Written by Robbie Durand, MA, CSCS
11 July 2006

In a previous column, the topic of beta-2 (b-2) agonists and their effects on muscle hypertrophy were discussed along with the pros and cons of using the drug. The beta adrenergic receptors are regulated not only by the catecholamines epinephrine and norepinephrine, but also by the thyroid hormones cortisol and testosterone.
Research has shown that testosterone administration promotes a rapid and dose dependent up-regulation of the fat cell b-receptors, which enhance lipolysis (i.e., fat mobilization).8 Not only are catecholamines involved in protein synthesis rates and muscle hypertrophy, but they’re major sources of human fat metabolism. Basal metabolic rate increases as much as seven to 15 percent with increased catecholamines. 31 When trying to get ripped up, stimulating catecholamines through the use of supplements can enhance resting metabolic rate. Remember, the largest fraction of total energy expenditure doesn’t come from exercise, but from your resting energy expenditure (approximately 65 to 75 percent). So if you had to pick the organ requiring the largest metabolic rate, which one would it be? Heart and kidneys have the highest (440 kcal/kg day), then liver (240 kcal/kg day), muscle (13 kcal/kg day) and finally fat (4.5 kcal/kg day).

Catecholamine Resistance
Catecholamines can increase resting metabolic rate through multiple pathways and are important for weight regulation. In fact there are some researchers who believe obesity may be due to “catecholamine resistance” similar to diabetics suffering from “insulin resistance.” In a study by Lonnqvist et al.,33 65 subjects were divided in two groups: those who were sensitive to catecholamines and those who weren’t. Both groups were subjected to an exercise stress protocol (i.e., 30 minutes at two-thirds of their maximum aerobic power) in combination with mental stress (i.e., color words), which can significantly enhance catecholamine secretion. The subjects who were classified as “catecholamine resistant” had a 50 percent reduction in the lipolytic response to exercise and mental stress, despite a 50 percent increased plasma noradrenaline (norepinephrine) response and a 350 percent increased plasma adrenaline (epinephrine) response. Interestingly, the cardiac responses to the exercise and mental stress were virtually identical between the groups.
Catecholamines have an effect on causing metabolic changes in adipose tissue. There are two types of fat cells in the body: white adipose tissue and brown adipose tissue. Both are heavily influenced by the sympathetic nervous system (has an active "stimulating" function), whereas the parasympathetic nervous system (has mainly a “relaxing” function) plays a minor role in adipose tissue lipolysis. The metabolic activity and biochemical properties of the two tissues are vastly different. It’s been reported that brown adipose tissue has a 10-fold higher metabolic activity than white adipose tissue.24 See Figure 1 for a biochemical breakdown between the two types of adipose tissues.

Brown and White Adipose Tissue
 White adipose tissue serves three functions: heat insulation, mechanical cushion and, a source of energy. It could also serve fourth function: making you look like a “fat-ass.” When white adipose tissue is mobilized as an energy source, triglycerides are broken down into free fatty acids from their glycerol backbone allowing them to enter circulation and be used as an energy source. On the other hand, brown adipose tissue, which derives its color from a rich supply of blood vessels for oxygen supply and abundant source of mitochondria, is found in different locations depending upon the species and/or age of the animal.
Brown adipose tissue releases fatty acids in the cell. For example, rats have more brown adipose tissue than humans.1,12 In newborn babies, brown fat makes up about five percent of the body mass and is located on the back, along the upper half of the spine and toward the shoulders. Brown fat is of great importance to babies because it helps protect against lethal cold exposure as it’s important for regulating body temperature via non-shivering thermogenesis.
 Shivering thermogenesis is created in the muscle by shivering or contacting. For example, when you’re cold your muscles start contracting to generate heat. In brown adipose tissue, heat production is increased without muscle involvement. Brown adipose tissue is heavily influenced by catecholamines; interestingly when catecholamines are blocked, brown adipose tissue is reduced, whereas chronic catecholamine production increases hypertrophy of brown adipose tissue.1
The mechanism of heat generation is related to the metabolism of the mitochondria. Mitochondria from brown adipose tissue have a specific carrier called uncoupling proteins that transfer protons from outside to inside without subsequent production of ATP. Basically this means in contrast to other cells, including white adipocytes, brown adipocytes utilize substrates to generate heat rather than ATP. The mitochondria are larger in brown adipose tissue as well as more abundant compared to white adipose tissue.11 During the adult life span in humans, brown adipose tissue becomes metabolically less active, although cold exposure can activate it. As mentioned previously, brown adipose tissue uses 60 percent of the extra oxygen used in non-shivering thermogenesis-induced cold-acclimated animals.3

The Main Side Effects of Catecholamines
Energy expenditure can be measured directly as heat production (thermogenesis), but is more commonly assessed indirectly as oxygen consumption.16 Based on the results of previous studies, brown adipose tissue is accepted as the major site for non-shivering thermogenesis. So how do you increase the metabolic activity of brown adipose tissue? Well, you can move to Antarctica and live in your posing trunks or you can increase norepinephrine activity. Norepinephrine stimulation of brown adipose tissue mimics the effects of cold-induced activation and promotes an increase in uncoupling chain protein-1 (UCP-1). UCP-1 causes heat generation and the burning of calories in the mitochondria, which are important for metabolic control. An increase in norepinephrine activity increases UCP-1 mRNA in brown fats, which is mediated by the b-3 receptor and subsequent increase in cAMP levels.5 In fact, UCP-1 is the major gene being expressed in adipose tissue responsible for non-shivering thermogenesis.19
There’s a disease termed “phaeochromocytoma” which leads to high circulating norepinephrine levels in man. Pheochromocytoma is a rare tumor usually occurring in the adrenal glands. As a result of the tumor, the adrenal glands produce too much adrenaline. Imagine the benefit— you would never have to take Ripped Fuel or Hydroxycut. The downside is that there are a host of side effects from this disease. As mentioned previously, during maturation brown adipose tissue disappears with aging, however in patients with pheochromocytoma, brown adipose tissue, which normally disappears after infancy, becomes “reactivated,” which may lead to excessive weight loss.
Catecholamines are potent thermogenic stimulators, however, one of the main side effects of catecholamines is that there are adverse reactions associated with their usage namely, tachycardia (fast beating heart), tremors and decreased serum K+ levels. This is mainly due to catecholamines binding to b-1 and b-2 receptors in heart and muscle. The b-2 receptor is the most commonly expressed receptor in most cells, with an abundant source on white adipose tissue. A third type of b-receptors called the b-3 receptor was thought to be the new pharmaceutical cure-all for obesity as the b-3 receptor is only located in adipose tissue and its activation doesn’t affect the nervous system.

Enhancing Fat Mobilization During Rest
Many researchers have hypothesized that the b-3 receptor to alpha-2adrenoceptor (a-2 adrenoceptors) ratio is the key to the regulation of thermogenesis and adipose tissue lipolysis. What’s so special about this combination? Stimulation of the a-2 adrenoceptors is anti-lipolytic. It basically halts fat mobilization from adipose tissue. a-2 adrenoceptors are distributed differently in men and women, as men tend to contain more a-2 adrenoceptors in their abdomen whereas women tend to have more a-2 adrenoceptors located in their hips and buttocks.
So how important are a-2 adrenoceptors for fat lipolysis? Well when you take a fat biopsy of adipose tissue ratios from a person’s butt, which is the hardest body part for many bodybuilders to get ripped up, you will find a three- to 10-fold higher concentration of a-2 adrenoceptors to beta receptors.38 It’s been demonstrated that epinephrine has a higher binding affinity than norepinephrine for the a-2 adrenoceptors.6 In addition, at low concentrations (i.e., rest), it’s been reported that a-2 adrenoceptors are activated. However during exercise, high NE levels stimulate b-receptors which activate lipolysis.39 In human fat cells, after b-agonist administration, there’s marked down regulation of the b-receptors, yet there’s no down regulation of the a-2 adrenoceptors.7 In fact, even after long term a-2 adrenoceptors agonist’s administration, there seems to be no down regulation of the a-2 adrenoceptors.7 If you’re trying to get ripped up adding some yohimbine to the supplement stack might be advantageous as a-2 adrenoceptors inhibits adenylyl cyclase activity, which in turn inhibits cAMP and turns off lipolysis!!!
Another little benefit to men is that administration of yohimbine has been shown to enhance penile erections because the penis has a high density of a-2 adrenoceptors. a-2 adrenoceptors have the opposite effect from the beta receptors on intracellular cAMP levels.

b-3 Agonists: A Great Start With a Poor Finish…
 So what makes the b-3 receptor so special? Gene studies of mass populations have shown that there’s strong evidence linking body mass index (BMI) and the b-3 gene, which indicates that the b-3 gene expression is a strong candidate for obesity.19 The b-3 receptor has a low-binding affinity for epinephrine, yet a high binding affinity for norepinephrine.4 b-3 receptors have a lower binding affinity for epinephrine compared to b-1 and b-2 receptors, however b-3 receptors have a higher binding affinity for noradrenaline than b-2 receptors, yet a lower binding affinity than b-1. Administration of a b-3 agonist has no effect on stimulating catecholamine release, which is quite different from many of the obesity drugs found on the market.12 White adipose tissue has a scarce number of b-3 receptors, but a much larger number of b-1 and b-2 receptors.12
Another interesting feature about the b-3 receptor is that in rat studies it’s highly resistant to down regulation, as are m2 receptors.32 The obesity treatment hypothesized by researchers was that if the b-3 receptor is hard to down regulate and produces significant thermogenesis it might be a practical approach to stimulating fat loss. So here’s the study that started the b-3 craze. Healthy volunteers were administered a dose of ephedrine, which stimulates all three b receptors in fat (b-1, b-2, b-3), however they also administered nadolol. Nadolol inhibits both the b-1 receptors, located chiefly in cardiac muscle and the b-2 receptors, located chiefly in the bronchial and vascular musculature. What they found was nothing short of amazing. Even though b-1and b-2 receptors were blocked, there was a 43 percent increase in thermogenesis, which was entirely mediated by the b-3 receptor. So the race was on…developing a b-3 agonist could increase thermogenesis without the side effects of nervousness and tremors because b-3 receptors are only located on adipose tissue.

The Mystery of White Adipose Tissue
In rats, the b-3 agonist administration was a tremendous success; b-3 agonist administration caused significant reductions in abdominal fat pads and a host of other beneficial mediators of fat lipolysis and was also found to be a potent anti-diabetic agent. b-3 agonist in mice or rats approximates doubling of total body energy expenditure after an acute dose.14 b-3 agonist administration also caused increases in hormone sensitive lipase (HSL) activity gene expression and also increases in uncoupling chain protein 1 (UCP-1) in adipose tissue. HSL is the major rate-limiting enzyme in adipose tissue lipolysis. By increasing HSL activity in adipose tissue more fatty acids are transported out of adipose to be used as an energy source. In fact, there’s an immediate increase in HSL gene activity that occurs with fasting.17 Your body is basically saying, “There’s no food coming so start mobilizing more adipose tissue as an energy source!”
So as stated before, there are very few b-3 receptors located on white adipose tissue and there are very few brown adipocytes in humans, so how is there a decrease in white adipose tissue if there are few receptor sites? In fact, many studies have suggested that there’s an induction of brown adipose tissue into white adipose cell.20,21 That’s right!! White adipocytes tissue starts developing brown adipose tissue characteristics. Interestingly, b-3 agonists have the ability to induce UCP-1 gene expression in white adipose tissue as well as brown adipose tissue.19
One study documented that four weeks of b-3 agonists administration caused a 62-percent increase in UCP-1 expression at week two and a 132-percent increase at week four.25 UCP-1 is the major source of thermogenesis in brown adipose tissue. Take away UCP-1 and all you have is worthless brown adipose cells with no metabolic activity. Mice that are genetically engineered to be UCP-1 deficient suffer extreme hypothermia (i.e. decreased body core temperature) and are cold insensitive. Conversely mice that over-express UCP1 are hyperphagic (eat excessively) and obesity resistant.15,16 Here was a really cool experiment, which documents how UCP-1 regulates the brown adipose cell. Researchers took adipocytes from mice that were genetically modified so they didn’t produce UCP-1 or UCP-1 deficient mice. They exposed the brown adipocytes to norepinephrine, which is a potent stimulator of UCP-1, and guess what happened? Nothing!!! The brown adipocytes didn’t increase thermogenesis, demonstrating that UCP-1 is the major source of thermogenesis in adipose tissue.25

Did Someone Hear a Toilet Flush…
Okay…here’s where you hear a big toilet flush for b-3 agonists. The research was overwhelming clear that b-3 agonists can increase thermogenesis and reduce body fat in rats, but when humans were studied, the results were only marginal. When b-3 agonists are administered acutely, there’s an increase in energy expenditure and lipolysis, with no effects on heart rate, catecholamines, or body core temperature.29 The problem is that long-term studies fail to show any change in fat lipolysis or changes in resting energy expenditure.
When obese men were administered b-3 agonists for 28 days, there was no change in 24-hour energy expenditure, body composition, catecholamines, or changes in fatty acid mobilization.12 The author concluded that unlike rat studies, which have shown b-3 receptors to be resistant to down regulation, human b-3 receptors are directly or indirectly down-regulated in response to b-3 agonists. Another study, which lasted for 14 days, found no changes in resting energy expenditure or fat metabolism.30 Barbe et al.,27 investigated the effect of all b-receptors (b-1, b-2 and b-3) on a very low-calorie diet (382 calories a day) for 28 days. A microdialysis pump was inserted in the abdomen after 28 days on the low-calorie diet and three types of beta agonist drugs (i.e., Dobutamine [b-1 agonist], Terbutaline [b-2 agonist] and CGP [partial-3 agonist]) were infused to measure changes to receptor sensitivity to fat tissue lipolysis.
Results of the study concluded that there was a significant up-regulation of the b-1 adrenergic pathway in adipose tissue. b-2 receptors increased sensitivity to catecholamine, yet there were no changes in receptor number. There was only a mild increase in b-3 receptor activity, further supporting that the b-3 receptor is only weakly involved in the lipolytic process in humans.
Another potential problem with b-3 agonists is that brown adipose tissue decreases with age and b-3 receptors are only sparsely located on white adipose tissue in humans (approximately 20 percent), whereas in rats, brown adipose tissue (approximately 90 percent) is abundant.31 Whether or not b-3 agonists will be proven to be useful is debatable given the low receptor number found in human tissue. The research basically shows that b-3 receptor is present in adipose tissue of both white and brown adipose tissue, yet its activation is only weakly involved in the lipolytic process in man. Based on the research, b-3 receptors located on brown adipose tissue play a minor role in the lipolytic actions in humans, although highly thermogenic in rats. This effect is probably due to the fact that rats have a high abundance of brown adipose tissue compared to humans.24

Stimulating Fat Loss Through b-Adrenergic System
 In fat cells, it’s clearly established that agents increasing lipolysis also stimulate the b-adrenergic system and increase cAMP levels. Catecholamines increase cAMP levels, whereas insulin decreases cAMP levels.22 No wonder ketogenic diets are so effective for getting ripped. Increases in cAMP increases lipolysis in both white and brown adipose tissue and also increases brown adipose tissue hypertrophy. In addition, UCP-1 is also stimulated by increasing cAMP levels.10 It seems that lipolysis is mainly dependent on the b-1 and b-2 receptors in adipose tissue; however these receptors are readily down-regulated.27 In fact, human fat cells have been shown to be 300 times more sensitive to Isoprenaline, which has b-1 and b-2 adrenoceptor activity, than b-3 agonists.36
When it comes to supplements, that good ole ephedrine and caffeine stack was great for stimulating all three b-receptors. For example, the caffeine, ephedrine and aspirin stack was so effective because ephedrine is a non-selective beta-agonist, while caffeine inhibited cAMP breakdown (keeps its activity high), and aspirin inhibited the negative feedback loop that reduces b-agonist production. Ephedrine stimulates all three beta receptors located on adipose tissue. Researchers have suggested that b-3 receptors may be a highly regulatory mechanism in fat cells after b-1 and b-2 receptors become desensitized. This may be the reason an increase in metabolic rate is seen after an ephedrine and caffeine stack is stopped, as subjects have been reported to continuously lose weight after discontinuation of caffeine and ephedrine.35 Another great thing about the caffeine-ephedrine stack is that it increases norepinephrine and norepinephrine and directly increases UCP-1 gene expression in both white and brown adipose tissue.24
Surprise, Surprise…
In conclusion, researchers once believed thermogenesis never occurs in white adipose tissue. Today, new research is questioning the validity of that claim. For example, a group of UCP-1 genetically deficient mice were exposed to a dose of b-3 agonists. Based on what we know about UCP-1 as a potent stimulator of thermogenesis, researchers thought nothing should happen. How wrong they were!! There was still an increase in metabolic rate and body temperature that occurred in the UCP-1-deficient animals, which was mediated by white adipose tissue.34 The results demonstrate that white adipose tissue has the capacity to increase thermogenesis through the b-3 receptor despite no effect on UCP-1.
When reviewing the literature, it seems that in conjunction with consuming thermogenic supplements, you should also increase your consumption of polyunsaturated fats, as one study reported that in comparison to saturated fats with equal calories, a diet high in polyunsaturated fats increased mitochondrial activity and higher UCP-1 content than with saturated fats.26 Researchers are looking into pharmaceutical drugs that can counteract obesity by increasing UCP-1 expression in other organs (i.e., white adipose tissue). Muscle might be the better alternative to increasing thermogenesis as muscle is the major site of free fatty acid utilization. Of the b-1 and b-2 receptors located in muscle, the b-2 receptor is the only receptor sub-type of importance for the adrenergic regulation of lipolysis in skeletal muscle and blood flow.28 Another positive benefit of increasing epinephrine during exercise is that epinephrine will cause vasodilatation of muscle, causing greater muscle swelling (a.k.a. pump) primarily mediated thru b-2 receptors located on skeletal muscle.

References
1. Lafontan M, Berlan M. Fat cell adrenergic receptors and the control of white and brown fat cell function. J Lipid Res, 1993 Jul;34(7):1057-91.
2. Sell H, Deshaies Y, Richard D. The brown adipocyte: update on its metabolic role. Int J Biochem Cell Biol, 2004 Nov;36(11):2098-104.
3. Foster DO and Frydman ML. Tissue distribution of cold-induced thermogenesis in conscious warm- or cold-acclimated rats reevaluated from changes in tissue blood flow: the dominant role of brown adipose tissue in the replacement of shivering by nonshivering thermogenesis. Can J Physiol Pharmacol, 57: 257–270, 1979.
4. Strosberg AD. Structure and function of the beta 3 adrenoreceptor. Adv Pharmacol, 1998;42:511-3.
5. Ricquier D, Bouillaud F, Toumelin P, Mory G, Bazin R, Arch J, Penicaud L. Expression of uncoupling protein mRNA in thermogenic or weakly thermogenic brown adipose tissue. Evidence for a rapid beta-adrenoreceptor-mediated and transcriptionally regulated step during activation of thermogenesis. J Biol Chem, 1986 Oct 25;261(30):13905-10.
6. Arner P, Kriegholm E, Engfeldt P, Bolinder J. Adrenergic regulation of lipolysis in situ at rest and during exercise. J Clin Invest, 1990 Mar;85(3):893-8.
7. Burns TW, Langley PE, Terry BE, Bylund DB. Studies on desensitization of adrenergic receptors of human adipocytes. Metabolism, 1982 Mar;31(3):288-93.
8. Lafontan M, Betuing S, Saulnier-Blache JS, Valet P, Bouloumie A, Carpene C, Galitzky J, Berlan M. Regulation of fat-cell function by alpha 2-adrenergic receptors. Adv Pharmacol, 1998;42:496-8.
9. Lean ME, James WP, Jennings G, Trayhurn P. Brown adipose tissue in patients with phaeochromocytoma. Int J Obes, 1986;10(3):219-27.
10. Jockers R, Issad T, Zilberfarb V, de Coppet P, Marullo S, Strosberg AD. Desensitization of the beta-adrenergic response in human brown adipocytes. Endocrinology, 1998 Jun;139(6):2676-84.
11. Morroni M, Barbatelli G, Zingaretti MC, Cinti S. Immunohistochemical, ultrastructural and morphometric evidence for brown adipose tissue recruitment due to cold acclimation in old rats. Int J Obes Relat Metab Disord, 1995 Feb;19(2):126-31.
12. Larsen TM, Toubro S, van Baak MA, Gottesdiener KM, Larson P, Saris WH, Astrup A. Effect of a 28-d treatment with L-796568, a novel beta(3)-adrenergic receptor agonist, on energy expenditure and body composition in obese men. Am J Clin Nutr, 2002 Oct;76(4):780-8.
13. Liu YL, Toubro S, Astrup A, Stock MJ. Contribution of beta 3-adrenoceptor activation to ephedrine-induced thermogenesis in humans. Int J Obes Relat Metab Disord, 1995 Sep;19(9):678-85.
14. Grujic, D, Susulic VS, Harper ME, Himms-Hagen J, Cunningham BA, Corkey BE, and Lowell BB.  3-Adrenergic receptors on white and brown adipocytes mediate  3-selective agonist-induced effects on energy expenditure, insulin secretion, and food intake. A study using transgenic and gene knockout mice. J Biol Chem, 272: 17686-17693, 1997.
15. Enerback, S, Jacobsson A, Simpson EM, Guerra C, Yamashita H, Harper ME, and Kozak LP. Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese. Nature, 387: 90-94, 1997.
16. Argyropoulos G, Harper ME. Uncoupling proteins and thermoregulation. J Appl Physiol, 2002 May;92(5):2187-98.
17. Berraondo B, Martinez JA. Free fatty acids are involved in the inverse relationship between hormone-sensitive lipase (HSL) activity and expression in adipose tissue after high-fat feeding or beta3-adrenergic stimulation. Obes Res, 2000 May;8(3):255-61.
18. Mitchell BD, Cole SA, Comuzzie AG, Almasy L, Blangero J, MacCluer JW, Hixson JE. A quantitative trait locus influencing BMI maps to the region of the beta-3 adrenergic receptor. Diabetes, 1999 Sep;48(9):1863-7.
19. Hatakeyama Y, Sakata Y, Takakura S, Manda T, Mutoh S. Acute and chronic effects of FR-149175, a beta 3-adrenergic receptor agonist, on energy expenditure in Zucker fatty rats. Am J Physiol Regul Integr Comp Physiol, 2004 Aug;287(2):R336-4
20. Cousin B, Cinti S, Morroni M, Raimbault S, Ricquier D, Penicaud L, Casteilla L. Occurrence of brown adipocytes in rat white adipose tissue: molecular and morphological characterization. J Cell Sci, 1992 Dec;103 ( Pt 4):931-42.
21. Nagase I, Yoshida T, Kumamoto K, Umekawa T, Sakane N, Nikami H, Kawada T, Saito M. Expression of uncoupling protein in skeletal muscle and white fat of obese mice treated with thermogenic beta 3-adrenergic agonist. J Clin Invest, 1996 Jun 15;97(12):2898-904.
22. Ortmeyer HK. Insulin decreases skeletal muscle cAMP-dependent protein kinase (PKA) activity in normal monkeys and increases PKA activity in insulin-resistant rhesus monkeys. J Basic Clin Physiol Pharmacol, 1997;8(4):223-35.
23. Granneman JG, Burnazi M, Zhu Z, Schwamb LA. White adipose tissue contributes to UCP1-independent thermogenesis. Am J Physiol Endocrinol Metab, 2003 Dec;285(6):E1230-6.
24. Cannon B, Nedergaard J. Brown adipose tissue: function and physiological significance. Physiol Rev, 2004 Jan;84(1):277-359. Review.
25. Matthias A, Ohlson KB, Fredriksson JM, Jacobsson A, Nedergaard J, Cannon B. Thermogenic responses in brown fat cells are fully UCP1-dependent. UCP2 or UCP3 do not substitute for UCP1 in adrenergically or fatty scid-induced thermogenesis. J Biol Chem, 2000 Aug 18;275(33):25073-81.
26. Matsuo T, Komuro M, Suzuki M. Beef tallow diet decreases uncoupling protein content in the brown adipose tissue of rats. J Nutr Sci Vitaminol,1996 Dec;42(6):595-601.
27. Barbe P, Stich V, Galitzky J, Kunesova M, Hainer V, Lafontan M, Berlan M. In vivo increase in beta-adrenergic lipolytic response in subcutaneous adipose tissue of obese subjects submitted to a hypocaloric diet. J Clin Endocrinol Metab, 1997 Jan;82(1):63-9.
28. Hagstrom-Toft E, Enoksson S, Moberg E, Bolinder J, Arner P. beta-Adrenergic regulation of lipolysis and blood flow in human skeletal muscle in vivo. Am J Physiol, 1998 Dec;275(6 Pt 1):E909-16.
29. van Baak MA, Hul GB, Toubro S, Astrup A, Gottesdiener KM, DeSmet M, Saris WH. Acute effect of L-796568, a novel beta 3-adrenergic receptor agonist, on energy expenditure in obese men. Clin Pharmacol Ther, 2002 Apr;71(4):272-9.
30. Buemann B, Toubro S, Astrup A. Effects of the two beta3-agonists, ZD7114 and ZD2079 on 24 hour energy expenditure and respiratory quotient in obese subjects. Int J Obes Relat Metab Disord, 2000 Dec;24(12):1553-60.
31. Rayner DV. The sympathetic nervous system in white adipose tissue regulation. Proc Nutr Soc, 2001 Aug;60(3):357-64.
32. Tate KM, Briend-Sutren MM, Emorine LJ, Delavier-Klutchko C, Marullo S, Strosberg AD. Expression of three human beta-adrenergic-receptor subtypes in transfected Chinese hamster ovary cells. Eur J Biochem, 1991 Mar 14;196(2):357-61.
33. Lonnqvist F, Wahrenberg H, Hellstrom L, Reynisdottir S, Arner P. Lipolytic catecholamine resistance due to decreased beta 2-adrenoceptor expression in fat cells. J Clin Invest, 1992 Dec;90(6):2175-86.
34. Granneman JG, Burnazi M, Zhu Z, Schwamb LA. White adipose tissue contributes to UCP1-independent thermogenesis. Am J Physiol Endocrinol Metab, 2003 Dec;285(6):E1230-6.
35. Toubro S, Astrup AV, Breum L, Quaade F. Safety and efficacy of long-term treatment with ephedrine, caffeine and an ephedrine/caffeine mixture. Int J Obes Relat Metab Disord, 1993 Feb;17 Suppl 1:S69-72.
36. Tavernier G, Barbe P, Galitzky J, Berlan M, Caput D, Lafontan M, Langin D. Expression of beta3-adrenoceptors with low lipolytic action in human subcutaneous white adipocytes. J Lipid Res, 1996 Jan;37(1):87-97.
37. Dieudonne MN, Pecquery R, Boumediene A, Leneveu MC, Giudicelli Y. Androgen receptors in human preadipocytes and adipocytes: regional specificities and regulation by sex steroids. Am J Physiol, 1998 Jun;274(6 Pt 1):C1645-52.
38. Galitzky J, Lafontan M, Nordenstrom J, Arner P. Role of vascular alpha-2 adrenoceptors in regulating lipid mobilization from human adipose tissue. J Clin Invest, 1993 May;91(5):1997-2003.
39. Arner P, Kriegholm E, Engfeldt P, Bolinder J. Adrenergic regulation of lipolysis in situ at rest and during exercise. J Clin Invest, 1990 Mar;85(3):893-8.