LrdViperScrpion

Wow, awesome post, thanks TCD.

w8lifter

Way cool....so what exactly do you do for GPP?...or did I miss that too? lol

Robboe

I posted this in the stubborn fat thread:

I weighed in 2lbs lighter this week, at 14st 6lbs, which is 202lbs.

Got up today at 10:30, took ECA (yes, took the E today, despite what Lyle says) and 2g L-Tyrosine.

Had a green tea while waiting and hit the gym by 11:15am. It would have been 11am, but i had to sort out my membership to that place, chanign my membership from 'induction' to 'full', whatever the fuck that means. basically, i pay less to use it now.

3 minute warm up.

5 minutes progressive running

4 minute walk.

2 minutes sprint.

2 minutes walk.

2 minutes sprint.

I did this just last night remember, can't expect to progress everytime.

30 minutes on the stepper, which proved rather easier than last night. From this i can derive that either: 1. E aids aerobic work more than anaerobic work OR 2. me forgetting to up the stepper program by 2 makes a LOT of difference. I somehow htink it's the former.

The E really made me sweat buckets too.

Here are some random thoughts from the stepper:

1. I hope to god they find Holly and Jessica alive (i was watching sky news on the stepper TV).

2. Skateboarding looks painful when you come off.

3. Surfing looks cool.

(numbers 2 + 3 are from me looking at the TV on the stepper next to me which had on Ex TV, which rocks, incidentally).

4. 9/11 was in my head. On that day i was on the exact same stepper in that very same gym watching coverage of events on sky news, so it broguth some memories back.

5. If you have any questions or queries to why i do certain things that i haven't already explained then feel free to ask. I'm not gonna bite anyone's head off in this thread. I'm trying to keep it as professional as possible actually. If you do have a question, i can't guarantee i'll have an answer, but i'll do my best to find out for you.

6. I'm really sad for thinking of an online journal when doing cardio.

7. I hope i don't get too drunk and end up scoring with an old biddy tonight...

Being held down by The Man

Dr. Pain

Why are you called 'The Chicken Daddy?"



Dp

Robboe

Not 100% sure, but i've come to this conclusion:


"Fuck knows".




Way to keep it professional Rob...

Being held down by The Man

Dr. Pain

Thanks....thought so


DP

w8lifter

I thought there was a story to it

Robboe

There was but it's from years ago and i've forgot it now.

Well, i ate a shit load last night. and drank a lot of frosty beverages.

I'm not gonna say much more than that, other than me and John Smith are very well acquainted now.

God, i just remembered i even fell asleep at the bar too.

We were at the aeroclub, which is the old terminal for newcastle airport years and years ago. It was quite small like. It looks onto the airfield so we were watching the planes land and take off, which was quite cool.

So i woke up this morning sweating from the heat and with my heart beat in my head (a feeling i hate with a passion).

It felt like no matter how much water i drank i was still dehydrated.

I pulled myself together and went to the gym. Didn't do my usual workout, don't think i could muster it really.

Squats: 4 sets of 4.
SLDLs: 2 sets of 2, 1 set of 6.
Hack: 4 sets of 4 (with a progressive weight).

3 sets of high rep speed seated calf raises and then 2 sets of standing calf raises.

Did some abs too, 2 sets of cable crunches.

Also note that none of these sets were to failure. I stopped just shy on all sets, except maybe the third set of the speed seated calf work.

That is actually quite high volume for me.

Being held down by The Man

Dr. Pain

Any "Old Biddies" receive a "Speed Set?"

DP

Robboe

lmao.


Actually, i didn't go to the coast, we changed plans and we're going there next sunday for the bank holiday weekend instead.

Being held down by The Man

w8lifter

Likely story....*searches WBB*

kuso

Make sure to post it when you find it

Tank316

great thread, really enjoying it. where do you get your dex and malto from?

P/RR/Sh Warrior.
Epic's new man beast.

Robboe

Just flying on to update this bad boy.

Tank, dextrose from a pharmacy in England called 'Boots'. Dunno if you have it over there? It costs like £1.50 for 1kg, which is like $2.50 or so American dollars.

The malto is just some of the dorian Yates approved, cause my gym sold me it on the cheap.

I got home from work today and went to the library, and boy does my local one suck camel dick.

I went in for some real-life forensic books, and they had arse-all.

I was also hoping for some good endocrinology books or something on neurotransmitters, but they had toss-all.

To sum up how shit my local library is: they have no immediate copies of 'The Hobbit' or 'The Silmarillion', the bastards. I've had to order them in.

Anyhoo, got to the gym even later than usual for the cardio.

Took 200mg caff and 2g L-Tyrosine.

5 minutes sprinting with progressive pace.

2 minutes walk.

3 minutes progressive sprinting.

3 minutes walk.

2 minutes sprint.

5 minute wait.

30 minutes on the stepper.

Sweat was, again, rining out of me.

Small piece of chicken upon my return and then a full meal about 20-30 minutes later.

I missed the newcastle match on TV tonight (we won 4-0) cause my cousin's kid is up. She's totally lush, but she's also a right little madam when she wants to be. We took her down to the Millenium bridge and then for a MacDonald's (not to worry, i resisted )

Incidentally, i've ordered some Yohimbine HCL caps from the US. They should hopefully be here in a few days. I'll give y'all some info on it, if you're unsure of what it is or how it works.

Hopefully i'll be able to go into some good detail about fat receptors (alpha and beta), but i just gotta get it all totally clear in my head first


I need to try and get some more ephedrine too. Which is gonna be annoying.


Hey, out of interest, has anyone bought and read the 'Bromocriptine' ebook by Lyle McDonald from qfac at all?

If so, what's it like?

I really wanna read it, but id rather have a hard copy and it's done in flash so cuting and pasting is out of the question, unless anyone knows any little tricks?

Being held down by The Man

Dr. Pain

TCD, I'm very interested in your analysis of the Yohimbine HCL. IMO it works best on gynoid fat distributions where there is preponderance of A-2 receptors. My recollection is poor concerning certain insulin issues, w8 may still have my resources on those.

But I wanted to tell you that since you are big on self-experimentation....when your BF levels are low enough...I am in possession of Dan's "Spot Reduction" formula based on Yohimbine.


DP

Robboe

Well i got quite a bit on the andrenergic system and fat receptors (since they're my new 'thing' - i seem to be obsessed with the whole fat burning thing right now).

And you're right about the a-2 receptors.

I'll post a lot more later, but i gotta go lift some weights now.

Being held down by The Man

Yanick

This was posted by DP a while ago on ABC, i think i was the only one that actually read it though, lol. A lot of it went right over my head because i was new to learning all about this stuff. I started to read it again and a lot of it makes perfect sense now. Not an article for a beginner, IMO.

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Introduction
Loss of body fat has become an obsession for Western society. Accordingly, overweight and obesity are associated with high risks for various pathophysiological conditions and a lower mortality rate. Approaches to body fat loss vary according to genetic and environmental factors. Moreover, regulation of both energy intake and energy expenditure can be moderated in several ways. The autonomic nervous system contributes to maintenance of homeostasis in the body by way of the sympathetic nervous system. This system stimulates energy mobilization and utilization in many tissues. Therefore, manipulation of the sympathetic nervous system may change body composition. This article will examine the role of fat tissue metabolism, the sympathetic nervous system, and a pharmaceutical approach to fat loss.
The physiological role of the sympathetic nervous system (SNS) is a major target of study for modulation of body weight and composition. The principal role players in the SNS are hormones called catecholamines and the adrenergic receptors (adrenoceptors) upon which they act. Aside from insulin, the catecholamines are the primary regulators of fat breakdown in cells by way of stimulation of adrenoceptors on the cell membrane. Activation of these adrenoceptors produces differing responses in the cell depending on receptor type, subtype and tissue. Two types of adrenoceptors, alpha- and beta-adrenoceptors, differentially stimulate or inhibit lipolysis and provide for dual control mechanisms within the fat cell.
A host of drugs that manipulate the SNS to reduce body fat have appeared and disappeared in the last few decades. Bryan Haycock published an article on Meso-Rx examining the role of beta-adrenergic receptors in fat loss and diet drugs that increase lipolysis (Pharmacological Approaches to Fat Loss: Targeting Beta-Adrenergic Receptors, July 1998, Vol. 1, No. 2) at the b -receptor and post-receptor levels. This article will examine the role of alpha-adrenoceptors and an alternative pharmaceutical approach to fat loss.
The first part of this article will discuss adrenoceptors and their function so that readers may comprehend the dual adrenergic regulation of lipolysis. The lipolytic process was discussed in Bryan's article (see above), but will be summarized here to acquaint those who have not read Bryan's article. The second installment of the article will examine the role of alpha2-adrenoceptors in adipose and other tissues and the ways they influence regulation of lipolysis. Finally, we will see how yohimbine, an alpha2-adrenoceptor antagonist can be of use in the pharmacological approach to fat loss.
Lipolysis Revisited
Adipose tissue, commonly called body fat, serves several functions in the body such as in storage and provision of energy, insulation, and mechanical support as in the sole of the foot or in the palm of the hand. The majority of human adipose tissue is metabolically active, although some depots appear to serve only a mechanical function and may be metabolically inactive (1). Adipose tissue is the body’s largest store of energy, accounting for 10-15 kg in a non-obese young adult. Supplying 3500 kcal per pound, 15 kg of body fat stores 135,000 kcal. Adipocytes (fat cells) regulate the energy balance of the entire organism by storing excess energy intake as triacylglycerols and releasing stored energy when demands are not met by other means. Each adipocyte contains roughly 0.04-0.06 ug of fat which accounts for ninety percent of the weight of adipose tissue (2).
Lipolysis is the process of breakdown and release of triacylglycerols (TGs) in adipocytes and is intensely regulated. Many physiological factors stimulate and inhibit the breakdown of TGs into free fatty acids (FFAs) and glycerol and their mobilization into the bloodstream to be used as fuel by other cells and tissues. Feeding, fasting, exercise and stress have pronounced and rapid effects on lipolysis via hormones and other endogenous substances (see Table 1). As well, clinical conditions such as diabetes and obesity are associated with alterations in lipolysis. Age and gender are also of importance.
Table 1. Some physiological modulators of lipolysis in humans.
State Effect on lipolysis Regulating hormones
Fed Inhibits Insulin by activity on HSL
Fasted Increases Increase in catecholamines and decrease in insulin
Exercise Increases Increase in catecholamines; decrease in insulin
Age Decreases Reduction in SNS activity and catecholamines
Gender Varies Sex hormones; regional deposit variations
Insulin and the catecholamines are the main regulatory hormones of lipid mobilization. Insulin is the major antilipolytic hormone because of its effects on enzymes within the adipocyte. Insulin also enables the entry of glucose into the cells by inducing glucose transporter activity. Glucose serves as the backbone for the glycerol molecule to which fatty acids attach and form TGs. The catecholamines serve a dual function of stimulation and inhibition of lipolysis. This nature of this duality will be discussed further so that the reader may understand how lipolysis is tightly regulated.
Hormones such as prostaglandins, adenosine, growth hormone and cortisol have permissive regulatory effects. Endocrine effects are due to circulating hormones, such as testosterone. Others are paracrine and autocrine effects from hormones secreted by the cell itself or from neighboring cells (18, . These mechanisms will not be discussed in depth here except for their role in mediating catecholamine-induced lipolysis.
We must first become acquainted with fat cell biology to comprehend the regulation of fat loss. Lipogenesis and lipolysis can be considered the Yin and Yang of adipose tissue metabolism. Lipogenesis is the process of fat accumulation and lipolysis is that of fat breakdown and release into the bloodstream. Bryan Haycock described the various systems in his article which readers are referred to for an in depth explanation. To avoid redundancy, the systems will be summarized here but with a greater examination of the adrenergic control via the adrenoceptors.
Triacylglycerol Storage
When carbohydrates are ingested, plasma glucose levels rise causing a release of insulin from the pancreas. Circulating insulin activates enzymes (acetyl-CoA carboxylase and fatty acid synthase) by inducing phosphorylation. This catalyzes the formation of fatty acids from glucose. Fatty acid uptake by the adipocytes results from activity of lipoprotein lipase (LPL). In addition to other hormones, insulin increases synthesis and activity of LPL; catecholamines, growth hormone and testosterone inhibit LPL. Differences in LPL activity partially account for regulation of adipose tissue distribution in various deposits. This may partly explain the typical diversity in adipose tissue deposition in regional deposits and between the two genders (e.g. upper body versus lower body, visceral versus subcutaneous deposits).
As mentioned previously, insulin enables entry of glucose into the cells via induction of glucose transporter activity. Glucose is then metabolized to glycerol where, along with fatty acids in the cell, they serve as substrates for TGs and are stored. Among other lipogenic effects, insulin stimulates the esterification process within the adipocyte, where three fatty acid chains attach to a glycerol molecule to form a TG. The primary action of insulin involves dephosphorylation of hormone sensitive lipase (HSL), which deactivates the enzyme. As will be described shortly, HSL catalyses the rate-limiting reaction in TG breakdown. Consequently, insulin is frequently referred to as the anti-lipolytic hormone.
Adrenoceptors and Lipolysis
Lipolysis is the process where TG molecules are hydrolyzed to fatty acids and glycerol. These products are then moved out of the fat cell by passive diffusion, carried across the cell membrane by protein transporters, or, in the case of FFAs, re-esterified back into TG within the fat cell or others nearby. The products are circulated through the bloodstream to various tissue and organs to serve as a source of fuel. The entire process is tightly regulated by numerous factors of which only the key players will be addressed here.
Recall that the rate-limiting enzyme for lipolysis within the adipocyte is HSL. Likewise, insulin and the catecholamines regulate HSL activity. Activation of HSL is regulated by a series of metabolic processes in the cell mediated by hormones and receptors in the cell membranes. Hormones secreted by glands or neurons, circulate and bind to receptors. This hormone/receptor complex initiates events that begin in the cell membrane, progress to the cell interior and end in a physiological response that may be inhibitory or stimulatory depending on receptor type and subtype. This is commonly called the second messenger system. The hormone itself is the first messenger which stimulates production of a second messenger that acts on systems within the cell to produce a cascade of events leading to the effect of the hormone. The series of steps and signals that take place linking the receptor and the effects within the cell is called signal transduction. As in most biological systems, negative feedback may inhibit the events of this interaction. To fully understand the complexity of this system, we will look at the cascade beginning with the receptors.
The physiological response by endogenous compounds or pharmaceuticals relies on their interaction with receptors in or on a cell. As we will see in the second installment, catecholamines and drugs (ligands) act upon these receptors and regulate metabolism in adipocytes and other cells. Some drugs, such as yohimbine, distinctly target a specific receptor to mediate a desired (or undesired) response. Let us examine what transpires when a ligand binds with a receptor.
Receptors are classified based on their structure and mechanism of action. The two classes of receptors are those that reside in the cell (intracellular receptors, such as steroid receptors) and those that span the cellular membrane and transfer an extracellular signal to an intracellular response. The G-protein-coupled (guanine nucleotide regulatory proteins) receptors are a large family of cell-surface receptors. The major receptors in the adipocyte membrane are the adrenergic receptors, or adrenoceptors, and are members of the G-protein family. Their most common feature is the long polypeptide chain that loops back and forth through the membrane seven times. This chain is physically and functionally linked to G proteins within the cell.
The catecholamines norepinephrine and epinephrine serve as the first messengers by binding to the adrenoceptors and stimulating the cascade system described above. The signal transduction depends on the type of adrenoceptor of which there are two types: alpha- and beta-adrenoceptors. These are further subtyped depending on structure, pharmacological response and second messenger. The alpha2- and beta-adrenoceptors share the same second messenger: cyclic adenosine monophosphate (cAMP). The alpha1-adrenoceptors’ second messenger is calcium or phosphatidylinostiol and has less significance in lipolysis.
The heterogeneity of the adrenoceptors on the adipocyte offers a dual control of lipolysis by differential recruitment by the catecholamines. This is based on their relative affinity for the different subtypes. Lipolysis is mediated primarily by three beta-adrenoceptors: beta-1, beta-2 and beta-3 (b 1, b 2, and b 3, respectively). Stimulation of the alpha2-adrenoceptor (a 2-adrenoceptor) is anti-lipolytic. That is, its activation inhibits lipolysis within the cell. To understand this dual regulation, let us take a look at the cascade mechanisms activated by surface cellular adrenoceptors.
G-coupled protein receptors, such as the adrenoceptors, link with G proteins just inside the cell membrane. The G proteins consist of three subunits with different binding and characteristic effects. This is commonly called the G protein effector system. When either of the catecholamines bind to an adrenoceptor on the adipocyte, it causes a conformational shift that activates one or more of these G protein subunits. Specificity of the hormonal response is regulated by one of the subunits coupling to different effector molecules within the cell. This specific coupling activates a cascade of signals within the cell ultimately leading to a physiological response.
The two families of the G-proteins that are involved with control of lipolysis are Gs and Gi. Beta-adrenoceptors couple with the Gs form and thereby activate adenylyl cyclase (AC), the key enzyme which produces cAMP. HSL, the enzyme that catalyzes breakdown of TGs, is regulated by cAMP. Therefore, activation of AC initiates metabolism of TGs.
As stimulation of the beta-adrenoceptors can be thought of as the "on" switch for lipolysis, the a 2-adrenoceptor can be considered the "off" switch. a 2-Adrenoceptors have been less studied than the beta-adrenoceptors; however, they are known to be linked to the Gi protein subunit complex. Activation of the a 2-adrenoceptor attenuates the production of cAMP by its inhibition on AC. The exact mechanism of this inhibition is not clearly understood. Several theories have been presented; the currently accepted is the dissociation of the subunits of the proteins from the Gi-protein complex, thereby inhibiting further transduction of the signal to AC (3, 4).
Recall that TGs are the lipid forms of energy stored in adipose tissue. Catecholamine-adrenoceptor mediated stimulation of AC promotes elevation of cAMP and, in turn, increases activity of cAMP-dependent protein kinase A (PKA). PKA activates HSL by phosphorylation and its translocation to the lipid droplets of TGs. Activated HSL breaks down TG to diacylglycerol (DG) and monoacylglycerol. Monoacylglycerol lipase (not under hormonal control) then hydrolyzes DGs to free fatty acids and glycerol. The net products of the breakdown of one TG are three molecules of fatty acids and one of glycerol.
Glycerol passively diffuses through the cell membrane into the extracellular fluid and bloodstream. The free fatty acids may have several fates. A portion of the liberated FFAs remains in the adipocyte to be re-esterified back to TG within the cell. The remaining are carried across the membrane by a transport protein (5) into the extracellular fluid and pass into the bloodstream, or they can be taken up by surrounding adipocytes and re-esterified into TGs. The fate of free fatty acids after TG breakdown are determined by a number of factors which will be discussed in detail in Part II.
Lipolysis is largely controlled by the amount of cAMP within the cell. Other hormones affect lipolysis at the post-receptor level by acting on specific enzymes or cofactors to increase cAMP or inhibit re-esterification of the FFAs. They will not be discussed in this article except where necessary.
Interplay of b - and a 2-adrenoceptors
An examination of the role of adrenoceptor affinity for the catecholamines will elucidate the beta/a 2-adrenoceptor interplay in regulation of lipolysis. Recall that the adrenoceptor population on adipocytes is heterogeneous. That is, there is a mixture of a 2–adrenoceptors and the subtypes of beta-adrenoceptors; the number and density of each varies among deposits of adipose tissue. The relative proportions of each greatly determine the biology of the adipose tissue. Brown adipose tissue (BAT), which is the major site of thermogenesis, which maintains body temperature, has a higher density of b 3-adrenoceptors than the other beta-adrenoceptors. The b 1- and b 2-adrenoceptors undergo desensitization and downregulation quickly, whereas the b 3-adrenoceptors do not. Although the metabolism and role of BAT is still controversial, it has been proposed that the b 3-adrenoceptors are essential for continuation of catecholamine responses under increased or sustained sympathetic activity (6).
The heterogeneity of adrenoceptors varies among species, gender, and deposits of adipose tissue. This topic in itself could easily constitute another article, but will be summarized here. Studies indicate that, of the species examined, human adipose tissue contains the highest density of a 2-adrenoceptors (7). Men and women display regional differences in lipolysis mostly due to varying populations of the adrenoceptors. Non-obese women generally have more subcutaneous fat in the gluteofemoral area (buttocks and thighs) than other areas. Non-obese men generally have a uniform distribution of subcutaneous fat. Obesity, however, exhibits pronounced gender differences. Obese women tend to accumulate fat in the gluteofemoral and lower abdominal areas. This is commonly called a gynoid pattern of fat distribution. Obese men typically accumulate fat in the subcutaneous abdominal area, which is called an android pattern. The exact causes of these gender differences in regional adiposity are neither absolute nor fully understood.
Hormones such as testosterone and estrogens are known to affect adrenoceptor gene expression. Studies with other species demonstrate that androgen administration increased a 2-adrenoceptor expression in intra-abdominal adipose tissue in hamsters. The same up-regulation of a 2-adrenoceptors has not been yet demonstrated in human males (8, 18). Conversely, in studies with humans testosterone administration up-regulated beta-adrenoceptors, especially in the abdominal region (9). Estrogen may have a role in the paracrine control of adipocytes, although the exact mechanisms are not clearly understood (10, 11).
Body fat also differs among regional deposits due to differences in metabolic activity. Subcutaneous body fat comprises about 80% of all adipose tissue (12). Visceral adipose tissue surrounds the stomach and the intestines, is drained by the portal vein and has direct access to the liver. Activity is highest in the visceral region where more fat is mobilized during times when there is a need for rapid energy supply, such as during physical exercise or lactation. Metabolic activity is lowest in the gluteofemoral area followed by the abdominal subcutaneous deposits. catecholamines are most active in the visceral area, followed by the subcutaneous abdominal and gluteofemoral areas. These regional variations are partially due to differences in adrenoceptor populations as well as blood supply (13, 14).
In vitro and in vivo studies show that adrenoceptor interplay accounts for the potency of catecholamine action and may be partly responsible for gender and site differences in lipolysis (13, 5, 14). Beta-adrenoceptors follow the order of expression: visceral>abdominal subcutaneous>peripheral subcutaneous, which includes gluteofemoral adipose tissue. a 2-Adrenoceptors follow the opposite order. Indeed, women generally have larger deposits of adipose tissue in the buttocks and thighs because of a higher number of a 2-adrenoceptors and reduced number of b 1- and b 2-adrenoceptors. Later discussion will elucidate how these site-specific differences in adrenoceptors affect regional fat mobilization.
The main factor associated with the preponderance of a 2-adrenoceptors is the increase in fat cell size (15, 16). Studies determined that gluteofemoral adipocytes in women are larger than those in men, thereby contributing to a higher a 2-antilipolytic effect of the catecholamines in gluteofemoral sites (15). The inverse has been observed in subcutaneous abdominal adipocytes in men (14, 17). Although the association has not been confirmed, it appears that this may be governed by sex hormones at the post-receptor level. Cell swelling and short-term modifications of cell volume could also affect metabolism and gene expression in the adipocytes. Therefore, fasting and cold exposure induce a reduction in fat cell size and a concomitant decrease in a 2-adrenoceptor binding sites (18).
The influence of obesity and fat deposits on lipolysis is not fully understood. However, an increase in fat cell size and cell number, such as seen in obesity and in aging, will increase the density of a 2-adrenoceptors and hinder weight loss attempts.
Regional variations in insulin receptor affinity and in post-receptor signaling contribute to site and gender variations as well (14, 19). In addition to their proposed effects on adrenoceptor expression, the sex hormones influence post-receptor mechanisms of lipolysis. Testosterone inhibits LPL although it is not known if this is solely adrenoceptor mediated. Estrogens and progesterone stimulate LPL and preferentially affect the gluteofemoral adipocytes.
In vitro and in situ studies have demonstrated that a 2-adrenoceptors may be highly significant in their regulatory role in lipolysis. Advanced techniques and pharmacological approaches using selective a 2- and b -agonists and antagonists reveal gender and tissue specific differences in adrenergic control of fat cell biology (14, 20-23). The next installment will discuss various interactions of a 2-adrenoceptors: the SNS, local blood flow, and relative affinity of the catecholamines for adrenoceptors in adipose tissue. Following this, we will consider how a 2-antagonists may fit into the pharmacological approach to fat loss.

In the previous installment of this article, we discovered the regulatory role of adrenoceptors on lipolysis by action of the catecholamines. This installment examines the relevance of the sympathetic nervous system in mediating levels of catecholamines in the body and the interactions of this system with adipose tissue. The role of a 2-adrenoceptors and a pharmacological approach that mediates these receptors is also discussed.
The Sympathetic Nervous System and a 2-Adrenoceptors
It is widely accepted that lipolysis is modulated by the sympathetic nervous system (SNS) and possibly the parasympathetic nervous system (PNS). The SNS and the PNS are the two arms of the autonomic nervous system of the body. The SNS, often called the "fight-or-flight" system, is a network of motor neurons that innervates smooth muscle, cardiac muscle and glands. The SNS mobilizes the body during extreme situations such as stress and exercise. The PNS, sometimes called the "resting and digesting" system, serves to counterbalance the effects of the SNS and conserve energy. The SNS may stimulate a gland to secrete or smooth muscle to contract, whereas the PNS inhibits that action. Generally, the SNS and PNS innervate the same organs; although, the SNS innervates more organs than the PNS. While adipose tissue is innervated solely by the SNS, the PNS may indirectly influence lipolysis.
Both systems comprise of neurons, and each neuron ends in a terminal synapse. These synapses mediate the transfer of information from one neuron to another or to an effector (target) cell. That information may be in the form of electrical impulses (flow of ions) or chemicals. Certain signals are transmitted while others are blocked. Just inside the terminal are vesicles containing neurotransmitters, the chemical signals. In response to a nerve impulse the neurotransmitters are released from the vesicles into the synaptic cleft, a narrow space between the presynaptic terminal and the postsynaptic membrane of a nerve or an effector cell. Neurotransmitters diffuse across the synaptic cleft and bind to specific receptors on the effector cell. They may also diffuse into the bloodstream or be degraded by enzymes. Some neurotransmitters are taken back up into the presynaptic neuron to be recycled in a process called re-uptake.
The major neurotransmitter of the PNS is acetylcholine (ACh), which binds to nicotinic and muscarine receptors. The two neurotransmitters of the SNS are acetylcholine and norepinephrine (NE). ACh is degraded quickly by acetylcholinesterase; hence its effects are short-lived. Stimulation of the SNS increases release of neurotransmitters inducing a response in the effector cells, which may be excitatory or inhibitory depending on the nature of the receptor that binds the neurotransmitter. Thus, the SNS regulates energy intake and expenditure according to genetic and environmental influence.
SNS stimulation increases plasma levels of the catecholamines by inducing secretion of NE from postganglionic terminals and release of epinephrine (E) from the adrenal medulla. Although NE lingers in the synaptic cleft for a longer period of time than ACh, NE has several fates. A portion of the NE diffuses out of the synaptic cleft into the bloodstream. Enzymes such as monoamine oxidase and catechol-O-methyltransferase (COMT) degrade a portion of NE. Much of the neurotransmitter is actively transported back into the terminal that released it and recycled. This re-uptake is moderated by a -adrenoceptors.
a 2-Adrenoceptors are found in the cell membrane of the neuron axon terminals and mediate rate neurotransmitter release. Some evidence shows that a 1-adrenoreceptors may be present on presynaptic membranes as well, but their existence is still disputed (1). When NE is released from the vesicles of the terminals, they come into contact with and stimulate the a 2-adrenoceptors, inhibiting further release of these same neurotransmitters. Such is the feedback system for NE release in the SNS.

Many pharmaceuticals interact with presynaptic a -adrenoceptors interfering with NE-mediated regulation of NE release and re-uptake. a 2-Antagonists are compounds that block the inhibiting effect of the a 2-adrenoceptors and, therefore, interfere with re-uptake of the synaptic NE. This allows NE to linger longer in synaptic clefts producing excessive stimulation and diffusion of excess NE into the bloodstream. a 2-Antagonists reserpine and yohimbine enhance NE release and inhibit NE re-uptake.
a 2-Adrenoceptors are present on many tissues and mediate a variety of functions. Pre- and postsynaptic a 2-adrenoceptors found on central and peripheral neural terminals mediate noradrenergic, cholinergic and serotonergic receptors. Recall that activation of these a 2-adrenoceptors inhibits release of neurotransmitters. Thus, blockage of the adrenoceptors will increase neurotransmitter release. As well, a 2-adrenoceptors are located on many other tissues and have important pharmacological implications. Some of these are discussed further when we address use of pharmaceuticals targeting the a 2-adrenoceptors for fat loss and their possible side effects.
a 2-Adrenoceptor Subtypes
Receptor-binding studies have demonstrated that several subtypes exist for alpha-adrenoceptors types, depending on species and tissue (2,3). In addition to genetic coding, pharmacological response to agonists and antagonists determine the classifications depending on their binding potency to the receptors. The most common probes used in these studies are agonists, such as clonidine, and antagonists: yohimbine and yohimbine-like compounds such as rauwolscine, corynanthine. Each of these compounds has various binding affinities for the alpha-adrenoceptors types. Some, such as yohimbine, exhibit weak binding to a 1-adrenoceptors as well as high affinity for the a 2-adrenoceptors.
As mentioned previously, species and tissue differences exist in a 2-adrenoceptor subtypes. For instance, human brain cortex presynaptic a 2-adrenoceptors are classified as a 2A or a 2D (4). Primarily a 2A-adrenoceptors mediate vascular effects, such as changes in blood pressure (5). Whereas, human kidney presynaptic a 2-adrenoceptors are classified as a 2C (6), further binding studies established that human adipocytes express only the a 2A-adrenoceptor subtype (7, 8).
These a 2-adrenoceptor subtypes are differentially regulated by their affinity for the physiological catecholamines and sensitivity to downregulation. The functional roles for the a 2-adrenoceptors continue to be explored. Pharmaceutical agonists and antagonists are being developed with greater selectivity for the individual subtypes. They may be used as therapeutics for treating glaucoma, hypertension, non-insulin dependent diabetes and as adjuncts to general anesthesia.
The SNS, a 2-Adrenoceptors and the catecholamines
catecholamines stimulate the adipocyte adrenoceptors on the basis of their relative affinity for each type of adrenoceptor. These hormones preferentially recruit the a 2-adrenoceptor at lower catecholamine levels than the beta-adrenoceptors, especially in tissues where a 2-adrenoceptors predominate (9,10). Consequently, the a 2-adrenoceptors will be recruited before the beta-adrenoceptors.
One study demonstrates that a 2-adrenoceptors modulate lipolysis at rest, whereas lipolysis is modulated by the beta-adrenoceptors during exercise (9). During physical activity, increased levels of E in the extracellular fluid maximally stimulate the beta-adrenoceptors and mask the inhibitory effect of the a 2-adrenoceptors. a 2-Adrenoceptors may exert a permanent inhibition on lipolysis, contributing to a tonic inhibitory component influenced by catecholamines on ‘basal lipolysis’ (11). In vitro studies support this observation by demonstration that many G proteins have a significant level of basal activity in the absence of an agonist (12). Therefore, the a 2-adrenoceptors could be considered the major lipolysis-regulating adrenoceptor on adipocytes.
To illustrate the regulatory mechanism of the dual adrenoceptors on the fat cells, let us consider the a 2-adrenoceptor as a ‘brake’ on lipolysis in the cell. At rest the a 2-adrenoceptors apply a slight pressure to the brakes on lipolysis even in the absence of an agonist, a compound which binds and stimulates the receptor. A slight rise in extracellular norepinephrine, such as seen in mild SNS stimulation (sitting at the computer typing all day), will increase the number of a 2-adrenoceptors being activated with a small number of beta-receptors activated as well. Since the a 2-adrenoceptors outnumber the beta-receptors in humans, this will apply the breaks to lipolysis harder, decreasing-lipolysis. During exercise, concentrations of NE and E from the SNS and the adrenal gland increase in the blood and fat tissue extracellular fluid. These higher levels of catecholamines increase stimulation of the beta-adrenoceptors, which then overshadow the a 2-adrenoceptor-induced activity. Basically, stimulated beta-adrenoceptors cut the brake cable on lipolysis and start the train of events promoting and increasing fat breakdown in fat cells.
Adipocytes are only one of the many tissues within the body that have adrenergic receptors. Thus, response to activation of the SNS will vary between tissues depending on the adrenoceptor types present on the cells, the relative proportion and the second messenger system within the cell. For instance, skeletal muscle blood vessel wall cells have both a 1- and b 2-adrenoceptors with the a 1-adrenoceptors lying close to the sympathetic nerve terminals. The b 2-adrenoceptors are on the endothelial surface of the blood vessels. Therefore, SNS activation usually produces predominantly vasoconstriction mediated by the a 1-adrenoceptors, whereas an increase in E activates the b 2-adrenoceptors causing vasodilation. Another important organ with dual adrenergic regulation is the pancreas. This interaction is explained when we examine a pharmaceutical approach that blocks the a 2-adrenoceptors.
a 2-Adrenoceptors and Blood Flow
SNS activity has an additional catecholamine-mediated effect on lipolysis in adipose tissue: blood flow. A coordination of local blood flow and metabolism carries away by-products of lipolysis and supplies energy substrates to tissues and organs in times of increased demand. Changes in blood flow can facilitate or inhibit movement of substrates, such as glycerol and non-esterified fatty acids (NEFA), that arise from lipolysis. Consequently, stimulation of the SNS increases lipolysis and blood flow; low SNS activity (such as during rest) inhibits lipolysis and blood flow. However, the increase in blood flow is not in proportion to rising concentrations of NEFA and glycerol. During strenuous exercise, adipose tissue blood flow does not increase sufficiently to remove all NEFAs released by lipolysis (13). A feedback system probably exists; however, it is not well understood. Vascular adrenoceptors that affect vasoconstriction and vasodilation may be responsible for this feedback. Studies using microdialysis have shown that the interplay of a 2- and b 2-adrenoceptors mediate vascular blood flow in adipose tissue (14,15).
Up until several years ago, in vitro and in vivo investigations on plasma circulating metabolites limited measurements of metabolism in adipose tissue. A technique called microdialysis allows for local manipulation and in situ studies of adipose tissue (16,17). It can be applied to individual subcutaneous deposits enabling investigation of specific-site metabolism. Microdialysis allows infusing adrenergic-active agents, such as beta- and alpha-agonists or antagonists, to manipulate adrenergic control and monitoring adipose tissue metabolites and local blood flow. Recent studies elucidate further the role of the catecholamines on regulation of adipose tissue metabolism, especially pertaining to regional and gender differences.
E and NE stimulate blood flow in adipose tissue by activation of the b -adrenoceptors on the walls of the blood vessels causing vasodilation. Stimulation of the a 1- and a 2-adrenoceptors, also on blood vessel walls, promote vasoconstriction. The distribution of these two types of alpha-adrenoceptors and their subtypes within the blood vessel walls mediate their sensitivity to vascular controls. Some vascular beds, such as the renal bed, respond primarily to a 1-adrenoceptor modulation (5). Whereas other beds, such as in cutaneous circulation, respond primarily to a 2-adrenoceptors (19,18). SNS regulation of local blood flow in the various adipose deposits may have important implications for lipolysis (20).
Results from in vitro and in vivo studies have had contradicting results depending on techniques utilized and physiological status of subjects. Without question, in vitro and in vivo results show that a 2-adrenoceptors predominate in the femoral vascular bed (in the lower body) by using various antagonists for the specific alpha-adrenoceptors (21-23). Microdialysis studies confirm a higher concentration of glycerol in gluteofemoral than abdominal adipose deposits possibly due to reduced local blood flow in gluteofemoral sites during resting basal conditions despite lower basal lipolysis rates (14,20).
Experiments using microdialysis have shown that perfusing adipose tissue with clonidine, an a 2-agonist, promoted an increase in extracellular glycerol concentrations. Vasoconstriction by stimulation of vascular a 2-adrenoceptors may be the primary determinant in glycerol and NEFA mobilization (20,24). Vasodilating agents infused via microdialysis produced a decrease in the removal of glycerol from the extracellular space of adipose tissue (24). The resulting decrease in blood flow may reduce the net removal of lipolysis metabolites from the extracellular fluid of adipose tissue.
NEFAs produced by lipolysis within the adipocytes may be more sensitive to change in blood flow. Glycerol is water-soluble and diffuses out of the adipocytes to move freely within extracellular fluid. NEFAs are not water-soluble and must be bound to protein carriers to move out of adipocytes and into the intracellular space. Newly NEFAs will therefore linger in the interstitial space surrounding adipocytes and possibly be reutilized (re-esterified) by surrounding adipocytes. Indeed, it has been shown that reduced blood flow in adipose tissue delayed NEFA and glycerol mobilization (25,26). Therefore, vasodilation induced by an antagonist that specifically blocks the a 2-adrenoceptors in the blood vessels of adipose tissue could increase lipolysis metabolite mobilization.
In vitro and in vivo studies suggest obesity may modify the response to the catecholamines due to differences in fat cell size, adrenoceptor populations and circulation (27-31). Continued investigation is needed to explain controversies in changes of regulatory mechanisms seen in altered physiological states. Additionally, physical exercise modifies changes in adipose tissue response to SNS. Gender differences are apparent during exercise, such as higher glycerol levels in circulating blood supply and in adipose tissue of women than in men. Microdialysis investigations report higher lipid mobilization from subcutaneous abdominal adipose tissue in women (9,32). Explanations for this gender response may be differences in adrenergic receptor population and activity. Glycerol levels in men were enhanced by a -adrenoceptor blockage. However, whether this was induced by direct blockage of adipocyte alpha-adrenoceptors or those of the vascular bed was not examined.

Thus far, this article has addressed the basic physiology of lipolysis and the interaction of the SNS and alpha-adrenoceptors. As alluded to throughout the preceding sections, manipulation of the SNS will have direct impact on lipolysis. It is useful to remember, however, that insulin is the main regulator of lipolysis. Therefore, as previously mentioned in Part 1 of this article, lowering insulin levels will allow for optimal manipulation of the SNS. Low levels of insulin increase plasma levels of catecholamines, stimulating lipolysis and loss of body fat. The SNS can also be manipulated by pharmaceuticals and naturally occurring substances. We will discover one such approach: mediation of the a 2-adrenoceptors.
Sympathomimetic compounds mimic the action of the SNS and release NE and E in addition to possessing direct b -adrenergic properties. Examples of these compounds are amphetamines, ephedrine and its various isomers. Isomers are compounds with the same formula but different molecular structure or different spatial arrangements. These differences greatly affect the activity/potency of the compound and the responses they elicit, as we will discover shortly.
Sympatholytic compounds inhibit adrenergic nerve activity in the SNS and some have direct postsynaptic adrenoceptor-blockage activity. Physiological responses of these compounds depend on several factors: chemical structure, type and subtype of adrenergic receptors (ARs), second messenger system (including G protein complex), and tissue site. Other factors include administration route of the compound, which influences absorption and metabolism, and dosage. To present a detailed discussion of pharmacology is beyond the scope of this article; therefore, only necessary details pertaining to the ensuing discussion are included.
Considered a sympatholytic, yohimbine has been used in herbal medicine for centuries. Yohimbine is one of a large family of indole alkaloids called yohimbanes. Indole alkaloids are naturally-occurring heterocylic amines derived from botanical sources. Yohimbine is the principal alkaloid found in extracts from the bark of the Pausinystlia yohimbe tree that grows in tropical West Africa and the Congo. It is structurally similar to reserpine and can also be isolated from the roots of Rauwolfia. Typical of many alkaloids, the yohimbanes have diverse pharmacological properties.
The basic yohimbane molecular structure contains five asymmetric carbons; yohimbine is one of 32 isomers within this family. The yohimbane alkaloids include antagonists that are selective for the alpha-AR. The selectivity of the various yohimbane alkaloids depends on the stereochemical configuration of the five carbon centers. That is, the shape and position of the various components of the compound determine how they interact with the receptors and potency of their response. Not only do they have differential activity at the alpha-AR types (a 1- versus a 2), but also within the subtypes (3,15,33).
Recall from the previous discussion on the a 2-AR subtypes that differences in their affinity for agonists and antagonists mediate the cell’s response. This interaction of yohimbane compounds and the AR subtypes determine their use as pharmacological tools and therapeutic agents. Therefore, the effects of the various yohimbanes will vary, as we shall see in our examination of the use of yohimbine.
Synthesized yohimbine and its isomer rauwolscine have been used as pharmacological tools to differentiate the alpha-ARs due to their selectivity as antagonists for the a 2-AR. Another isomer, corynanthine, is used for its selectivity for the a 1-AR. They have served as probes for classification of AR types and to assess a 2 adrenergic functions in man for several decades. Herbal preparations from plant parts, however, have been used as aphrodisiacs and euphorics for centuries. Recently, yohimbine has been promoted as a dietary supplement to enhance athletic performance and fat loss. This and various clinical applications will be examined in this article.
Early investigations demonstrate the activity of yohimbine as an a 2-antagonist that increases NE release and induces a hyperadrenergic state (33). Pharmaceutical studies show that yohimbine has high selectivity for the a 2-AR and weak affinity for the a 1-receptors. Its isomer rauwolscine has higher selectivity for the a 2-AR with little or no selectivity for the a 1 type. Later tissue and cells studies explained the mechanisms of various effects of yohimbine when administered to humans and other species by revealing the presence of a 2-AR and their functions at several sites within the body. Differential affinity of yohimbine and its isomers for the a 2-AR subtypes may also explain variability in tissue-specific responses.
Clinically, yohimbine has been administered to induce anxiety in psychiatric patients, orthostatic hypotension and other autonomic failure conditions, adjunct therapy for opiate withdrawal, and male organic impotence (15,34). It is widely used by veterinarians to reverse sedation or anesthesia in animals. Other therapeutical applications currently under research are as a glucose-dispersal agent for treatment of non-insulin dependent diabetes and to treat adverse effects of anti-depressants.
Yohimbine and Fat Loss
Since a 2-ARs are present on adipose tissue and inhibit lipolysis, yohimbine has been proposed as a pharmaceutical approach to fat loss. In vitro results demonstrated that E, a non-selective agonist for a /b -ARs, produced less lipolysis than a selective beta-agonist (33). However, when an a 2-antagonist, such as yohimbine, was added, E induced the same rate of lipolysis as the beta-agonist. Clinical investigations report yohimbine administration (0.2 mg/kg total body weight) increases plasma levels of NEFAs and glycerol in obese and non-obese women as well as in men (26,35,36). Yohimbine increased weight loss when used with hypocaloric diets in several studies by preventing an adaptive lowering of the SNS that usually occurs with most calorie-restriction (37). Resting energy expenditure did not change in a group of obese and lean women when administered yohimbine (38). However, exercise energy expenditure in same subjects was significantly potentiated along with accompanying parameter of lipolysis
Results from many studies conclude that the primary lipid-mobilizing effect of y