Editorial: Current Challenges for Targeting Brown Fat Thermogenesis to Combat Obesity

Frontiers in Endocrinology, vol. 11, pp. 600341

Abstract

Just over a decade has passed since metabolically active brown adipose tissue (BAT) was unequivocally identified in healthy adult humans. Since then, researchers have provided evidence of expression of the thermogenic molecule uncoupling protein 1 (UCP1) in human BAT, as well as its energy dissipating capacity. Additionally, clinical cross-sectional analysis suggested that a decline in BAT activity with aging, as judged from [ 18 F]FDG-PET/CT, coincides with the development of obesity and insulin resistance. These major observations provided a rationale to investigate BAT as a potential target for preventing obesity.Indeed, several studies have demonstrated that cold exposure and adrenomimetic agents strongly activate BAT thermogenesis, and thus energy expenditure in humans. However, the extent to which stimulating BAT thermogenesis decreases adiposity in humans remains unclear. Moreover, therapeutic strategies aimed at general stimulation of the sympathetic nervous system (SNS) and adrenergic receptors involved may not be applicable for obese and diabetic patients, because of potential negative side-effects on cardiovascular function.While implementation in humans remains challenging, recent studies in mice have yielded insights in molecular mechanisms underlying thermogenic regulation of brown and brown-like (brite/beige) adipocytes, highlighting their ability to reduce insulin resistance and atherosclerosis (1). These include identification of UCP1-independent thermogenesis as well as peripheral organderived endocrine factors and metabolites capable of triggering adipocyte thermogenesis. Activating these non-canonical mechanisms through genetic manipulation or pharmacological agents suppresses obesity and its associated complications in mice. The major challenge remains translating preclinical scientific advances to humans. To bridge basic research with clinical investigation, this Research Topic reviews the current advances in human BAT pathophysiology, novel molecular mechanisms regulating adipose thermogenesis, and remaining challenges in this field. In addition to the aforementioned imaging techniques, BAT functionality might be estimated from the circulating BAT-derived secretome (i.e. 'batokines') or microRNAs, although the utility of these metrics is debated. Similarly, BATassociated metabolites may well be indicative of BAT activity. In this regard, oxygenated polyunsaturated fatty acid metabolites (oxylipins), could be a surrogate marker for BAT activity and/or amount, as Dieckmann S et al. show that murine BAT is distinguishable from WAT by oxylipin profiling.These advances in non-invasive methodology are potentially valuable in performing future cross-sectional studies with large numbers of participants as well as longitudinal studies with repeated BAT measurements, thereby facilitating investigations into BAT biology in humans.The identification of novel molecular circuits involved in BAT thermogenesis may lead to the discovery of targetable pathways for the development of practicable pharmacotherapies for adiposity and related (cardio)The SNS is undoubtedly a central regulator of adipose thermogenesis. A concept gaining increasing attention is that non-neuronal systems can also In addition, mechanisms governing the generation of precursors committed to thermogenic adipocyte cell fate are poorly understood, especially in humans.Given the difficulty of obtaining an abundant source of human progenitors for study, pluripotent stem cells (PSCs), as implemented by Yao X et al., are promising tools to elucidate such mechanisms. However, several challenges have been presented, including the weak efficacy of thermogenic differentiation, which precludes greater utilization. Another future challenge will be the generation of efficient in vitro models resembling human adipose tissue.

Authors 4

1. Takeshi Yoneshiro corresponding

   The University of Tokyo · University of California, San Francisco

   Affiliation as printed

   Diabetes Center, University of California, San Francisco, San Francisco, CA, United States

   Division of Metabolic Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan

2. Rosalía Rodríguez‐Rodríguez

   Universitat Internacional de Catalunya

   Affiliation as printed

   Basic Sciences Department, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya, Barcelona, Spain

3. Matthias Johannes Betz

   University of Basel · University Hospital of Basel

   Affiliation as printed

   Department of Endocrinology, Diabetes and Metabolism, University Hospital Basel and University of Basel, Basel, Switzerland

4. Patrick C.N. Rensen Aachen Division of Endocrinology Department of Medicine, Leiden University Medical Center Einthoven Laboratory for Experimental Vascular Medicine

   Leiden University Medical Center

   Affiliation as printed

   Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, Netherlands

   Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, Netherlands