Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
ReviewMicroRNAs in brown and beige fat
Introduction
Over the past decades the worldwide population suffering from obesity has severely increased [1]. According to the world health organization (WHO) 1.9 billion human adults are overweight and more people die of overweight and obesity than of underweight and famine (WHO, 2014). Excessive fat accumulation is a result of an imbalance in energy homeostasis caused by an increased calorie intake versus calorie expenditure. Various studies show that obesity and overweight are major health problems as they increase the risk of developing other diseases such as type 2 diabetes, cardiovascular disease and certain types of cancer [2]. Therapeutic options to treat obesity are lacking and understanding the underlying molecular mechanisms would help develop new, more efficient anti-obesity therapies. Current therapeutic options include dietetic and exercise treatment as well as bariatric surgery. Available pharmacological therapy to date, such as Orlistat and Liraglutide, are only indicated in special cases and can cause severe side effects [3,4]. In previous studies, we and others have established microRNAs (miRNAs) as relevant biomarkers of metabolism [5,6]. Furthermore, recent research underlines the critical role of miRNAs in the regulation of adipose tissue and metabolism [7]. miRNAs have been reported to directly or indirectly regulate signaling pathways essential for the development and differentiation as well as function of adipose tissue.
There are two kinds of adipose tissue in mammals: white adipose tissue (WAT) and brown adipose tissue (BAT) [8]. The main tissue responsible for storing energy in form of triglycerides is WAT. WAT accumulates excessive energy in form of fat and is distributed throughout the whole body. The major WAT depots are classified based on their location as visceral or gonadal WAT (vWAT or gWAT, respectively) versus subcutaneous or inguinal WAT (scWAT or iWAT, respectively). White adipocytes feature unilocular lipid droplets, and considerably vary in size depending on the lipid load [9]. Contrary to WAT, BAT utilizes stored chemical energy for the production of heat in a process called non-shivering thermogenesis (NST) [10]. The involvement of BAT in heat production has long been known [11], but it was believed to play a major role only in newborns. Although interscapular BAT is the major thermogenic depot in infants, BAT appears to be widely distributed throughout the body during the first decade of life [12]. Anatomical studies showed that interscapular BAT disappears with advancing years [12], however, brown adipocytes can be found also in adults in the deeper regions of the body [12]. It has only been in the last decade that metabolically active BAT was identified in adult humans using positron emission tomography (PET) coupled with computer tomography (CT) imaging of radioactive glucose uptake (FDG-PET/CT) [[13], [14], [15], [16]]. FDG-PET/CT clearly detected active BAT in the supraclavicular and neck regions as well as in the mediastinum [13,14,[16], [17], [18]].
Brown adipocytes contain a high abundance of mitochondria and small multilocular lipid droplets. The protein mainly responsible for NST is the uncoupling protein 1 (UCP1), which is located in the membrane of mitochondria and uncouples the proton gradient to generate heat [19,20]. BAT is highly innervated by the sympathetic nervous system, which releases norepinephrine (NE) and the cotransmitter ATP which is rapidly converted to adenosine upon cold stimulation [21]. NE activates G protein-coupled receptors, thereby inducing the production of cyclic AMP (cAMP) and activation of protein kinase A (PKA) in brown adipocytes [17]. Regarding the action of adenosine in BAT, there are important species differences: adenosine activates human and murine brown adipocytes, but inhibits activation of BAT from hamster or rat [17,[22], [23], [24], [25]].
In addition to WAT and BAT, inducible brown adipocytes also called beige or brite (brown-in-white) adipocytes exist in WAT depots, mainly iWAT/scWAT [26]. These cells are induced upon cold acclimatization and can dissipate energy as heat, a process also known as “browning” [27,28]. Morphologically, beige adipocytes share major characteristics with classical brown adipocytes, including multilocular fat droplets, a high mitochondrial content and expression of “brown” genes, including Ucp1, cell death-inducing DNA fragmentation factor alpha-like effector A (Cidea), peroxisome-proliferator-activated receptor γ-coactivator 1α (Pgc-1α), protein PR domain containing 16 (Prdm16) and CCAAT/enhancer-binding protein β (C/EBPβ) [28]. Several studies indicate that brown adipocytes have a different origin than white and beige adipocytes (Seale et al., 2008). Nonetheless, it is still under debate whether mature white adipocytes have the ability to transdifferentiate, or “un-mask” into beige adipocytes, or whether beige cells derive from a separate precursor cell line, which shares the same origin as white adipocytes, by de-novo differentiation [[29], [30], [31]]. Interestingly, Long and colleagues showed that the origin of beige adipocytes is very heterogenous depending on the location of WAT depots [32].
Section snippets
Brown fat: function of miRNAs in brown adipogenesis
The development and function of brown adipocytes is tightly regulated by various hormones and proteins factors [28,33,34]. We and others have previously demonstrated that miRNAs also play a critical role in brown adipose tissue as transcriptional regulators and biomarkers [5,7]. Extracellular miRNAs can be found in fluids, including blood and urine, packaged in extracellular vesicles or in microparticle-free form [[35], [36], [37], [38]]. Their level has been linked to the status and
Beige fat-specific miRNAs: Role of miRNAs in browning
In addition to being critical regulators of brown adipocyte development and function, recent studies revealed that miRNAs potentially play a central role in beige adipocytes [61]. Understanding the regulatory mechanism of miRNAs during this process may help developing new therapeutic approaches to increase energy expenditure and combat obesity. Thus, we present here the current research on miRNAs specifically involved in the browning process (Fig. 2).
Involvement of miRNAs in the regulation of both brown adipocytes and browning process
Recent studies demonstrated that several miRNAs play important roles in both brown adipocytes and the browning process. Some miRNAs, such as miR-30 and miR-27, have identical effects in both brown and beige adipocytes, respectively [[68], [69], [70], [71], [72]]. In contrast miR-378 remains the only characterized miRNA to have opposite functions in brown and beige adipogenesis [73]. Here, we present the current research on miRNAs involved in both brown adipocytes and the browning process (Fig. 3
Summary and perspectives
In the last few years, BAT has been linked to amelioration of overweight and gained more interest as potential target of novel therapeutic tools for the fight against obesity [17]. Recently, inducible brown adipocytes in WAT depots, called beige or brite cells, have gained more interest due to their capability for energy expenditure and their positive effect on diet-induced obesity [104]. Besides hormones and protein factors, miRNAs are also key regulators of brown adipogenesis and the
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