Elsevier

Pharmacology & Therapeutics

Volume 192, December 2018, Pages 141-149
Pharmacology & Therapeutics

Brown adipose tissue and lipid metabolism: New strategies for identification of activators and biomarkers with clinical potential

https://doi.org/10.1016/j.pharmthera.2018.07.002Get rights and content

Abstract

Development of therapeutic agents directed towards increasing brown adipose tissue (BAT) energy expenditure to combat obesity and its comorbidities is currently an area of intense research. Both preclinical and clinical studies have suggested a potentially significant role for BAT in regulating whole body energy expenditure as well as glucose and lipid metabolism. Lipids, particularly long chain fatty acids (LCFAs), are recognized as integral substrates in mediating the primary heat-producing functions of BAT, and to date thought to be principally sourced from stored intracellular lipid droplets. While this prior understanding is not disputed, recent evidence has demonstrated the importance of lipids derived from the circulation, including those from dietary sources and from tissue lipolysis, especially white adipose tissue lipolysis. Moreover, recent studies have shed further light on a potential role for BAT as an autocrine, paracrine and endocrine organ, with lipids as key signaling molecules. Advances in metabolomics have enabled high-resolution exploration of biomolecules that may be associated with various physiological processes and potentially pathological states. Such approaches have led to several novel lipid species recently being associated with BAT function and dysfunction. Further exploration of the circulating lipidome will likely reveal additional novel BAT biomarkers that can inform development of BAT-directed therapies. This review will address current progress and new strategies to identify and characterize BAT-associated lipids which may represent both novel activators and/or activity biomarkers with both research and clinical utility.

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.

References (108)

  • L. Kang et al.

    Nanocarrier-mediated co-delivery of chemotherapeutic drugs and gene agents for cancer treatment

    Acta Pharmaceutica Sinica B

    (2015)
  • C.M. Kastorini et al.

    The effect of Mediterranean diet on metabolic syndrome and its components: a meta-analysis of 50 studies and 534,906 individuals

    Journal of the American College of Cardiology

    (2011)
  • P. Lee et al.

    Non-pharmacological and pharmacological strategies of brown adipose tissue recruitment in humans

    Molecular and Cellular Endocrinology

    (2015)
  • M. Maeki et al.

    Advances in microfluidics for lipid nanoparticles and extracellular vesicles and applications in drug delivery systems

    Advanced Drug Delivery Reviews

    (2018)
  • P.J. Meikle et al.

    Lipidomics: potential role in risk prediction and therapeutic monitoring for diabetes and cardiovascular disease

    Pharmacology and Therapeutics

    (2014)
  • J. Nedergaard et al.

    The browning of white adipose tissue: some burning issues

    Cell Metabolism

    (2014)
  • J. Orava et al.

    Different metabolic responses of human brown adipose tissue to activation by cold and insulin

    Cell Metabolism

    (2011)
  • B.M. Owen et al.

    FGF21 acts centrally to induce sympathetic nerve activity, energy expenditure, and weight loss

    Cell Metabolism

    (2014)
  • T. Romu et al.

    A randomized trial of cold-exposure on energy expenditure and supraclavicular brown adipose tissue volume in humans

    Metabolism, Clinical and Experimental

    (2016)
  • M. Schiener et al.

    Nanomedicine-based strategies for treatment of atherosclerosis

    Trends in Molecular Medicine

    (2014)
  • F. Sofi et al.

    Accruing evidence on benefits of adherence to the Mediterranean diet on health: an updated systematic review and meta-analysis

    American Journal of Clinical Nutrition

    (2010)
  • L. Sun et al.

    A synopsis of brown adipose tissue imaging modalities for clinical research

    Diabetes & Metabolism

    (2017)
  • F. Villarroya et al.

    The Lives and Times of Brown Adipokines

    Trends in Endocrinology and Metabolism

    (2017)
  • G. Ailhaud et al.

    An emerging risk factor for obesity: does disequilibrium of polyunsaturated fatty acid metabolism contribute to excessive adipose tissue development?

    The British Journal of Nutrition

    (2008)
  • K. Almind et al.

    Ectopic brown adipose tissue in muscle provides a mechanism for differences in risk of metabolic syndrome in mice

    Proceedings of the National Academy of Sciences of the United States of America

    (2007)
  • Z.H. Alshehry et al.

    Plasma lipidomic profiles improve on traditional risk factors for the prediction of cardiovascular events in type 2 diabetes mellitus

    Circulation

    (2016)
  • M.N. Barber et al.

    Plasma lysophosphatidylcholine levels are reduced in obesity and type 2 diabetes

    PLoS One

    (2012)
  • A. Bartelt et al.

    Brown adipose tissue activity controls triglyceride clearance

    Nature Medicine

    (2011)
  • A. Bartelt et al.

    Thermogenic adipocytes promote HDL turnover and reverse cholesterol transport

    Nature Communications

    (2017)
  • J.F. Berbee et al.

    Brown fat activation reduces hypercholesterolaemia and protects from atherosclerosis development

    Nature Communications

    (2015)
  • D.P. Blondin et al.

    Selective impairment of glucose but not fatty acid or oxidative metabolism in brown adipose tissue of subjects with type 2 diabetes

    Diabetes

    (2015)
  • D.P. Blondin et al.

    Increased brown adipose tissue oxidative capacity in cold-acclimated humans

    The Journal of Clinical Endocrinology and Metabolism

    (2014)
  • M.R. Boon et al.

    LysoPC-acyl C16:0 is associated with brown adipose tissue activity in men

    Metabolomics

    (2017)
  • P. Bostrom et al.

    A PGC1-alpha-dependent myokine that drives brown-fat-like development of white fat and thermogenesis

    Nature

    (2012)
  • Bray, G. A., & Ryan, D. H. (2014). Update on obesity pharmacotherapy. Annals of the New York Academy of Sciences, 1311,...
  • B. Cannon et al.

    Brown adipose tissue: function and physiological significance

    Physiological Reviews

    (2004)
  • A.L. Carey et al.

    Ephedrine activates brown adipose tissue in lean but not obese humans

    Diabetologia

    (2013)
  • A.L. Carey et al.

    Novel pharmacological approaches to combat obesity and insulin resistance: targeting skeletal muscle with 'exercise mimetics'

    Diabetologia

    (2009)
  • A.L. Carey et al.

    Chronic ephedrine administration decreases brown adipose tissue activity in a randomised controlled human trial: implications for obesity

    Diabetologia

    (2015)
  • M. Chondronikola et al.

    Brown adipose tissue improves whole-body glucose homeostasis and insulin sensitivity in humans

    Diabetes

    (2014)
  • S. Cinti

    Transdifferentiation properties of adipocytes in the adipose organ

    American Journal of Physiology. Endocrinology and Metabolism

    (2009)
  • C. Cohade et al.

    Uptake in supraclavicular area fat ("USA-Fat"): description on 18F-FDG PET/CT

    Journal of Nuclear Medicine

    (2003)
  • A.M. Cypess et al.

    Cold but not sympathomimetics activates human brown adipose tissue in vivo

    Proceedings of the National Academy of Sciences of the United States of America

    (2012)
  • A.M. Cypess et al.

    Identification and importance of brown adipose tissue in adult humans

    The New England Journal of Medicine

    (2009)
  • A.M. Cypess et al.

    Anatomical localization, gene expression profiling and functional characterization of adult human neck brown fat

    Nature Medicine

    (2013)
  • F. De Lorenzo et al.

    Central cooling effects in patients with hypercholesterolaemia

    Clinical Science (London, England : 1979)

    (1998)
  • A.A. van der Lans et al.

    Cold acclimation recruits human brown fat and increases nonshivering thermogenesis

    The Journal of Clinical Investigation

    (2013)
  • K. Eisinger et al.

    Lipidomic analysis of serum from high fat diet induced obese mice

    International Journal of Molecular Sciences

    (2014)
  • K. Esposito et al.

    Mediterranean diet and weight loss: meta-analysis of randomized controlled trials

    Metabolic Syndrome and Related Disorders

    (2011)
  • F.M. Fisher et al.

    FGF21 regulates PGC-1alpha and browning of white adipose tissues in adaptive thermogenesis

    Genes and Development

    (2012)
  • Cited by (10)

    • Inducible beige adipocytes improve impaired glucose metabolism in interscapular BAT-removal mice

      2021, Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
      Citation Excerpt :

      In human adults, beige adipocytes are present in supraclavicular fat of human body [15,16]. The activation of brown adipocytes has been considered as an attractive target for therapeutic interventions in obesity and metabolic diseases [17–21]. Studies in mouse models have shown that BAT activation can improve hyperlipidemia and harmful effects of obesity [5,22].

    • The role of brown and beige adipose tissue in glycaemic control

      2019, Molecular Aspects of Medicine
      Citation Excerpt :

      However, the main difficulty in establishing reliable biomarkers lies in the identification of molecules that are selective for BAT (Chen et al., 2016; Nakhuda et al., 2016). Perhaps a combination of several biomarkers could provide a more accurate estimation of BAT activity; the increasing use of screening methods for BAT-secreted factors and metabolites will most certainly help to achieve this goal (Xiang et al., 2018). Current experimental advancements in the measurement of human BAT activity include (less invasive) infrared thermography, magnetic resonance spectroscopy and MRI (Hu et al., 2013; Lee et al., 2011; Raiko et al., 2015).

    • Environmental Endocrinology: Basic Concepts

      2023, Endocrinology (Switzerland)
    View all citing articles on Scopus
    View full text