1

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

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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

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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.

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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.

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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.

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