Review Article
Brown adipose tissue and novel therapeutic approaches to treat metabolic disorders

https://doi.org/10.1016/j.trsl.2014.11.002Get rights and content

In humans, 2 functionally different types of adipose tissue coexist: white adipose tissue (WAT) and brown adipose tissue (BAT). WAT is involved in energy storage, whereas BAT is involved in energy expenditure. Increased amounts of WAT may contribute to the development of metabolic disorders, such as obesity-associated type 2 diabetes mellitus and cardiovascular diseases. In contrast, the thermogenic function of BAT allows high consumption of fatty acids because of the activity of uncoupling protein 1 in the internal mitochondrial membrane. Interestingly, obesity reduction and insulin sensitization have been achieved by BAT activation-regeneration in animal models. This review describes the origin, function, and differentiation mechanisms of BAT to identify new therapeutic strategies for the treatment of metabolic disorders related to obesity. On the basis of the animal studies, novel approaches for BAT regeneration combining stem cells from the adipose tissue with active components, such as melatonin, may have potential for the treatment of metabolic disorders in humans.

Introduction

Adipose tissue is one of the largest organs in the body and plays an important role in central energy balance and lipid homeostasis.1 Two types of adipose tissue are found in mammals, white adipose tissue (WAT) and brown adipose tissue (BAT). WAT functions to store energy, whereas BAT specializes in energy expenditure.2

In WAT cells, energy is stored via synthesis of triglycerides (TGs) that accumulate in lipid vesicles. WAT is composed of visceral and subcutaneous fat and represents 10% of healthy body weight.3, 4 Excess WAT is related to several metabolic disorders. Although visceral fat is less sensitive to insulin than subcutaneous fat, both fat tissues play a role in the development of type 2 diabetes mellitus (T2DM) and cardiovascular complications.5, 6, 7, 8 In addition, an increase in fatty acids (FAs), derived from excessive WAT energy storage, leads to an increased liver glucose output and consequent production of atherogenic lipids such as very low-density lipoproteins.9

In contrast, BAT plays an important thermogenic function in neonatal mammals, rodents, and hibernators, helping to counteract the cold stress of birth.2, 3 In adult mammals, BAT has the capacity to modulate energy balance by metabolizing FAs and dissipating the energy produced as heat.10 The ability of BAT to burn fat could be used as a novel therapeutic strategy to combat obesity and metabolic diseases.

Therefore, the goal of this review is to identify therapeutic approaches with the potential to regenerate BAT in humans to treat metabolic disorders.

After a brief overview of BAT in terms of its origin, its physiological properties, and the key molecular signals for BAT differentiation, this review summarizes the pathways currently used in the research community for BAT regeneration in animals and new routes that need to be investigated.

Section snippets

Origin and Role of BAT

It was believed that white and brown adipocytes arise from the same precursor cells.11 However, DNA microarray studies revealed that brown adipocytes do not share a progenitor with white adipose cells but rather have the same origin as skeletal muscle cells.12, 13 Lineage-tracing experiments suggested a model in which tripotent cells in the central dermomyotome give rise to dermis, epaxial muscle, and brown fat.14 BAT precursor cells express myogenic factor 5, suggesting their close

Peroxisome proliferator–activated receptor γ and cytosine–enhancer-binding protein

The 2 main transcriptional factors involved in the adipogenesis of brown and white adipocytes are peroxisome proliferator–activated receptor γ (PPARγ) and cytosine–enhancer-binding protein (C/EBP).28, 29, 30, 31 Impairment of PPARγ or C/EBP in mice reduces BAT recruitment.32 This fact suggests that both factors are necessary for adipogenic differentiation.32 However, specifically for BAT differentiation, other factors may be needed because PPARγ and C/EBPα have been used to induce mesenchymal

Catecholamines

Treatment of genetically and diet-induced obese rats with β3-adrenergic agonists ameliorates their pathologic condition. Moreover, UCP1-positive brown adipocytes are observed in areas of WAT because of the direct transdifferentiation of differentiated unilocular adipocytes. Catecholamines can also stimulate BAT differentiation and UCP1 expression in rats.96 In vitro studies have shown that catecholamines, epinephrine and NE play an important role in the stimulation of brown preadipocyte

Conclusions

Several studies have investigated the clinical relevance of BAT as a therapeutic target for patients at risk of developing metabolic diseases. However, upregulation via transcription factors and the role of the different molecular factors in regenerating and-or stimulating BAT need to be better understood to avoid undesirable effects in humans. Alternatively, novel therapeutic approaches for BAT regeneration have been investigated recently in animal models, with intense research efforts on the

Acknowledgments

Conflicts of Interest: The authors report no conflicts of interest. All authors have read the journal's policy on conflicts of interest. All authors have read the journal's authorship agreement.

This work was supported in part by grants from the Consejería de Economía, Innovación y Ciencia (Junta de Andalucía, the Ministerio de Economía y Competitividad (grant number SAF 2013-45752-R) excellence project, grant number CTS-6568) and the Instituto de Salud Carlos III (Fondo de Investigación

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