Role of brown adipose tissue in metabolic syndrome, aging, and cancer cachexia

Abstract

Brown adipose tissue (BAT) plays a fundamental role in maintaining body temperature by producing heat. BAT that had been know to exist only in mammals and the human neonate has received great attention for the treatment of obesity and diabetes due to its important function in energy metabolism, ever since it is recently reported that human adults have functional BAT. In addition, beige adipocytes, brown adipocytes in white adipose tissue (WAT), have also been shown to take part in whole body metabolism. Multiple lines of evidence demonstrated that transplantation or activation of BAT or/and beige adipocytes reversed obesity and improved insulin sensitivity. Furthermore, many genes involved in BAT activation and/or the recruitment of beige cells have been found, thereby providing new promising strategies for future clinical application of BAT activation to treat obesity and metabolic diseases. This review focuses on recent advances of BAT function in the metabolic aspect and the relationship between BAT and cancer cachexia, a pathological process accompanied with decreased body weight and increased energy expenditure in cancer patients. The underlying possible mechanisms to reduce BAT mass and its activity in the elderly are also discussed.

Keywords

brown adipose tissue / beige adipocyte / anti-obesity / anti-diabetes / cancer cachexia / aging

Introduction

Adipose tissue is an essential organ in regulating energy homeostasis. Human and small mammals exhibit mainly two different types of fat tissue, namely, white adipose tissue (WAT) and brown adipose tissue (BAT). BAT, as a thermogenic organ, is involved in the maintenance of body temperature. BAT consumes energy by generating heat through the expression of uncoupling protein 1 (UCP1) in its inner mitochondrial membrane [¹]. BAT, as an endocrine organ, also plays a key role in glucose and lipid metabolism by consuming fatty acids (FAs) and glucose and regulating energy homeostasis [²,³]. Human adults possess functional BAT and the presence and/or activity of BAT is negatively related to age, body mass index (BMI), and glucose level [⁴–⁶]. Thermogenesis is a major function of BAT in rodent and human adult [⁷–⁹]. In terms of human neonates, the core and skin temperature can decrease immediately after delivery at a rate of approximately 0.1 and 0.3 °C per minute, respectively, due to physical characteristics and environmental factor [¹⁰]. To prevent hypothermia, the neonate should activate nonshivering thermogenesis (NST), which is associated with lipolysis in BAT to accelerate heat production [¹¹]. In newborn sheep, impaired BAT thermogenesis results in life-threatening hypothermia [¹²]. Human neonates who died of cold syndrome also show BAT depletion, whereas healthy neonates exhibit a considerable amount of BAT [¹³]. Therefore, BAT might also be important for human neonates to maintain body temperature. However, the thermogenic function of BAT in human neonates is not well studied due to the absence of safe protocol for temperature challenge.

Brown adipocyte arises from progenitor cell that shares common myogenic transcriptional characteristic, such as Myf5 and Pax7 [¹⁴–¹⁶]. PRD1-BF-1-RIZ1 homologous domain 16 (PRDM16) and CCAAT/enhancer binding protein-β (C/EBPβ) complexes that induce the expression of peroxisome proliferator-activated receptor g (PPARg) and peroxisome proliferator-activated receptor-g coactivator-1 (PGC-1), key regulators of the brown fat programming, are responsible for the differentiation of brown adipocyte from myoblast [¹⁴,¹⁷]. As a third type of adipocyte, beige cells that are recruited in WAT by cold exposure or β3-adrenoceptor agonist treatment express large amount of UCP1, a specific marker of brown adipocyte [¹⁸,¹⁹]. Beige cell originates from PDGFRα⁺CD34⁺Sca1⁺ precursor cell rather than from Myf5-positive myoblast [¹⁵,²⁰], but its gene characteristics show a similarity to that of classical BAT [²¹]. For the brown adipogenesis, brown adipocyte-specific proteins such as PGC-1α, PRDM16, and UCP1 are essential [²²]. UCP1, mainly expressed in brown adipocytes and beige cells, releases chemical energy as heat by dissipating pH gradient generated by oxidative phosphorylation [²³,²⁴]. Originally, UCP1- deficient mouse has an impairment of thermoregulation, whereas UCP1 deficiency is not associated with hyperphagia or obesity due to a compensation mechanism of UCP2 induction [²⁵]. However, UCP1 ablation results in obesity and impairment of diet-induced thermogenesis at thermoneutrality [²⁶]. Thus, UCP1 is essential for thermoregulation and control of metabolism in thermoneutral condition.

Although the different functions between classical brown adipocytes and beige cells should be elucidated, both cells express thermogenic genes and thereby play a critical role in the maintenance of body temperature under cold environment. Therefore, brown and beige adipocytes are promising targets for the treatment of obesity and its related metabolic disorders.

Anti-obesity effect of BAT and beige fat

When energy intake exceeds energy consumption, obesity occurs as a result of caloric imbalance. Although decreasing energy intake is the primary option to prevent and treat obesity, the effort is not effective. BAT, as a thermogenic organ, provides a new therapeutic strategy for the treatment of obesity because BAT activity is negatively correlated with BMI in human [⁴,²⁷–²⁹].

When the BAT from healthy mouse is transplanted in mouse to simply increase its mass, increased BAT mass prevents and reverses obesity in high-fat diet (HFD)-induced obese mice [³⁰–³²] and Ob/Ob mice [³³]. Transplanted BAT increases the activity of endogenous BAT by secreting IL-6 [³⁰], adiponectin [³³], or unknown potential cytokines [³¹,³²]. These findings suggested that increased BAT mass enhances energy expenditure, which results in an anti-obesity effect. Nevertheless, BAT transplantation is not applicable to human. Cell-based strategy, such as transplantation of thermogenic adipocytes that are differentiated in vitro from autologous cells after autopsy, is considered an alternative option to overcome this issue [³⁴].

Cold exposure-induced NST remarkably reduces body weight in HFD-induced rodent models or fat mass in human subjects [³⁵–³⁷] , since cold exposure activates BAT and induces the recruitment of beige adipocytes in WAT. Cold challenge activates sympathetic nervous system (SNS) to release noradrenaline (NE) that binds to β3-adrenergic receptor (β3-AR) and eventually promotes the expression of UCP1 in BAT [³⁸,³⁹] and WAT [⁴⁰,⁴¹]. The treatment of CL-316243, a β3-AR agonist, also reduces adiposity in rodent models through activating BAT thermogenesis [⁴²,⁴³]. In addition, eosinophils, type II cytokines, and group 2 innate lymphoid cells (ILC2) play important roles in beige fat formation [⁴⁴–⁴⁶]. Fibroblast growth factor 21 (FGF21) [⁴⁷,⁴⁸], bone morphogenetic proteins (BMPs) [⁴⁹–⁵¹], and cardiac natriuretic peptide [⁵²] also regulate brown and beige fat activity, thereby reducing body weight by activating thermogenesis in rodent models. In obese human subjects, a clinical study with LY2405319, a FGF21 mimetic, shows beneficial metabolic effects with modest body weight reduction [⁵³]. In addition to a β3-AR agonist and FGF21 mimetic, natural compounds, such as capsaicin and capsinoid, can reduce body fat mass in small rodents and humans [⁵⁴] by activating transient receptor potential cation channel, subfamily V, member 1, which stimulates SNS to release NE and enhances the activity of BAT [⁵⁴–⁵⁸]. For clinical usage of these compounds, defined clinical studies are required because BAT activation could induce adverse effects on other metabolic diseases such as atherosclerosis.

In spite of the anti-obesity potential of BAT, BAT activation-induced lipolysis increases more plasma lipoprotein remnant than that of hepatic clearance capacity, thereby aggravating the atherosclerotic plaque development and instability in ApoE- or LDLR-deficient mice [⁵⁹]. However, BAT activation in APOE*3-Leiden.CETP transgenic mice, which preserves hepatic remnant clearance, protects atherosclerosis. It indicates that BAT activation attenuates atherosclerosis only when the liver can clear lipoprotein remnants [⁶⁰]. Therefore, clinical application with chemicals or natural compounds for the activation of BAT should be carefully considered yet for patients who possess metabolic complications, except for simple obesity.

Role of BAT and beige fat in diabetes mellitus (DM)

BAT tightly regulates the systemic level of FA and glucose that are the main fuel for UCP1-mediated BAT thermogenesis [²,⁸,⁶¹]. The BAT mass ranging from ~30 g to 300 g is able to contribute to 20% of daily resting energy expenditure (REE) [⁴,⁶²]. In addition, BAT mass and its ability to uptake glucose in basal and cold environment are decreased in obese and diabetes patients [²⁷–²⁹], indicating that decreased BAT activity is associated with DM. The number of studies describing that BAT mass or its activity mediates insulin resistance has been increasing in recent years. In streptozotocin-induced and autoimmune-mediated type 1 DM (T1DM) mice, BAT transplantation improves glucose tolerance and reverses polydipsia, polyphagia, and polyuria that are major symptoms of T1DM, resulting in euglycemia [⁶³,⁶⁴]. Furthermore, BAT transplantation in HFD and Ob/Ob mice significantly enhances glucose tolerance and insulin sensitivity [³⁰–³³]. Implantation of differentiated human UCP1-positive beige adipocytes or functional brown adipocytes differentiated from human pluripotent stem cells (hPSCdBA) also enhances glucose tolerance in mice [⁶⁵–⁶⁷]. Additionally, prolonged exposure to cold or CL-316,243 treatment increases BAT mass and results in improved glucose intolerance in obese rat [³⁶,⁴²,⁴³]. In humans, cold-induced BAT activation also increases glucose uptake by ~12 folds [⁶⁸] and enhances glucose homeostasis and insulin sensitivity [⁶⁹]. These studies supported that activated BAT markedly increases the uptake rate of triglyceride, ameliorating the insulin resistance in mice [⁶¹].

These beneficial effects are, at least in part, from batokines defined as cytokines released from BAT. BAT expresses FGF21, IL-6, adiponectin, T3, BMP8B, prostaglandin D2 synthase (PTGDS), Nrg4, VEGFA, and VEGFB [⁷⁰–⁷²]. In particular, FGF21 [⁷³–⁷⁵], IL-6 [³⁰,⁷⁶,⁷⁷], adiponectin [³³], PTGDs [⁷⁸], and BMP8B [⁵¹] reverse hyperglycemia and improve insulin sensitivity through autocrine and/or endocrine mechanisms. Nrg4 regulates glucose homeostasis by activating ErbB3 and ErbB4 signaling pathway in the liver [⁷⁹]. Additionally, VEGFA and VEGFB exhibit antidiabetic effect through endocrine and paracrine mechanisms [⁸⁰–⁸³].

For the clinical application of BAT activation on obesity or DM, determining molecules with remarkable efficiency as that of cold exposure or CL-316,243 would be a valuable therapeutic approach.

Mass and activity of BAT in aging

According to the ¹⁸F-FDG PET-CT imaging analysis, most prominent ¹⁸F-FDG uptake regions are cervical-supraclavicular and paracervical adipose tissues in human [⁴–⁶]. The gene characteristics of human UCP1⁺ brown adipocytes are more similar to those of mouse beige adipocytes than those of mouse classical brown adipocytes [¹⁹,⁸⁴]. The amount of BAT after cold stimulus is inversely correlated with age, and BAT is barely detected in the elderly who is more than 60 years old [⁸⁵]. The reason why BAT mass is reduced in human is unknown. Wide distribution of BATs in human neonates is associated with NST for protection against cold because they possess an immature heat generation mechanism. However, adults exhibit another mechanism to produce heat from shivering and voluntary muscular activity in cold environment. Therefore, a transition from nonshivering to shivering thermogenic mechanism might exist with aging [⁸⁶,⁸⁷].

The proposed mechanisms for the reduction of BAT in the elderly include defective hormonal signals (pituitary growth hormone and sex hormones) [⁸⁵], BAT stem cell alteration [⁸⁸], mitochondrial dysfunction [⁸⁹], and decreased brain activity [⁹⁰]. Sex hormones, such as estrogens and androgens, decline in late adulthood and inhibit the activity of glucocorticoids that negatively regulate BAT activity [⁸⁵]. Aging is accompanied with progressive impairment of stem cell function, which leads to the regenerative defect of BAT in the elderly [⁸⁸]. Reduced sensitivity to sympathetic tone, accumulated DNA mutations and ROS damages could be possible explanations for the defective function of stem cell in the elderly [⁸⁸,⁸⁹]. Recently, the central nervous system is suggested to be responsible for the decreased BAT activity in aging. After cold exposure, regional brain FDG uptake analyzed by ¹⁸F-FDG PET-CT imaging is remarkably attenuated in an old man compared with that in a young man [⁹⁰]. Given that brain circuit mediates the autonomic nervous system that is dysfunctional in obesity and aging, impairment of central nervous activity could have caused BAT inactivity in the elderly. Liver-derived FGF21 regulates insulin sensitivity, mitochondrial activity, lipid metabolism, ketogenesis, and lifespan extension in mice. More than 30% of female FGF21-Tg mice extend their lifespan to approximately 44 months [⁹¹] by activating AMPK and Sirt1 [⁹²], that promote longevity [⁹³]. BAT increases FGF21 secretion after cold exposure or chemical compound administration [⁹⁴]. In addition, FGF21 overexpression increases the perithymic BAT and protects age-related thymic lipoatrophy, thereby delaying immune senescence. The reduction of thymic lipotoxicity induced by BAT lipid uptake can be regarded as one of the most important mechanisms for the delay of immune senescence [⁹⁵]. The cause of attenuated BAT activity in the elderly is multifactorial. Thus, considerable amount of work is needed to understand the underlying mechanisms for the reduction of BAT in the elderly.

Role of BAT in cancer cachexia

BAT activation has received considerable attention for the development of cancer cachexia in animal model. Cancer cachexia is a multifactorial syndrome defined as a continuous loss of skeletal muscle and fat mass that cannot be completely reversed by conventional nutritional support. Therefore, cancer cachexia eventually leads to progressive functional impairment. The diagnostic criteria for cachexia in clinic include weight loss of higher than 5% of stable body weight over the past six months, ongoing weight loss that is higher than 2% in patients with a BMI of less than 20 kg/m², or depletion of skeletal muscle mass (sarcopenia) [⁹⁶]. Cancer patients who lose weight show higher REE than those of patients with a stable weight [⁹⁷].

Enhanced thermogenesis in BAT is suggested as a primary reason for increased REE in certain cancer patients [⁹⁸], since elevation of BAT activity results in hypermetabolic diseases and is partially responsible for the weight loss in tumor-bearing mice [⁹⁹]. In C26 colon carcinoma-induced cachectic mice, β3-AR that is responsible for the activation of BAT, is activated and thereby induces delipidation in BAT with a higher induction of UCP1 at the protein level [¹⁰⁰]. Furthermore, ¹⁸F-FDG PET imaging shows more BAT positive sites in cachectic C26 colon carcinoma-bearing mouse than that of nontumor-bearing mouse [¹⁰¹], supporting that cancer cachexia could be associated with increased BAT activity in animal models. Adipose tissue browning, the recruitment of beige cells in WAT, is also found in cachexia mouse model. Adipose tissue specific Prdm16 deficient mouse inhibits adipose tissue wasting in Lewis lung carcinoma (LLC)-bearing tumorigenesis [¹⁰²]. Tumor-derived IL-6 and β3-AR activation is associated with cancer cachexia-mediated adipose tissue browning in genetically engineered cancer cachexia mice, and neutralization of IL-6 or β3-AR significantly ameliorates cancer cachexia [¹⁰³]. Although the main role of IL-6 on metabolism remains poorly understood, IL-6, at least in part, contributes to systemic metabolism by regulating BAT activation and adipose tissue browning [⁷⁶,¹⁰⁴]. Introduction of IL-6 in brain using adenoviral system significantly increases UCP1 expression only in sympathetic innervated BAT, not denervated one, indicating that IL-6 activates BAT through β3-AR signaling pathway [⁷⁶]. Additionally, tumor cell-derived parathyroid-hormone-related protein (PTHrP) is responsible for cancer cachexia [¹⁰²]. While PTHrP treatment does not alter tumor size, it leads to cancer cachexia-associated weight loss with skeletal muscle wasting in LLC-bearing mouse. Instead, blocking PTHrP with neutralizing antibody prevents adipose tissue and skeletal muscle wasting. Furthermore, PTHrP shares G-protein-couple receptor signaling pathway with β3 agonists to upregulate UCP1 expression at protein level in white and brown adipocytes [¹⁰²]. Therefore, tumor cell-derived IL-6 and PTHrP might play an important role in cancer cachexia by activating BAT and/or adipose tissue browning at least in mouse tumor models.

However, it is not clear yet whether BAT activation contributes to cancer cachexia in human. In human periadrenal tissue, BATs are observed in 80% of total 25 cancer patients compared with the 13% of total 16 age-matched healthy subjects [¹⁰⁵]. ¹⁸F-FDG PET-CT study with a small number of cancer patients revealed that the prevalence of activated BAT in cancer patients (~50%) is similar to that in healthy control subjects (~56%) [²⁹]. Discrepancies in previous results may result from the individual difference in BAT activity because BAT activation is regulated by various factors such as age, sex, outdoor temperature, obesity, and exercise [⁴,¹⁰⁶]. Therefore, well-designed studies with a large number of cancer patients and appropriate control subjects are required to investigate the effect of BAT activation on cancer cachexia.

Signaling pathways for BAT activation and browning

The activation of β3-AR and its downstream signaling is a major signaling pathway for thermogenic gene induction. FGF21, an endocrine hormone, belongs to the FGF family and regulates BAT activation through β3-AR signaling. To induce thermogenic ability, FGF21 directly binds to adipocytes [¹⁰⁷] and consequently activates BAT or inguinal adipocytes by increasing sympathetic activity [¹⁰⁸] and/or enhancing PGC-1α, a key factor of browning [¹⁰⁹]. Type II cytokine plays an important role in beige formation during cold exposure and exercise by adrenergic regulation [⁴⁴]. Cold exposure or excise induces beige formation by increasing the expression level of eosinophil-derived IL-4 and activates M2 macrophage-derived catecholamine through IL4Ra signal pathway [¹¹⁰,¹¹¹]. In particular, IL-33-mediated activation of type 2 innate lymphoid cells (ILC2s) promotes the expansion of PDGFRα⁺ bipotential adipocyte precursors and the commitment to beige adipocytes via IL4Ra pathway [¹¹¹]. Alternatively, activated ILC2s also secrete methionine-enkephalin peptides that directly induce UCP1 expression and browning in the IL4Ra independent pathway [⁴⁶]. Adiponectin also regulates cold-induced browning by promoting M2 macrophage in WAT with unknown mechanism [¹¹²].

However, BMPs induce thermogenic genes without adrenergic pathways. BMPs, as pleiotropic members of the transforming growth factor b superfamily, regulate adipogenesis through BMP receptors (type I and II) rather than b3-AR, as evidenced by the fact that the ablation of type 1A BMP receptor in brown adipogenic progenitor cells prevents brown adipogenesis in BAT. Instead, the ablation of BAM receptor promotes beige cell recruitment by increased sympathetic input to WAT [¹¹³]. BMP4 requires PGC-1b and PGC-1a for white to brown transition of mouse WAT and human adipose stem cells, respectively [⁴⁹,¹¹⁴]. BMP7 is originally identified as a hormone for bone formation, but it regulates BAT growth and activation in vitro and in vivo through p38 MAP kinase-mediated PGC-1a and PGC-1b [⁵⁰]. In addition, BMP7 also enhances white-to-beige transition in primary adipocytes [¹¹⁴].

Although various signaling pathways and cell types involved in BAT activation and browning have been uncovered, better understanding of crosstalk among signaling pathways is required for the development of drugs that stimulate BAT activation on the purpose of clinical application in the near future.

Conclusions

BAT plays an important role in human physiology and metabolic diseases. BAT transplantation or its activation enhances energy expenditure, reduces weight loss, improves insulin sensitivity, and reverses hyperinsulinemia in animal and human studies. The recruitment of beige cells in WAT also shows similar effects. However, BAT activation could deteriorate cancer cachexia. From the pathophysiological point of view, BAT activation is associated with cancer cachexia in animal models. In addition, direct evidence between BAT activity and human cancer cachexia has not been observed yet. In the elderly, BAT mass and activity are negatively correlated with aging. Therefore, BAT activation with chemicals or natural compounds could be a new therapeutic strategy to treat obesity and metabolic diseases and extend life span.

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