired BAT function has been implicated in the pathophysiology of these conditions, a causal role for impaired BAT function in human metabolic disease has
Written declaration
This manuscript has not been published and is not under consideration for publication elsewhere.
Conflict of interest statement
Professors Kingwell and Meikle have licensed lipid biomarkers to Zora Biosciences Oy, Finland. The other authors report no disclosures.
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