Beige fat: A New Hope for Metabolic Disorder

Transcription

1 Young Biomedical Scientists Forum(YBSF) Beige fat: A New Hope for Metabolic Disorder Harim Kim(2) 1 Ewha University, School of Medicine, 52, Ewhayeodae-gil, Seodaemun-gu, Seoul Korea k @ybsf21.org Abstract: 베이지색지방이란갈색지방과비슷한기능을가진지방으로서, 최근에백색지방이베이지색지방으로변모될수있다는연구결과가발표되고있다. 갈색지방과베이지색지방은모두 UCP1이라는단백질을미토콘드리아에발현하여, 미토콘드리아막간공간의수소이온을열에너지로전환하기때문에일반세포보다에너지를많이소모할수있다. 따라서백색지방을베이지색지방으로유도할경우, 비만등여러대사증후군을해결할수있다. 이때백색지방의변모를유도하는주요요인은추위와 β 3-agonists등을통한교감신경계의작동이다. PPAR- γ 와전사인자인 prdm 16은 UCP1 단백질의발현을조절하고, BMP7과 TZDs는 prdm16 mrna를증가시키며, Pgc-1 α 와 vegf는베이지색지방의발달을조절하는것으로알려졌다. 실제로쥐에서의베이지색지방유도를통해비만을비롯해인슐린저항과동맥경화를예방하는효과를확인해비만과당뇨그리고각종대사증후군의치료에전망을보이고있다. 하지만아직베이지색지방을활성화하는정확한온도조건이밝혀지지않았기때문에상업적, 의학적활용단계는아니며, 일부밝혀지지않은정확한메커니즘과부작용에관한연구가진행되어야할것으로보인다. 1. INTRODUCTION Previous scientific research defined adipose tissues in two types: either white adipose tissue (WAT) or brown adipose tissue (BAT). However, recent research has brought up a new page on studies of brown fat: adults have WAT that can be transformed to beige fat, which has similar function as brown adipose tissues (BAT). The new discovery has brought a new approach to treatment of obesity and now scientists has figured out several pathways or influence that leads WAT to turn to BAT. BAT plays a key role of thermogenesis in mammals and therefore have been crucial in their survival and resistance to fluctuating temperature. The major location of BAT in mammals is interscapular and renal regions. BAT contains higher density of mitochondria than WAT and also possesses a specialized mitochondrial protein called UCP1 (uncoupling protein-1) (Fedorenko, 2012). When body is exposed to cold temperature, BAT is capable of non-shivering thermogenesis through lipolysis of adipose tissues. Beige adipose tissues are tissues that are WATs at basal state but serve as BAT under specific condition, including the expression of UCP1 protein and thermogenesis. 2. FUNCTION OF BROWN FAT As is mentioned above, BAT and beige adipose tissue convert energy into heat. From the viewpoint of cell which performs cellular respiration in order to gain ATPs, thermogenesis is a waste of energy. In effect, brown and beige fat interferes with standard cellular respiration cycle in order to heat mammalian body. Within mitochondria, energies are transferred via electron transport chain (ETC) to pump H+ from mitochondrial matrix to intermembrane space. When H+ comes back to mitochondrial matrix by force made by electrochemical gradient, ATP synthase transforms ADP into ATP in normal cells. In brown and beige cells, UCPs literally makes protons leak; that is, instead of converting electrochemical gradient into ATP, UCPs let protons return to cellular matrix bypassing ATP synthase, only to produce heat (Figure 1). Figure 1 Proton-leak not only produces heat but also activates metabolism in that cells need to pump much more protons out of matrix in order to synthesize the same amount of ATPs. As a consequence, body consumes more energy. In mice, energy consumed by proton-leak takes up around 20-30% of the resting metabolic rate (RMR) (Rolfe and Brand, 1996). This means that proton-leak can change energy consumption, resulting in either weight gain or weight loss (Harper et al., 2008). Out of all the UCPs, UCP1 is primarily responsible for

2 BAT and beige adipocyte function. In an experiment conducted by Feldmann and his fellow scholars (2009), mice whose UCP1 is ablated showed higher propensity to activates the function of beige adipocytes by inducing UCP1 expression in WAT and developing beige adipocytes from preadipocyte cells (reviewed in Harms et al., 2013). In be obese. Also, in an experiment where transgenic mice expressed UCP1 in WAT, the mice were leaner than wild type mice (reviewed in Klaus et al., 2012). Most importantly, genetic polymorphisms of UCP1 gene in the promoter region (A3826G SNP) has been found to be related with obesity or weight gain (reviewed in Jia et al., 2010). UCP3 is also thought to influence BAT and beige fat function; however, there are only convincing hypothesis and further studies are required. 3. INDUCEMENT OF BEIGE FAT FROM WHITE ADIPOSE TISSUE 3.1 Origin and development of beige fat Though both beige and brown cells are responsible for producing heat, they are separate adipocytes. They are found in different areas in body and also come from different progenitors. The precursor of brown fat express Myf5; however, precursors of beige adipocyte does not express Myf5. They also show difference in thermogenesis mechanism. (Figure 2) There are two main ways beige adipocyte can come into being: either be created directly from precursor cell or be reversibly transformed from WAT. According to experiment conducted by Wang et al., most beige cells come directly from precursor cell rather than being transformed from WAT (Figure 3). The most common way beige adipocytes are created is through sympathetic nerve activity, that is, exposure to cold and β -adrenergic agonists especially β3-agonists (Figure 3). This makes sense in that cold works as stress for most living creatures and therefore activate sympathetic nerve activity, corresponding with the effect of β -adrenaline. In effect, cold promotes sympathetic outflow to BAT through neural activity and encourages BAT to produce catecholamines (Nguyen, K.D. et al., 2011, reviewed in Morrison, 2012) which triggers the inducement of beige cell. Sympathetic nerve activity the same sense, norepinephrine helps increase the expression of thermogenic genes in body, leading to the function of beige or brown fat (Collins, 2012) Out of all factors, cold is the major factor that turns on sympathetic nerve activity. Mice that are exposed to cold tended to develop more beige fat from WAT as adaptation (Vitali, 2012). Activating β 3-adrenaline pathway by CL 316, 243 achieved similar result as cold exposure (reviewed in Harms et al, 2013). Some scholars predict that the density of sympathetic nerve fibers determine the propensity of beiging of WAT, which proves the huge role sympathetic nerve plays in beiging (Murano, 2009). Another protein that is related to cold exposure is C2(Foxc2). Prolonged cold exposure in mice elevates the expression of Foxc2 protein in mice. In fact, mice overexpressing Foxc2 in WAT and BAT, the WAT reduced in quantitiy and a lot of them turned in to tissues capable of thermogenesis (Reviewed in Cederberg, 2001). Further studies revealed that Focx2 encourages mitochondrial biogenesis and angiogenesis in fat tissues (Reviewed in Harms et al., 2013). Figure Regulation of beiging of White Adipose Tissue 2

3 If cold is the major driving force that transforms or even creates beige fat, there are numerous factors that can control the acivity of beige adipocytes. One such factor is PPAR- γ : it promotes UCP1 to be expressed in WAT; it is then cold or adrenergic agonists that finalize beiging (Figure 3). Another such factor is Prdm 16, a transcriptional factor that is heavily expressed in BAT (Seale et al., 2007). In case Prdm 16 is expressed in ectopic tissues, it induces UCP1 from myoblasts and white fat precursors, making them thermogenic adipocytes (Seale et al., 2008). Thus Prdm16 is an important factor in determining cell fate, especially in beiging a cell. Indeed, when Prdm 16 is highly expressed, the tissue carries much higher possibility to beige than other cells and thus high Prdm 16 expression helps weight loss and glucose tolerance it comsumes a lot of energy including glucose (Seale et al., 2011). Bone morphogenic protein 7 (BMP7) also helps develop beige adipose tissue in that it is necessary for BAT development by increasing Prdm 16 mrna in brown and white adipocyte precursor cells. Thizaolidinediones (TZDs) induces transformation to thermogenic adipose tissue by increasing Prdm 16 expression. MiR-133, a muscle-induced micro RNA suppresses expression of Prdm 16; however, cold exposure inhibits the expression of mir-133 in adipose tissues and thus promotes BAT formation or beiging of WAT (Reviewed in Harms et al., 2013). As is discussed above, sympathetic nerve density promotes development of BAT and beige fat. Blood vessel development around BAT and beige fat also helps the efficiency of thermogenesis because it carries more oxygen and nutrients to adipocytes that are needed for their activity. Vascular endothelial growth factor (vegf) is known to facilitate beiging of adipocytes through unknown mechanism, though its effects on vessels are not to be disputed. In fact, vegf is proven to prevent metabolic diseases in mice by increasing BAT portion and beige fat (Reviewed in Harms et al., 2013). Pgc-1α is called as master regulator of BAT and beige adipocytes. It is not necessary for BAT development but it induces UCP1 expression. Also, if expressed in muscle, coupled with effects of irisin, it stimulates beige fat development. Ppar-γ has similar expression and reacts with TZD agonists. Fgf21 is known to help the activity of Pgc-1α in recruiting beige fat and Natriuretic peptide promotes lipolysis in adipocytes. Other factors like orexin and BMP family are also responsible for regulating adipocyte development (Figure 4). 4. APPLICATION IN MEDICINE As of today, the most prominent field where induced BAT (or beige fat) can be applied is obesity. There have been proven experiments with mice that stimulating beige fat or brown fat promotes weight loss (reviewed in Harms et al., 2013). It is true that chemical uncoupler 2,4-dinitrophenol (DNP) was once deemed as a perfect weight loss solution. However, because of the risk it carries, including hyperthermia and death, it failed. Fortunately, the discovery of beige fat suggests the possibility of selective respiratory uncoupling in adipose tissues, enabling safe weight loss. The obesity treatment can be achieved by factors that induce the transformation of WAT to beige fat: PGC-1α, Prdm16, cold, β 3-Agonists, Irisin, FGF-21, etc. Activation of beige fat can also bring positive effects on metabolism itself. It is obvious that beige fat makes use of a lot of body energy which leads to decreased fat mass in body. Also, it capitalizes on nutrients available in body fluid such as glucose and triglyceride. This resulted in glucose tolerance and improved lipid metabolism in mice model (Bartelt et al., 2011). Also, there are some evidence that beige fat development helps prevent insulin resistance and atherosclerosis (Chang et al., 2012). Medical benefits and its usage are to be further clarified, but it is certain that study on beige fat will help fight obesity and metabolism disorder. Figure 4 5. ANTICIPATED FURTHER STUDIES As is reviewed above, there are many benefits and applications found and to be found in the study of beige fat. However, for the practical use of beige fat, there are several challenges. One is the thermal influence on functions of beige fat. Experiment conducted by Cannon and Nedergaard revealed that beige fat is only advantageous in thermoneutral environment. In their experiment, mice that are raised in thermoneutral environment (28 30 C) did not affect weight loss or weight gain. Slightly chilly environment (20 22 C) 3

4 showed advantage of normal mice over UCP1 deficient mice, which are not capable of producing heat through brown or beige fat. Also, some experiments revealed that prolonged cold exposure do not activate brown fat and beige fat function. In an experiment by Wang et al., mice were exposed to cold for 3 days and treated with beige fat inducers, but only to find out that new WAT develop. Although many experiments undoubtedly prove advantage of beige fat, the thermal effect on beige fat function should still be figured out further. The applications of beige fat function on products are already on market, but considering the unsure effects, it needs more testing and confirmation. More importantly, most experiments on brown and beige fat revolve around mice studies, not human ones. Considering the ethical issues, more in vitro experiment is needed for the actual efficacy of products utilizing brown or beige fat function. Even though the thermal influence is verified, the efficacy of utilizing brown fat therapeutically is another question. It is sure it can burn fat more efficiently but how much it can burn is still not known. Currently, some products insist that wearing devices that induces cold can burn up to 1,000 calories a day but it is yet groundless story. Another major issue involved with beige fat is that some of its functional mechanisms are still not known not to mention its effects on other organs or even emotions. As is obvious from figure 4, there are many pathways that activate beige fat transformation or activity. But the mechanisms that stimulate orexin or bmp7 are still unknown; some receptors are not found or even its existence is not sure. Although other pathways have been figured out, the effects of excessive or concurrent stimulus is yet to be known. Considering that excessive stimulus on sympathetic nervous system would not be good for both physical and mental health, there certainly is a critical point of its use. In this regard, practical application of beige fat function looks yet premature. The prospect on beige fat technology should not be rosy: for its therapeutic use, scientists should still experiment with its limitations and supplementary effects. 6. REFERENCE [1] Bartelt, A. et al. Brown adipose tissue activity controls triglyceride clearance. Nat. Med. 17, (2011). [2] Busiello Rosa et al. Mitochondrial uncoupling proteins and energy metabolism. Frontiers in Physiology 2015; 6. doi: /fphys [3] Cannon, B. & Nedergaard, J. Brown adipose tissue: function and physiological significance. Physiol. Rev. 84, (2004). [4] Cederberg, A. et al. FOXC2 is a winged helix gene that counteracts obesity, hypertriglyceridemia, and diet-induced insulin resistance. Cell 106, (2001). [5] Chang, L. et al. 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