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Brown adipose tissue: a potential link to Raynaud’s phenomenon
Author: Tim Dekker Date: 26-06-2015
Department of Pathology and Medical Biology Supervisor: G. Krenning
University of Groningen Bachelor essay
2 Inhoudsopgave
Abstract ... 3
Introduction ... 3
Central nervous system and thermoregulation ... 4
Thermogenesis and Obesity ... 6
Perivascular adipose tissue ... 6
UCP1 ... 8
Neuropeptide Y ... 9
Conclusion ... 10
Perspectives ... 11
Acknowledgements ... 12
References ... 12
3 Abstract
Raynaud’s phenomenon is a condition that is characterized by exaggerated vasoconstriction of the peripheral vasculature. This response is most often seen when subjected to cold exposure or stress.
Unfortunately the mechanism leading to Raynaud’s phenomenon is largely unknown. However, people suffering from Raynaud’s phenomenon have a lower core body temperature than controls.
The lower core body temperature can be related to brown adipose tissue (BAT), because BAT generates heat. Brown adipose tissue thermogenesis can be disrupted by an impairment in the proteins that are responsible for thermogenesis, for example uncoupling protein 1 (UCP1). Lacking UCP1 impairs thermogenesis. Not only BAT itself could be impaired, also the sympathetic nervous system could be impaired. The sympathetic nervous system is responsible for stimulating BAT to generate heat. If this stimulation has been reduced, BAT thermogenesis will decrease. Local adipose tissue that shares many similarities with BAT is peripheral vascular adipose tissue (PVAT). PVAT can reduce vasoconstriction by releasing vasodilatating agents, but also by thermogenesis.
In conclusion, Raynaud’s phenomenon may be caused by an impairment in BAT thermogenesis.
Introduction
Raynaud’s phenomenon is a condition in which vasospasms occur in the peripheral arteries in hands, feet and nose (Garciá-Carrasco et al., 2008). Cold exposure is the best known factor that is able to induce these vasospasms, but there are other known causes. Other factors that are known to cause vasospasm include vibrations and emotional stress (Garciá-Carrasco et al., 2008; Saigal et al., 2010;
Herrick, 2005).
Raynaud’s phenomenon is characterized by the loss of blood flow towards the fingers, toes and nose.
This loss of blood flow manifests itself in the change of colour of the skin. Usually the skin loses its healthy colour and becomes pale. When the skin has been closed off of blood for too long, the skin will turn blue because of the lack of oxygen. After the vasospasm attack, the blood flow towards the skin will resume like usual. During this event the skin will become red and there will be a sensation of pain. The prevalence for Raynaud’s phenomenon is 4,85% according to a recent meta-analysis study (Garner et al., 2015). In contrast to the common belief that Raynaud’s phenomenon is a rare
condition, it may very well be a frequently occurring disease. However, the origin of Raynaud’s phenomenon is not clearly defined.
Its prevalence is also higher in women than in men (Garner et al., 2015).
The mechanism that causes Raynaud’s phenomenon is not yet fully understood, even though
Raynaud’s phenomenon has been first diagnosed in 1862 (Herrick, 2005). Unfortunately research has not been able to clearly describe the mechanism or several mechanisms that play a role in Raynaud’s phenomenon. However, there are several insights that partially help to understand Raynaud’s phenomenon. Unfortunately, the best way to treat Raynaud’s phenomenon is by avoiding factors that may potentially trigger a vasospasm attack (Garciá-Carrasco et al., 2008).
Raynaud’s phenomenon is usually regarded as a condition that is caused by the overactivation of the sympathetic system in response to several stimuli like cold exposure (Herrick, 2005). The basis of this response is a natural reaction. It prevents decreasing of our core body temperature by the
constriction of our small peripheral blood vessels (Prete et al., 2014). These small peripheral blood vessels include arteries, arterioles and venules. It would be expected that patients with Raynaud’s phenomenon do have a higher core body temperature, because of the peripheral vasoconstriction.
This prevents the body to lose heat to its environment. However, the core body temperature of these particular subjects is lower compared to the core temperature of controls (Greenstein et al.,
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1995). This implies that there may be an active role reserved for thermoregulation within Raynaud’s phenomenon.
Possibly, the patients that suffer from Raynaud’s phenomenon have an impaired thermoregulation system. However, this impairment does not directly involve the peripheral vasoconstriction. Instead, thermogenesis may be impaired (Flavahan, 2015).
The lower core body temperature of patients with Raynaud’s phenomenon despite the excessive vasoconstriction, suggests that thermogenesis may play an active role in this condition. There are several ways heat can be produced, but in this review the emphasis will lie on non-shivering thermogenesis. Non-shivering thermogenesis is the production of heat by brown adipose tissue (BAT). There is a possibility that an impairment of thermogenesis by BAT can be causal to Raynaud's phenomenon. In this review the role of brown adipose tissue on Raynaud’s phenomenon will be elaborated. The hypothesis states that a decrease in BAT activity or volume can cause RP by impaired thermogenesis and via vasoactive factors that are secreted by BAT around blood vessels. This review will focus on important aspects that are crucial to thermogenesis.
BAT cells contain many small triglyceride droplets and many mitochondria (Betz & Enerbäck, 2015).
BAT has been proven to be important in non-shivering thermogenesis. BAT was first found in
rodents, where it had an important function in thermoregulation (Cannon & Nedergaard, 2004). Until recently it was thought that adult humans did not have any BAT, only infants were known to have BAT (Cypess et al., 2009).
Central nervous system and thermoregulation
In order for BAT to properly function as a thermogenic adipose tissue, it needs input from its environment. This input is indirectly given from the skin, since the skin is the organ that has direct contact with the outside environment.
The skin contains neurons that have specific receptors that for either warmth or cold. These receptors are called warm or cool cutaneous thermal sensory receptors (Tupone et al., 2014). The warm and cool neurons have connection with the dorsal horn which is in its turn connected with the preoptic area (POA) in the hypothalamus (Tupone et al., 2014; Nakamura & Morrison, 2007). The POA contains among others warm-sensitive neurons. These warm-sensitive neurons have an
intrinsically inhibiting effect on the neurons present in the dorsal medial hypothalamus that regulate the activation of BAT. These warm-sensitive neurons do get input from the neurons present in the skin. Either warm sensory receptors, cold sensory receptors or both can be activated in the skin. The warm sensory receptors have an excitation range from 30 degrees Celsius to 50 degrees Celsius and the cold sensory receptors have an excitation range that starts at 10 degrees Celsius and ends at 40 degrees Celsius (Tupone et al., 2014). The warm-sensitive neurons get excited by the input of the warm sensory receptor via glutamate. The stimulation of the warm-sensitive neurons inhibits the neurons present in the dorsal medial hypothalamus (DMH) by releasing GABA
(Tupone et al., 2014; Nakamura & Morrison, 2007). By high inhibition of the dorsal medial
hypothalamus these neurons will not excite and cannot stimulate other neurons. However, the cool sensory receptors have the opposite reaction. The sensory neurons that contain these receptors inhibit the warm-sensitive neurons by excretion of GABA. This impairs the inhibiting functionality of the warm-sensitive neurons. Because of this inhibition, the dorsal medial hypothalamus neurons that regulate thermogenesis do not get inhibited. The DMH stimulates the raphe pallidus that has
sympathetic nerve ending leading to BAT (Tupone et al., 2014). An overview of thermoregulation by the hypothalamus can be seen in Figure 1. Via the raphe pallidus BAT gets stimulated and will in turn
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generate more heat. Except the BAT-activating neurons present in the raphe pallidus, there are also serotonin neurons present. These serotonin neurons enhance the activity of BAT by inhibiting the GABAergic effect on BAT. If warm-sensitive neurons do not get inhibited by the cold sensory neurons the activity of BAT will decrease.
Thus, in order for BAT to properly function it needs the skin. The skin senses the temperature of the environment and sends signals towards the hypothalamus. The hypothalamus then decides whether it is needed to stimulate BAT to generate heat.
Figure 1: A schematic overview of the stimulation of BAT (Adapted from Tupone et al., 2014).
Impairment in this system may lead to increased or decreased thermogenesis. Either the warm or cold sensitive neurons could be impaired, which gives the upper hand to the other one. Another option is that there are disruptions in the brain or in the nerves leading to BAT. The last possibility would most likely be related to Raynaud’s phenomenon. If the brain fails to stimulate thermogenesis through BAT, the body temperature would not rise if shivering thermogenesis does not occur either.
If no impairment present in the nerves that lead from the brain to the blood vessels, it may cause an exaggerated vasoconstriction to compensate for the loss of temperature.
6 Thermogenesis and Obesity
In obesity induced mice their genetic defect is often related to uncoupling protein 1 (UCP1) (Feldmann et al., 2009). UCP1 is a protein that plays a role in the generation of heat. A detailed explanation of the pathway of UCP1 will be explained later.
An impairment regarding the functionality of UCP1 causes mice to generate less heat. Instead of generating heat via UCP1 like normal mice, obesity induced mice do not. Obese induced mice do not use energy storages in BAT in order to generate heat, which means there will be more left (Kozak &
Anunciado-Koza, 2008). This will cause the mouse to gain weight (Feldmann et al., 2009).
However, this is not always the case. There are also reports that mice without UCP1 or a non- functioning UCP1 are obesity resistant (Xiaotun et al., 2003; Enerbäck et al., 1997). These mice, however, are cold-sensitive (Enerbäck et al., 1997). This means that these mice use an alternative way to burn fat, instead of non-shivering thermogenesis. Other ways of generating heat have been suggested to play a role in their obesity resistance. Mice lacking UCP1 could use inefficient
alternatives to generate heat, for example shivering thermogenesis. It should be noted that thermogenesis in mice is focused on non-shivering thermogenesis; instead of shivering
thermogenesis and that the latter is inefficient when it comes to the generation of heat (Kozak &
Anunciado-Koza, 2008; Xiaotun et al., 2003). When exposed to normal temperature, mice lacking UCP1 do not have to use these inefficient ways to burn fat. Therefore, at normal temperatures they are not obesity resistant (Feldmann et al., 2009).).
In humans it is found that patients suffering from obesity have a lower BAT activity (van Marken Lichtenbelt et al., 2009). Bat activity is inversely correlated with BMI (van Marken Lichtenbelt et al., 2009; Cypess et al., 2009). Unfortunately, BAT activity could not be correlated with thermogenesis (van Marken Lichtenbelt et al., 2009). On the other hand, BAT activity was found to be correlated to the change of temperature in the distal vasculature because of cold exposure (van Marken
Lichtenbelt et al., 2009). This indicates that BAT does influence the temperature of the skin. This is in particular interest regarding Raynaud’s phenomenon. If BAT is able to maintain a stable skin
temperature during cold exposure, vasoconstriction does not have to take place. Unfortunately there are as of yet no studies published that found a correlation between obesity and Raynaud’s
phenomenon. This would have shed more light on the role that BAT plays in Raynaud’s phenomenon.
In summary, BAT activity is negatively correlated with obesity. There was no clear negative correlation between BAT volume and obesity.
Perivascular adipose tissue
Most commonly known adipose tissues are White adipose Tissue (WAT) and BAT, less known is peripheral vascular adipose tissue (PVAT). PVAT is adipose tissue that is found around blood vessels.
PVAT is a relatively new subject within the study of vascular function and dysfunction. At first it was thought to have no actual influence on the blood vessels except that of offering support (Chang et al., 2012; Miao & Li, 2012). However, PVAT does have many other functions that do involve the vasculature.
PVAT is known to play a role in vasodilatation, vasoconstriction, thermogenesis, angiogenesis and inflammation as can be seen in Figure 2 (Chang et al., 2013). Even though PVAT does produce factors that have vasoconstrictive properties, PVAT is a more potent vasodilatator than a vasoconstrictor (Gao et al., 2007).
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Figure 2: Multiple functions of PVAT that influence the vasculature.
aFGF, acidic fibroblast growth factor; IGFBP-3, insulin-like growth factor-binding protein-3; IL, interleukin; MCP, monocyte chemotactic protein; TNF, tumor necrosis factor; UCP-1, uncoupling protein-1 (Chang et al., 2013).
Vasodilatating factors that are produced by PVAT can be either endothelium-dependent or endothelium-independent (Gao et al., 2007). Several vasodilatating agents from PVAT are already well known, including nitric oxide, prostacyclin and adiponectin. Besides these vasodilatating agents, PVAT also produces one or more agents that are as of yet unknown. These factors are known as PVAT-derived relaxing factor (PVRF) (Szasz & Webb, 2007). Unlike the known vasodilatating factors produced by PVAT, PVRF can be endothelium-dependent as endothelium independent. The factors that originate from PVAT are largely transferable, which means PVAT does not need direct contact in order to influence the vascular tone of the nearby blood vessel (Gao et al., 2005).
As mentioned before PVAT does not only influence the vascular tone, it can also have other properties. One of these properties that is of special interest, because of its relation to BAT and Raynaud’s phenomenon is the generation of heat.
PVAT is known to be able to generate heat in a similar way as BAT. However, the phenotype of PVAT is different when looked at different blood vessels (Brown et al., 2014). Even though the phenotype of PVAT has its differences at different locations, it has many similarities with BAT. The first similarity that is found between BAT and PVAT is that their structure is very much alike (Chang et al., 2012).
Both in BAT and PVAT there are many mitochondria present, as well as many fat droplets. In WAT however, less mitochondria can be found and it usually has one large fat droplet that takes up almost all of the space in the cell. Except these obvious similarities, there are also many similarities in protein expression. UCP1, PGC1α/ß and Cidea are proteins that play key role in the generation of heat in BAT and are therefore highly expressed in BAT. UCP1 is a protein that plays a role in the generation of heat by BAT. PGC1 is a class of proteins that play a role in the synthesis of
mitochondria, and are important in the process of thermogenesis. Idea is a protein that is linked to reduced thermogenesis and lipolysis (Zhou et al., 2003). These proteins are also highly expressed in
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PVAT, but not in WAT (Chang et al., 2012). This further elaborates the similarities between BAT and PVAT.
These similarities indicate that PVAT also has an important role in thermogenesis. This aspect can be related to Raynaud’s phenomenon, since this condition manifests itself in the peripheral vasculature.
UCP1
The most notable protein that plays a very important role in thermogenesis by BAT cells, is UCP1. The heat that is produced by BAT is largely the result of the functioning of UCP1 (Kozak & Anunciado- Koza, 2008). Although there have been suggestions that UCP1 is not per se crucial in order to maintain a stable temperature, it is very likely one of the most important proteins that play a role in thermogenesis in BAT (Xiaotun et al., 2003). UCP1 can be found in the mitochondria of BAT (Kozak &
Anunciado-Koza, 2008). The density of mitochondria in BAT is higher than in any other tissue found in the body (Kozak & Anunciado-Koza, 2008). UCP2 and UCP3 can also be found in the mitochondria but at a very low concentration compared to UCP1. UCP2 and UCP3 could also not be associated with thermogenesis and their potential role in obesity (Nedergaard et al., 2001).
The high amount of mitochondria found in BAT is required for its thermogenic property (Betz &
Enerbäck, 2015).
Mitochondria produce ATP by oxidizing products that come from the citric cycle which takes place in the cytoplasm. Several complexes transport protons out of the mitochondrial matrix into the
intermembrane space by oxidizing products from the citric cycle. The last complex, however,
transports a proton from the intermembrane space into the mitochondrial matrix (Nedergaard et al., 2001). These complexes together are called the respiratory chain. This process is accompanied by the production of ATP from ADP and a third phosphate. ATP is a form of energy that can be used by the cell.
UCP1 is a protein that is also present on the border of the intermembrane space and the
mitochondrial matrix. It allows protons to be return to the mitochondrial matrix. By allowing protons to return to the mitochondrial matrix, there are fewer protons present in the intermembrane space to be used by the last complex that produces ATP. UCP1 essentially lowers the ATP production, but does not change the oxidation rate. It does not influence how the previous complexes behave, so those complexes still pump protons into the intermembrane space to be used by the last complex. By not influencing the oxidation but lowering the ATP that can be produced, the net energy gain has been decreased. The energy that could not be used to produce ATP dissipates into heat. Since BAT cells have many mitochondria, the heat production can be high.
Figure 3 shows that the receptor that is linked to UCP1 is the ß3-receptor (Nedergaard et al., 2001;
Tupone et al., 2014). This receptor can be found on BAT cells. ß3-receptor can either be activated by adrenaline or noradrenalin. The ß3-receptor is linked to G protein-coupled receptor. This G protein has a Gas alpha subunit. Which means it utilizes adenylyl cyclase to produce cAMP. Increased cAMP increases PKA. PKA then produces free fatty acids (FFA) from a triglyceride droplet that is present in BAT. This FFA will be used in the citric cycle by acetyl-COA.
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Figure 3: The molecular pathway leading to UCP1 and heat generation (Nedergaard et al., 2001).
In an as of yet unknown mechanism this increases the activity of UCP1 present in the mitochondria.
There have been several possible mechanisms proposed (Nedergaard et al., 2001). UCP1 could be inhibited by ATP, although this does not have to be the case. UCP1 may also be stimulated by FFA either direct or indirect via IPA, it could also be directly stimulated by the ß3-receptor. The exact pathway is unfortunately still unknown.
Thus, UCP1 is a protein that plays an important role in thermogenesis in BAT. UCP1 allows protons to return to the mitochondrial matrix, so it cannot directly be used to produce ATP. Instead, heat will be generated
Neuropeptide Y
Neuropeptide Y (NPY) is known to play a role in the regulation of food intake (Kalra & Kalra, 2004).
NPY is one of the main regulators of food intake and an increase in NPY causes an increase in food intake (Kalra & Kalra, 2004). This increased intake of food will eventually cause obesity. NPY is able to increase food intake, by influencing the dorsomedial hypothalamus (Yang et al., 2009). The
hypothalamus is the main regulator regarding food intake. Not only is NPY important in the
regulation of food intake, it also plays a role in energy expenditure. When NPY expression is knocked down in the dorsomedial hypothalamus, energy expenditure was higher (Chao et al., 2011). Also BAT activity was higher after NPY knockdown, which is related to higher energy expenditure. NPY is inhibiting BAT activity and therefore energy expenditure. However, not only NPY expression in the dorsomedial hypothalamus plays a role in influencing BAT activity. NPY can also mediate an effect via the arcuate nuclei of the hypothalamus. NPY is able to reduce sympathetic outflow (Shi et al., 2013).
By reducing the sympathetic outflow, NPY can reduce energy expenditure. This includes energy expenditure by BAT through thermogenesis.
Since BAT may possibly play a role in Raynaud’s phenomenon, NPY can be one of the factors that decrease the core body temperature. This reduction can, as explained before, cause an exaggerated vasoconstriction of the peripheral vasculature in order to reduce a further decrease of body
temperature.
Except this possible indirect mechanism of NPY relating to Raynaud’s phenomenon, it is also directly related to vasoconstriction and maybe vasospasms. NPY is a neurotransmitter that can cause vasoconstriction of the peripheral vasculature (Zukowska et al., 2003). This neuropeptide is likely a regulator that associates obesity and BAT activity with Raynaud’s phenomenon.
Thus, NPY is a regulator of energy metabolism. It is able to increase energy levels by increasing food intake and by decreasing energy expenditure, including BAT thermogenesis.
10 Conclusion
In conclusion, Raynaud’s phenomenon can be caused by an impairment relating to BAT. This impairment can be related to the functioning of BAT, but it can also be related to the pathways that stimulate the activity of BAT. PVAT that surrounds the vasculature can also play a role in Raynaud’s phenomenon by a misbalance of the secretion of vasoactive factors. If this imbalance favors the vasoconstrictive factors in the peripheral vasculature, vasoconstriction is more easily established.
Figure 4: A summary of the components that can play a role in the pathology of Raynaud’s phenomenon.
In Figure 4 components that can play a role in the pathology of Raynaud’s phenomenon are summarized. It starts with the skin that can sense the temperature. This information about the temperature will be processed by the hypothalamus. If the temperature is low, the hypothalamus will stimulate BAT activity through the sympathetic nervous system. Stimulation of BAT increases the generation of heat, thermogenesis. An impairment that stops BAT from generating heat in response to cold exposure can cause Raynaud’s phenomenon and obesity. Raynaud’s phenomenon is
characterized by exaggerated vasoconstriction of the peripheral vasculature. PVAT shares many traits with BAT and can induce vasodilatation, directly by releasing vasodilatating agents and indirectly by the generation of heat. A higher local temperature can prevent exaggerated vasoconstrictions. NPY also plays a role in BAT thermogenesis, it decreases BAT activity. NPY mediated reduction of BAT activity can be related to Raynaud’s phenomenon and obesity.
The mechanism that causes Raynaud’s phenomenon as a result impaired BAT functionality, remains unknown. It can be suggested that it is a compensation mechanism. Patients suffering from
Raynaud’s phenomenon have a lower core body temperature compared to controls and therefore may have a lower or Impaired BAT activity. Impaired BAT generates less heat. In turn, this will cause the core body temperature to decrease. If the skin is then subjected to cold exposure, the
hypothalamus will induce exaggerated peripheral vasoconstriction in an attempt to maintain the core body temperature.
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Local impairments, like a disrupted PVAT function in the peripheral vasculature may also contribute to Raynaud’s phenomenon. PVAT has numerous functions, including mediating vasodilatation, vasoconstriction and thermogenesis. An increased release of vasoconstrictive agents causes local vasoconstriction. Besides this obvious pathway leading to vasoconstriction, its thermogenic property should be not be neglected. Local thermogenesis may contribute to a decreased reaction to cold exposure. Local heat generation may counteract the need of vasoconstriction, by increasing the temperature of the skin.
Not only Raynaud’s phenomenon is related to reduced thermogenesis. Obesity is known to be inversely correlated to BAT activity and thus thermogenesis. Obesity is a condition that can be used to discover mechanisms concerning BAT, which can be used to understand Raynaud’s phenomenon.
Lower BAT activity in obesity is related to UCP1 and NPY. A defect in UCP1 causes obesity in thermoneutral conditions. Lack of UCP1 causes BAT to be unable to generate heat and therefore is unable to burn fat. NPY can also induce obesity by influencing the sympathetic nervous system. NPY inhibits the activation of BAT by the sympathetic nervous system in order to reduce energy
expenditure.
However, BAT is not the only tissue that is able to generate heat. Shivering thermogenesis by skeletal muscles could also be involved in the lower core body temperature found in Raynaud’s
phenomenon. It should be noted, however, that the decrease in core body temperature may be too low to be compensated by shivering thermogenesis.
Unfortunately there were no articles that found a correlation between obesity and Raynaud’s
phenomenon. This means that a thermogenesis impairment found in obesity does not have to be the same as in Raynaud’s phenomenon. A more detailed study regarding obesity and Raynaud’s
phenomenon can shed light on the shared treats concerning thermogenesis.
A more direct step to confirm the role of thermogenesis in Raynaud’s phenomenon is by measuring BAT activity in patients with Raynaud’s phenomenon.
Perspectives
It would be interesting to look into the relation of thermogenesis with Raynaud’s phenomenon. Since the main trigger to induce exaggerated vasoconstriction in Raynaud’s phenomenon is cold exposure, it is indicated that there must be a relation to thermogenesis. It should be noted that Raynaud’s phenomenon does not have to be a peripheral centered condition. It may as well be regulated by the hypothalamus, which plays a large role in maintaining and changing the core body temperature.
Attempting to treat Raynaud’s phenomenon with a thermogenic agent, would also shed light on the possible thermogenic basis of Raynaud’s phenomenon. 7-oxo-DHEA, a thermogenic steroid, has been used to treat Raynaud’s phenomenon (Ihler & Chami-Stemmann, 2003). It is important to note that this was merely a very small experiment with one patient and no controls. The patient had no attacks of exaggerated vasoconstriction when using 7-oxo-DHEA. Discontinuation led to the returning of these attacks. This suggests that patients with Raynaud’s phenomenon benefit from the use of thermogenic agents. It is important to take possible side effects into account.
Cold exposure promotes the forming of atheriosclerotic plaques (Dong et al., 2013). This cold exposure activates lipolysis, which leads to high cholesterol in the blood circulation (Dong et al., 2013). The cold exposure stimulated BAT activity which led to higher lipolysis and consequently higher cholesterol found in the blood circulation.
The combination of vasodilatating drugs with thermogenic agents may be a good comprise.
Combining these two to counteract Raynaud’s phenomenon can lower the dose needed to treat
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Raynaud’s phenomenon. As a consequence, there will be fewer side effects present. This benefits the patient greatly, especially those with mild vasospasm attacks.
Acknowledgements
I would like to thank G. Krenning for supervising this essay.
References
Betz, M. J., & Enerbäck, S. (2015). Human Brown adipose tissue: what we have learned so far.
Diabetes, 64(7), 2352-60
Brown, N. K., Zhou, Z., Zhang, J., Zeng, R., Wu, J., Eitzman, DT., Chen, Y. E., & Chang, L. (2014)
Perivascular adipose tissue in vascular function and disease: a review of current research and animal models. Arterioscler Thromb Vasc Biol, 34(8), 1621-30. doi: 10.1161/ATVBAHA.114.303029
Cannon, B., & Nedergaard, J. (2004). Brown adipose tissue: function and physiological significance.
Physiol Rev, 84(1), 277-359
Chang, L., Milton, H., Eitzman, D. T., & Chen, Y. E. (2013). Paradoxical roles of perivascular adipose tissue in atherosclerosis and hypertension. Circ J, 77(1), 11-8
Chang, L., Villacorta, L., Li, R., Hamblin, M., Xu, W., Dou, C., Zhang, J., Wu, J., Zeng, R., & Chen, Y. E.
(2012). Loss of perivascular adipose tissue on peroxisome proliferator-activated receptor-γ deletion in smooth muscle cells impairs intravascular thermoregulation and enhances atherosclerosis.
Circulation, 126(9), 1067-78. doi: 10.1161/CIRCULATIONAHA.112.104489
Chao, P. T., Yang, L., Aja, S., Moran, T. H., & Bi, S. (2011). Knockdown of NPY expression in the dorsomedial hypothalamus promotes development of brown adipocytesand prevents diet- induced obesity. Cell Metab, 13(5), 573-83. doi: 10.1016/j.cmet.2011.02.019.
Cypess, A. M., Lehman, S., Williams, G., Tal, I., Rodman, D., Goldfine, A. B., Kuo, F. C., Palmer, E.
L., Tseng, Y. H., Doria, A., Kolodny, G. M., & Kahn, C. R. (2009). Identification and importance of brown adipose tissue in adult humans. N Engl J Med, 360(15), 1509-17
Dong, M., Yang, X., Lim, S., Cao, Z., Honek, J., Lu, H., Zhang, C., Seki, T., Hosaka, K., Wahlberg, E., Yang, J., Zhang, L., Länne, T., Sun, B., Li, X., Liu, Y., Zhang, Y., & Cao, Y. (2013).
Cold exposure promotes atherosclerotic plaque growth and instability via UCP1-dependent lipolysis.
Cell Metab, 18(1), 18-29. doi: 10.1016/j.cmet.2013.06.003
Enerbäck, S., Jacobsson, A., Simpson, E. M., Guerra, C., Yamashita, H., Harper, M. E., & Kozak, L. P.
(1997). Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese. Nature, 287(6628), 90-4
Feldmann, H. M., Golozoubova, V., Cannon, B., & Nedergaard, J.(2009). UCP1 ablation induces obesity and abolishes diet induced thermogenesis in mice exempt from thermal stress by living at thermoneutrality. Cell Metab, 9(2), 203-9. doi: 10.1016/j.cmet.2008.12.014.
Flavahan, N. A. (2015). A vascular mechanistic approach to understanding Raynaud phenomenon.
Nat Rev Rheumatol, 11(3), 146-58. doi: 10.1038/nrrheum.2014.195
13
Gao, Y. J., Zeng, Z. H., Teoh, K., Sharma, A. M., Abouzahr, L., Cybulsky, I., Lamy, A., Semelhago, L.,
& Lee, R. M. (2005). Perivascular adipose tissue modulates vascular function in the human internal thoracic artery. J Thorac Cardiovasc Surg, 130(4), 1130-6
Gao, Y.-J., Lu, C., Su, L.-Y., Sharma, A. M., & Lee, R. M. K. W. (2007). Modulation of vascular function by perivascular adipose tissue: the role of endothelium and hydrogen peroxide. British Journal of Pharmacology, 151(3), 323–331. doi:10.1038/sj.bjp.0707228
García-Carrasco, M., Jiménez-Hernández, M., Escárcega, R. O., Mendoza-Pinto, C., Pardo-Santos, R., Levy, R., Maldonado, C. G., Chávez, G. P., & Cervera, R. (2008). Treatment of Raynaud’s phenomenon. Autoimmun Rev, 8(1), 62-8. doi: 10.1016/j.autrev.2008.07.002
Garner, R., Kumari, R., Lanyon, P., Doherty, M., & Zhang, W. (2015) Prevalence, risk factors and associations of primary Raynaud's phenomenon: systematic review and meta-analysis of observational studies. BMJ Open, 5(3), e006389. doi: 10.1136/bmjopen-2014-006389 Greenstein, D., Gupta, N. K., Martin, P., Walker, D. R., & Kester, R. C. (1995). Impaired thermoregulation in Raynaud’s phenomenon. Angiology, 46(7), 603-11.
Herrick, A. L. (2005). Pathogenesis of Raynaud’s phenomenon. Rheumatology (Oxford), 44(5), 587-96.
Ihler, G., & Chami-Stemmann, H. (2003). 7-oxo-DHEA and Raynaud's phenomenon. Med Hypotheses, 60(3), 391-7.
Kalra, S. P., & Kalra, P. S. (2004). NPY and cohorts in regulating appetite, obesity and metabolic syndrome: beneficial effects of gene therapy. Neuropeptides, 38(4), 201-11
Kozak, L. P., & Anunciado-Koza, R. (2008). UCP1: its involvement and utility in obesity. Int Obes (Lond), 32, S32-8.doi : 10.1038/ijo.2008.236
Liu, X., Rossmeisl, M., McClaine, J., Riachi, M., Harper, M. E., & Kozak, L. P. (2003). Paradoxical resistance to diet-induced obesity in UCP1-deficient mice. J Clin Invest, 111(3), 399-407.
doi: 10.1172/JCI200315737
Miao, C. Y., & Li, Z. Y.(2012). The role of perivascular adipose tissue in vascular smooth muscle cell growth. Br J Pharmacol, 165(3), 643-658. doi: 10.1111/j.1476-5381.2011.01404.x
Nakamura, K., & Morrison, S. F. (2007). Central efferent pathways mediating skin cooling-evoked sympathetic thermogenesis in brown adipose tissue. Am J Physiol Regul Integr Comp Physiol, 292(1), R127-36.
Nedergaard, J., Golozoubova, V., Matthias, A., Asadi, A., Jacobsson, A., & Cannon, B. (2001). UCP1:
the only protein able to mediate adaptive non-shivering thermogenesis and metabolic inefficiency.
Biochim Biophys Acta, 504(1), 82-106
Prete, M., Fatone, M. C., Favoino, E., & Perosa, F.(2014). Raynaud’s phenomenon: from molecular pathogenesis to therapy. Autoimmun Rev, 13(6), 655-67. doi: 10.1016/j.autrev.2013.12.001 Saigal, R., Kansal, A., Mittal, M., Singh, Y., & Ram, H. (2010). Raynaud’s phenomenon. J Assoc Physicians India, 58, 309-13.
14
Shi, Y. C., Lau, J., Lin, Z., Zhang, H., Zhai, L., Sperk, G., Heilbronn, R., Mietzsch, M., Weger, S., Huang, X.
F., Enriquez, R. F., Baldock, P. A., Zhang, L., Sainsbury, A., Herzog, H., & Lin, S. (2013).
Arcuate NPY controls sympathetic output and BAT function via a relay of tyrosine hydroxylase neurons in the PVN. Cell Metab, 17(2), 236-48. doi: 10.1016/j.cmet.2013.01.006
Szasz, T., & Webb, R. C.(2012). Perivascular adipose tissue: more than just structural support. Clin Sci (Lond), 122(1), 1-12. doi: 10.1042/CS20110151.
Tupone, D., Madden, C. J., & Morrison, S. F. (2014) Autonomic regulation of brown adipose tissue thermogenesis in health and disease: potential clinical applications for altering BAT thermogenesis.
Front Neurosci, 8, 14. doi: 10.3389/fnins.2014.00014
van Marken Lichtenbelt, W. D., Vanhommerig, J. W., Smulders, N. M., Drossaerts, J. M., Kemerink, G.
J., Bouvy, N. D., Schrauwen, P., & Teule, G. J.(2009). Cold-activated Brown adipose tissue in healthy men. N Engl J Med, 360(15), 1500-8. doi: 10.1056/NEJMoa0808718
Yang, L., Scott, K. A., Hyun, J., Tamashiro, K. L., Tray, N., Moran, T. H., & Bi, S. (2009). Role of
dorsomedial hypothalamic neuropeptide Y in modulating food intake and energy balance. J Neurosci, 29(1), 179-90. doi: 10.1523/JNEUROSCI.4379-08.2009
Zhang, W., Cline, M. A., & Gilbert, E. R. (2014). Hypothalamus-adipose tissue crosstalk: neuropeptide Y and the regulation of energy metabolism. Nutr Metab (Lond), 11, 27. doi: 10.1186/1743-7075-11- 27
Zhou, Z., Yon Toh, S., Chen, Z., Guo, K., Ng, C. P., Ponniah, S., Lin, S. C., Hong, W., & Li, P. (2003).
Cidea-deficient mice have lean phenotype and are resistant to obesity. Nat Genet, 35(1), 49-56.
Zukowska, Z., Pons, J., Lee, E. W., & Li, L. (2003). Neuropeptide Y: a new mediator linking sympathetic nerves, blood vessels and immune system? Can J Physiol Pharmacol, 81(2), 89-94
