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Browning and thermogenic programing of adipose tissue
Accepted Manuscript Browning and thermogenic programing of adipose tissue Florian W. Kiefer, MD, PhD
PII:
S1521-690X(16)30051-3
DOI:
10.1016/j.beem.2016.09.003
Reference:
YBEEM 1112
To appear in:
Best Practice & Research Clinical Endocrinology & Metabolism
Please cite this article as: Kiefer FW, Browning and thermogenic programing of adipose tissue, Best Practice & Research Clinical Endocrinology & Metabolism (2016), doi: 10.1016/j.beem.2016.09.003. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Browning and thermogenic programing of adipose tissue
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Florian W. Kiefer, MD, PhD
Clinical Division of Endocrinology and Metabolism, Department of Medicine III, Medical
University of Vienna, Waehringer Guertel 18 – 20, A-1090 Vienna, Tel: +43 1 40400 43120,
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email: [email protected]
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Key words: beige and brown adipocytes, thermogenesis, energy expenditure
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Abstract The view of adipose tissue as solely a fat storing organ has changed significantly over the past two decades with the discoveries of numerous adipocyte-secreted factors, so called
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adipokines, and their endocrine functions throughout the body. The newest chapter added to this story is the finding that adipose tissue is also a thermogenic organ contributing to energy expenditure through actions of specialized, heat-producing brown or beige
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adipocytes. In contrast to bone fide brown adipocytes, beige cells develop within white fat depots in response to various stimuli such as prolonged cold exposure, underscoring the
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great thermogenic plasticity of adipose tissue. The energy dissipating properties of beige and/or brown adipocytes hold great promise as a novel therapeutic concept against obesity and related complications. Hence, identifying the specific thermogenic adipocyte populations in humans and their pathways of activation are key milestones of current
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metabolism research. Here we will discuss the recent advances in the understanding of the
Introduction
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molecular and physiological mechanisms of adipose tissue browning.
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Due to its energy dissipating and anti-obesity properties, brown adipose tissue (BAT) has become a major focus of metabolism research in recent years. The discovery of active BAT in humans by
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fluorodeoxyglucose positron emission tomography coupled with computed
tomography ([18F]-FDG-PET/CT) and the negative correlation between BAT activity and obesity have further spurred interest in harnessing the therapeutic potential of brown fat ([1-3] and extensively reviewed in this issue of Best Pract Res Clin Endocrinol Metab). In contrast to white adipose tissue (WAT), brown fat is specialized in energy expenditure
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through uncoupled respiration which is predominantly mediated by the major thermogenic factor uncoupling protein- 1 (UCP-1). This process results in increased fatty acid oxidation and the generation of heat (thermogenesis) [4, 5]. In addition to bone fide WAT and BAT,
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another fat type has recently been identified called “beige” or “brite” (from brown and white). A unique feature of beige adipocytes is that they possess characteristics of both, white and brown adipocytes. In response to cold or certain pharmacological or genetic
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stimuli, UCP-1 expressing beige adipocytes can emerge within white adipose depots and waste significant amounts of chemical energy, similar to classic brown fat cells. This
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phenomenon, called browning or beiging, is associated with significant protection against obesity and related metabolic complications in numerous preclinical models [6-8]. Hence, browning of WAT has evolved as an intriguing concept for the treatment of obesity in humans. Recent research has therefore concentrated on the identification of the cellular
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origin and the factors regulating the formation of beige adipocytes.
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Fat comes in different colors – white, beige, and brown In principle three types of fat have been described in mammals with very distinct
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characteristics based on anatomical location, morphology, developmental origin, and function (Fig. 1 and [9, 10]). The differences between white, beige, and brown adipocytes will be highlighted here with particular emphasis on beige cells given their most recent discovery and their unique role in the browning of adipose tissue. A. Anatomical location The distribution of distinct fat cell types throughout the body has been studied predominantly in mice but recent clinical studies have tried to compare the results from
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rodents with humans [11, 12]. Classic white adipocytes are located in fat depots throughout the body with some compartments such as the visceral fat showing higher exclusivity for white adipocytes than others [13]. Beige adipocytes can emerge within certain WAT depots;
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the subcutaneous fat of the inguinal or axillary region of rodents has been shown to be particularly susceptible to the induction of beige cells [14]. However, our own work has demonstrated that also the visceral fat compartment can undergo dramatic thermogenic
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remodeling [15]. The bone fide brown adipocytes reside in dedicated depots which are mainly located in the interscapular and cervical region in mice [13, 16]. In humans FDG-
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positive brown fat is most typically found in the cervical, supraclavicular, parasternal, and sometimes perirenal region [1-3, 17, 18]. The close proximity to the vasculature of the neck has led to evolutionary speculations that the heat generating qualities of BAT may have been
B. Morphology
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relevant for temperature regulation of the blood flowing to the brain.
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The morphological differences between white and brown fat are already evident on a macroscopic level. Brown fat appears much darker due to its high number of (iron-
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containing) mitochondria [19]. Microscopically, white adipocytes possess one large lipid droplet (Fig. 1A), whereas brown adipocytes have multilocular lipid droplets (Fig. 1C) which allow for faster mobilization of lipid stores and fatty acid oxidation. Beige fat contains both, white and brown shaped cells and has therefore a greater variability in lipid droplet size (Fig. 1B and [8, 13]).
C. Beige adipocytes are inducible
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A hallmark of the browning process is the emergence of UCP-1 expressing beige adipocytes within white fat depots. Whereas very few or no beige cells are present in white fat at thermoneutrality, prolonged cold exposure significantly increases the number of beige
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adipocytes particularly in subcutaneous fat depots. In addition to cold exposure, a large number of other factors have been identified to contribute to the thermogenic programming of adipose tissue. Amongst these factors are transcriptional (co)regulators, circulating
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molecules, and pharmacological substances such sympathomimetics [6-8, 13, 20, 21]. Some of the endocrine factors that are involved in the regulation of adipose browning will be
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reviewed later in this manuscript. The aforementioned “inducibility” of beige cells does not only occur in vivo but can also be reproduced on a molecular level in vitro. When comparing the expression of classic brown fat marker genes of isolated adipocytes, beige cells have a very similar genetic signature as white adipocytes under basal conditions. However in
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response to stimulation with adrenergic agonists, expression of brown fat marker genes and cellular respiration are particularly increased in the beige cells, now mimicking the molecular and functional characteristics of bone fide brown fat cells [9, 22].
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A very recent report showed that browning of WAT can also occur in humans. In this study in intensive care patients the authors found that severe burn injuries led to an increase of UCP-
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1 positive beige cells within the subcutaneous fat with a maximum several weeks after the injury. This observation was linked to the severe adrenergic stress and the prolonged elevation of norepinephrine levels seen after such burn injuries [23].
D. Developmental origin
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The developmental origin of the various fat cell types is a current matter of heavy investigations and the number of genetic factors controlling the fate of adipocyte precursors is constantly growing. Elegant lineage tracing studies have been performed to determine
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the progenitor cells that give rise to distinct adipocyte populations. This work has been extensively reviewed elsewhere [13, 21, 24, 25]. With respect to beige adipocyte formation, two general concepts have been proposed. One is the precursor model which suggests that
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beige adipocytes are derived from distinct progenitor cells upon certain stimuli such as cold exposure or beta adrenergic stimulation [26]. The other concept is the transdifferentiation
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model or as it should be rather called the interconversion model because it proposes that mature white adipocytes can convert into beige adipocytes when appropriately challenged [27, 28]. There is high-quality evidence from the aforementioned lineage tracing studies for both theories, so it is reasonable to assume that both are correct. It is also possible that
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additional factors such as the genetic background, the environment (e.g. ambient temperature), or fat depot-specific differences determine how the beige cells are ultimately formed. In line with this notion, large variabilities in the browning capacity of WAT have
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been found between different mouse strains supporting the view that the genetic
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background is predetermining the potential for adipose tissue browning [29, 30].
Is human BAT brown or beige? In 2009 three groups reported independently that active BAT is present in adult humans and that it can be detected by [18F]-FDG-PET/CT [1-3]. Human BAT activation can be achieved through moderate cold exposure which results in increased resting energy expenditure [17, 31, 32] and when performed chronically over a period of several weeks leads to a reduction of body fat mass [33]. A negative association between cold-induced BAT activity and the
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degree of obesity has been reported [34], however it is still a matter of debate what is cause and consequence. Ever since these discoveries researcher have tried to better understand the biology and physiology of human brown fat. Therefore biopsy studies have been
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performed from FDG positive or negative fat depots to determine the molecular signature of human BAT and to analyze functional characteristics such as cell respiration and mitochondrial enzyme activity. By comparing the results from human fat biopsies with those
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from mouse fat depots, researchers have tried to address the question whether human BAT resembles the molecular and functional aspects of bone fide brown or beige fat [11, 12, 35-
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37]. Not surprisingly there is evidence for both, which can in part be explained by the large heterogeneity of the human fat samples studied. FDG-positive BAT depots are often located in deep neck areas and are therefore not easily accessible. Another caveat most of these studies have in common is the fact that the marker genes that are used for genetic profiling
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of the human BAT depots have previously been identified in mouse tissues and may not be the appropriate markers to distinguish between beige and brown fat in humans. Nevertheless human BAT is a metabolically highly active tissue with a respiratory capacity up
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to 50-fold greater than WAT and comparable to rodent BAT when normalized to the
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mitochondrial content [37].
Endocrine regulators of the adipose thermogenic program The list of identified endogenous factors controlling BAT activity or browning of WAT is constantly growing; some of these factors are circulating hormones secreted from various tissues including liver, skeletal muscle, or heart emphasizing that the thermogenic programming of adipose tissue is at least in part mediated by an active interorgan crosstalk [6, 8].
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A. FNDC5/Irisin One of these endocrine factors that has recently received a lot of interest is the myokine irisin, termed after the Greek messenger goddess Iris. Irisin is the cleavage product of the
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membrane protein fibronectin type III domain-containing protein 5 (FNDC5) whose expression is increased in response to exercise in human and murine skeletal muscle. Irisin stimulates the browning of WAT through specific actions on the preadipocyte population but
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also induces thermogenic gene expression in mature adipocytes [38, 39]. Currently there is some discussion about the regulation of irisin concentrations in human studies with some
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inconsistent results being published [40, 41]. Of course, as with any new hormone, there are many open questions such as: what is the irisin receptor in adipocytes and what is the downstream signal? Is the cleavage of FNDC5 into irisin a regulated process? It will be imperative to address these questions if this pathway wants to be pursued as a therapeutic
B. FGF21
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approach.
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Another hormone that has been in the center of attention is fibroblast growth factor 21 (FGF21) which is mainly secreted by the liver but is also expressed in other tissues. FGF21
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has become a focus of clinical trials for obesity and diabetes because it has many beneficial effects on metabolism including increased glucose uptake, improved insulin sensitivity, and weight reduction [42]. FGF21 acts in concert with the cofactor β-Klotho which is required for interaction with FGF receptors. Some of the FGF21 actions are mediated by stimulating fatty acid oxidation and energy dissipation through browning of adipocytes [43]. In humans circulating FGF21 correlates with brown fat activity determined by FDG uptake in PET/CT studies and in human brown adipocytes FGF21 and FNDC5 have additive effects on norepinephrine stimulated thermogenesis [44, 45].
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C. Natriuretic peptides There is also accumulating evidence of a cross talk between the heart and the adipose tissue. Not only are adipokines contributing to cardiovascular function but also heart hormones
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such as the natriuretic peptides can control fat function including non-shivering thermogenesis and fatty acid oxidation [46]. For instance infusion of the brain natriuretic peptide which is usually elevated in heart failure patients causes increased UCP-1 expression
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in subcutaneous fat and enhanced energy expenditure in mice [47]. These findings also raised the question whether the energy dissipating actions of natriuretic peptides can
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promote cachexia as observed in end stage heart failure patients. D. Parathyroid hormone (PTH) and PTH-related peptide
Browning-induced cachexia has in fact been demonstrated in two other mouse models, one
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being lung cancer and the other being kidney failure. Particularly interesting from the perspective of an endocrinologist is that the browning process in both models was PTH receptor dependent. In one study the authors performed partial nephrectomy in mice to
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induce secondary hyperparathyroidism [48]. In another study also done in Bruce Spiegelman’s lab, a Lewis lung carcinoma model was used which is associated with
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paraneoplastic PTH-related peptide secretion [49]. Elevated concentrations of both, PTH and PTH-related peptide resulted in increased energy wasting and worsening of cachexia in these mouse models of kidney failure and lung cancer. However these effects were abolished in adipose tissue PTH receptor knockout mice arguing for a fat-specific PTH receptor signaling pathway. Intrigued by these results they went on to study neck fat biopsies from subjects with primary hyperparathyroidism and healthy controls and found increased expression of some of the browning markers in patients with hyperparathyroidism. These studies emphasize that there may be medical conditions such as certain types of cancer, in which
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the promotion of brown fat thermogenesis and energy expenditure may not be beneficial at
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all but may in fact become a target for therapeutic inhibition.
Summary
Accumulating evidence from preclinical studies suggests that exploiting the thermogenic
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function of brown and/or beige fat could be an effective treatment for obesity, type 2 diabetes, and associated complications. Given the overabundance of WAT in obese subjects,
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reprogramming of white fat depots towards an energy dissipating organ poses a particularly intriguing concept. This browning process has been successfully achieved in numerous animal studies and proof-of-concept has also been demonstrated in humans. However, the specific human adipocyte populations capable of acquiring a brown-like phenotype and the
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detailed molecular mechanisms leading to this phenotype are still being investigated. A large number of factors including some endocrine mediators has already been identified to regulate the thermogenic programming of WAT and new pathways are constantly added.
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The β3-agonist mirabegron, a drug only approved for the treatment of overactive bladder, has recently been shown to activate pre-existing BAT in humans similar to cold exposure
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[50]. While it remains to be seen in additional studies if mirabegron can effectively reduce excess body weight, no approved pharmacological substances yet exist to induce browning of WAT in humans. Given that energy homeostasis is a tightly controlled process, it will be interesting to see whether enhanced energy expenditure through brown of beige fat based therapies will be compensated by other mechanisms such as increased hunger and food intake.
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Practice Points •
Promotion of BAT or browning of WAT have shown great promise as anti-obesity strategies in preclinical studies
browning process •
Beige adipocytes possess characteristics of both, white and brown fat cells depending upon endogenous or external stimuli
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The emergence of thermogenically active beige adipocytes is a hallmark of the
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Activation of BAT and browning of WAT can also occur in humans and is associated
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with enhanced energy expenditure
Research Agenda
To date no pharmacological therapies exist to induce browning of WAT in humans
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A better understanding of the heterogeneous brown/beige fat cell population in
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humans is essential for the development of novel therapeutic concepts Factors controlling the thermogenic programming of adipocytes are currently heavily
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•
investigated
It remains to be seen whether increased energy expenditure through therapeutic
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activation of BAT or beige fat is sufficient to maintain weight loss in humans or if compensatory mechanisms such as increased food intake will mitigate the effects
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Figure 1:
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Representative hematoxylin and eosin staining of (A) white, (B) beige, and (C) brown adipose tissue from mice.
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PII:
S1521-690X(16)30051-3
DOI:
10.1016/j.beem.2016.09.003
Reference:
YBEEM 1112
To appear in:
Best Practice & Research Clinical Endocrinology & Metabolism
Please cite this article as: Kiefer FW, Browning and thermogenic programing of adipose tissue, Best Practice & Research Clinical Endocrinology & Metabolism (2016), doi: 10.1016/j.beem.2016.09.003. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Browning and thermogenic programing of adipose tissue
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Florian W. Kiefer, MD, PhD
Clinical Division of Endocrinology and Metabolism, Department of Medicine III, Medical
University of Vienna, Waehringer Guertel 18 – 20, A-1090 Vienna, Tel: +43 1 40400 43120,
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email: [email protected]
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Key words: beige and brown adipocytes, thermogenesis, energy expenditure
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Abstract The view of adipose tissue as solely a fat storing organ has changed significantly over the past two decades with the discoveries of numerous adipocyte-secreted factors, so called
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adipokines, and their endocrine functions throughout the body. The newest chapter added to this story is the finding that adipose tissue is also a thermogenic organ contributing to energy expenditure through actions of specialized, heat-producing brown or beige
SC
adipocytes. In contrast to bone fide brown adipocytes, beige cells develop within white fat depots in response to various stimuli such as prolonged cold exposure, underscoring the
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great thermogenic plasticity of adipose tissue. The energy dissipating properties of beige and/or brown adipocytes hold great promise as a novel therapeutic concept against obesity and related complications. Hence, identifying the specific thermogenic adipocyte populations in humans and their pathways of activation are key milestones of current
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metabolism research. Here we will discuss the recent advances in the understanding of the
Introduction
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molecular and physiological mechanisms of adipose tissue browning.
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Due to its energy dissipating and anti-obesity properties, brown adipose tissue (BAT) has become a major focus of metabolism research in recent years. The discovery of active BAT in humans by
18
fluorodeoxyglucose positron emission tomography coupled with computed
tomography ([18F]-FDG-PET/CT) and the negative correlation between BAT activity and obesity have further spurred interest in harnessing the therapeutic potential of brown fat ([1-3] and extensively reviewed in this issue of Best Pract Res Clin Endocrinol Metab). In contrast to white adipose tissue (WAT), brown fat is specialized in energy expenditure
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through uncoupled respiration which is predominantly mediated by the major thermogenic factor uncoupling protein- 1 (UCP-1). This process results in increased fatty acid oxidation and the generation of heat (thermogenesis) [4, 5]. In addition to bone fide WAT and BAT,
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another fat type has recently been identified called “beige” or “brite” (from brown and white). A unique feature of beige adipocytes is that they possess characteristics of both, white and brown adipocytes. In response to cold or certain pharmacological or genetic
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stimuli, UCP-1 expressing beige adipocytes can emerge within white adipose depots and waste significant amounts of chemical energy, similar to classic brown fat cells. This
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phenomenon, called browning or beiging, is associated with significant protection against obesity and related metabolic complications in numerous preclinical models [6-8]. Hence, browning of WAT has evolved as an intriguing concept for the treatment of obesity in humans. Recent research has therefore concentrated on the identification of the cellular
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origin and the factors regulating the formation of beige adipocytes.
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Fat comes in different colors – white, beige, and brown In principle three types of fat have been described in mammals with very distinct
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characteristics based on anatomical location, morphology, developmental origin, and function (Fig. 1 and [9, 10]). The differences between white, beige, and brown adipocytes will be highlighted here with particular emphasis on beige cells given their most recent discovery and their unique role in the browning of adipose tissue. A. Anatomical location The distribution of distinct fat cell types throughout the body has been studied predominantly in mice but recent clinical studies have tried to compare the results from
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rodents with humans [11, 12]. Classic white adipocytes are located in fat depots throughout the body with some compartments such as the visceral fat showing higher exclusivity for white adipocytes than others [13]. Beige adipocytes can emerge within certain WAT depots;
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the subcutaneous fat of the inguinal or axillary region of rodents has been shown to be particularly susceptible to the induction of beige cells [14]. However, our own work has demonstrated that also the visceral fat compartment can undergo dramatic thermogenic
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remodeling [15]. The bone fide brown adipocytes reside in dedicated depots which are mainly located in the interscapular and cervical region in mice [13, 16]. In humans FDG-
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positive brown fat is most typically found in the cervical, supraclavicular, parasternal, and sometimes perirenal region [1-3, 17, 18]. The close proximity to the vasculature of the neck has led to evolutionary speculations that the heat generating qualities of BAT may have been
B. Morphology
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relevant for temperature regulation of the blood flowing to the brain.
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The morphological differences between white and brown fat are already evident on a macroscopic level. Brown fat appears much darker due to its high number of (iron-
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containing) mitochondria [19]. Microscopically, white adipocytes possess one large lipid droplet (Fig. 1A), whereas brown adipocytes have multilocular lipid droplets (Fig. 1C) which allow for faster mobilization of lipid stores and fatty acid oxidation. Beige fat contains both, white and brown shaped cells and has therefore a greater variability in lipid droplet size (Fig. 1B and [8, 13]).
C. Beige adipocytes are inducible
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A hallmark of the browning process is the emergence of UCP-1 expressing beige adipocytes within white fat depots. Whereas very few or no beige cells are present in white fat at thermoneutrality, prolonged cold exposure significantly increases the number of beige
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adipocytes particularly in subcutaneous fat depots. In addition to cold exposure, a large number of other factors have been identified to contribute to the thermogenic programming of adipose tissue. Amongst these factors are transcriptional (co)regulators, circulating
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molecules, and pharmacological substances such sympathomimetics [6-8, 13, 20, 21]. Some of the endocrine factors that are involved in the regulation of adipose browning will be
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reviewed later in this manuscript. The aforementioned “inducibility” of beige cells does not only occur in vivo but can also be reproduced on a molecular level in vitro. When comparing the expression of classic brown fat marker genes of isolated adipocytes, beige cells have a very similar genetic signature as white adipocytes under basal conditions. However in
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response to stimulation with adrenergic agonists, expression of brown fat marker genes and cellular respiration are particularly increased in the beige cells, now mimicking the molecular and functional characteristics of bone fide brown fat cells [9, 22].
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A very recent report showed that browning of WAT can also occur in humans. In this study in intensive care patients the authors found that severe burn injuries led to an increase of UCP-
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1 positive beige cells within the subcutaneous fat with a maximum several weeks after the injury. This observation was linked to the severe adrenergic stress and the prolonged elevation of norepinephrine levels seen after such burn injuries [23].
D. Developmental origin
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The developmental origin of the various fat cell types is a current matter of heavy investigations and the number of genetic factors controlling the fate of adipocyte precursors is constantly growing. Elegant lineage tracing studies have been performed to determine
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the progenitor cells that give rise to distinct adipocyte populations. This work has been extensively reviewed elsewhere [13, 21, 24, 25]. With respect to beige adipocyte formation, two general concepts have been proposed. One is the precursor model which suggests that
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beige adipocytes are derived from distinct progenitor cells upon certain stimuli such as cold exposure or beta adrenergic stimulation [26]. The other concept is the transdifferentiation
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model or as it should be rather called the interconversion model because it proposes that mature white adipocytes can convert into beige adipocytes when appropriately challenged [27, 28]. There is high-quality evidence from the aforementioned lineage tracing studies for both theories, so it is reasonable to assume that both are correct. It is also possible that
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additional factors such as the genetic background, the environment (e.g. ambient temperature), or fat depot-specific differences determine how the beige cells are ultimately formed. In line with this notion, large variabilities in the browning capacity of WAT have
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been found between different mouse strains supporting the view that the genetic
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background is predetermining the potential for adipose tissue browning [29, 30].
Is human BAT brown or beige? In 2009 three groups reported independently that active BAT is present in adult humans and that it can be detected by [18F]-FDG-PET/CT [1-3]. Human BAT activation can be achieved through moderate cold exposure which results in increased resting energy expenditure [17, 31, 32] and when performed chronically over a period of several weeks leads to a reduction of body fat mass [33]. A negative association between cold-induced BAT activity and the
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degree of obesity has been reported [34], however it is still a matter of debate what is cause and consequence. Ever since these discoveries researcher have tried to better understand the biology and physiology of human brown fat. Therefore biopsy studies have been
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performed from FDG positive or negative fat depots to determine the molecular signature of human BAT and to analyze functional characteristics such as cell respiration and mitochondrial enzyme activity. By comparing the results from human fat biopsies with those
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from mouse fat depots, researchers have tried to address the question whether human BAT resembles the molecular and functional aspects of bone fide brown or beige fat [11, 12, 35-
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37]. Not surprisingly there is evidence for both, which can in part be explained by the large heterogeneity of the human fat samples studied. FDG-positive BAT depots are often located in deep neck areas and are therefore not easily accessible. Another caveat most of these studies have in common is the fact that the marker genes that are used for genetic profiling
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of the human BAT depots have previously been identified in mouse tissues and may not be the appropriate markers to distinguish between beige and brown fat in humans. Nevertheless human BAT is a metabolically highly active tissue with a respiratory capacity up
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to 50-fold greater than WAT and comparable to rodent BAT when normalized to the
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mitochondrial content [37].
Endocrine regulators of the adipose thermogenic program The list of identified endogenous factors controlling BAT activity or browning of WAT is constantly growing; some of these factors are circulating hormones secreted from various tissues including liver, skeletal muscle, or heart emphasizing that the thermogenic programming of adipose tissue is at least in part mediated by an active interorgan crosstalk [6, 8].
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A. FNDC5/Irisin One of these endocrine factors that has recently received a lot of interest is the myokine irisin, termed after the Greek messenger goddess Iris. Irisin is the cleavage product of the
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membrane protein fibronectin type III domain-containing protein 5 (FNDC5) whose expression is increased in response to exercise in human and murine skeletal muscle. Irisin stimulates the browning of WAT through specific actions on the preadipocyte population but
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also induces thermogenic gene expression in mature adipocytes [38, 39]. Currently there is some discussion about the regulation of irisin concentrations in human studies with some
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inconsistent results being published [40, 41]. Of course, as with any new hormone, there are many open questions such as: what is the irisin receptor in adipocytes and what is the downstream signal? Is the cleavage of FNDC5 into irisin a regulated process? It will be imperative to address these questions if this pathway wants to be pursued as a therapeutic
B. FGF21
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approach.
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Another hormone that has been in the center of attention is fibroblast growth factor 21 (FGF21) which is mainly secreted by the liver but is also expressed in other tissues. FGF21
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has become a focus of clinical trials for obesity and diabetes because it has many beneficial effects on metabolism including increased glucose uptake, improved insulin sensitivity, and weight reduction [42]. FGF21 acts in concert with the cofactor β-Klotho which is required for interaction with FGF receptors. Some of the FGF21 actions are mediated by stimulating fatty acid oxidation and energy dissipation through browning of adipocytes [43]. In humans circulating FGF21 correlates with brown fat activity determined by FDG uptake in PET/CT studies and in human brown adipocytes FGF21 and FNDC5 have additive effects on norepinephrine stimulated thermogenesis [44, 45].
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C. Natriuretic peptides There is also accumulating evidence of a cross talk between the heart and the adipose tissue. Not only are adipokines contributing to cardiovascular function but also heart hormones
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such as the natriuretic peptides can control fat function including non-shivering thermogenesis and fatty acid oxidation [46]. For instance infusion of the brain natriuretic peptide which is usually elevated in heart failure patients causes increased UCP-1 expression
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in subcutaneous fat and enhanced energy expenditure in mice [47]. These findings also raised the question whether the energy dissipating actions of natriuretic peptides can
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promote cachexia as observed in end stage heart failure patients. D. Parathyroid hormone (PTH) and PTH-related peptide
Browning-induced cachexia has in fact been demonstrated in two other mouse models, one
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being lung cancer and the other being kidney failure. Particularly interesting from the perspective of an endocrinologist is that the browning process in both models was PTH receptor dependent. In one study the authors performed partial nephrectomy in mice to
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induce secondary hyperparathyroidism [48]. In another study also done in Bruce Spiegelman’s lab, a Lewis lung carcinoma model was used which is associated with
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paraneoplastic PTH-related peptide secretion [49]. Elevated concentrations of both, PTH and PTH-related peptide resulted in increased energy wasting and worsening of cachexia in these mouse models of kidney failure and lung cancer. However these effects were abolished in adipose tissue PTH receptor knockout mice arguing for a fat-specific PTH receptor signaling pathway. Intrigued by these results they went on to study neck fat biopsies from subjects with primary hyperparathyroidism and healthy controls and found increased expression of some of the browning markers in patients with hyperparathyroidism. These studies emphasize that there may be medical conditions such as certain types of cancer, in which
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the promotion of brown fat thermogenesis and energy expenditure may not be beneficial at
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all but may in fact become a target for therapeutic inhibition.
Summary
Accumulating evidence from preclinical studies suggests that exploiting the thermogenic
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function of brown and/or beige fat could be an effective treatment for obesity, type 2 diabetes, and associated complications. Given the overabundance of WAT in obese subjects,
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reprogramming of white fat depots towards an energy dissipating organ poses a particularly intriguing concept. This browning process has been successfully achieved in numerous animal studies and proof-of-concept has also been demonstrated in humans. However, the specific human adipocyte populations capable of acquiring a brown-like phenotype and the
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detailed molecular mechanisms leading to this phenotype are still being investigated. A large number of factors including some endocrine mediators has already been identified to regulate the thermogenic programming of WAT and new pathways are constantly added.
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The β3-agonist mirabegron, a drug only approved for the treatment of overactive bladder, has recently been shown to activate pre-existing BAT in humans similar to cold exposure
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[50]. While it remains to be seen in additional studies if mirabegron can effectively reduce excess body weight, no approved pharmacological substances yet exist to induce browning of WAT in humans. Given that energy homeostasis is a tightly controlled process, it will be interesting to see whether enhanced energy expenditure through brown of beige fat based therapies will be compensated by other mechanisms such as increased hunger and food intake.
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Practice Points •
Promotion of BAT or browning of WAT have shown great promise as anti-obesity strategies in preclinical studies
browning process •
Beige adipocytes possess characteristics of both, white and brown fat cells depending upon endogenous or external stimuli
•
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The emergence of thermogenically active beige adipocytes is a hallmark of the
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•
Activation of BAT and browning of WAT can also occur in humans and is associated
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with enhanced energy expenditure
Research Agenda
To date no pharmacological therapies exist to induce browning of WAT in humans
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A better understanding of the heterogeneous brown/beige fat cell population in
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•
humans is essential for the development of novel therapeutic concepts Factors controlling the thermogenic programming of adipocytes are currently heavily
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•
investigated
It remains to be seen whether increased energy expenditure through therapeutic
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•
activation of BAT or beige fat is sufficient to maintain weight loss in humans or if compensatory mechanisms such as increased food intake will mitigate the effects
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Figure 1:
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Representative hematoxylin and eosin staining of (A) white, (B) beige, and (C) brown adipose tissue from mice.
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