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Androgen Effect on Body Composition and Fat Metabolism
Symposium Article
Androgen Effect on Body Composition and Fat Metabolism MICHAEL
D. JENSEN, MD
Recognizing the adverse metabolic effects of predominantly visceral body fat distribution associated with low testosterone levels, researchers have investigated the effects of androgen treatment on body fat distribution in men. This presentation reviews the results of research on acute and longer-term effects of treatment with testos-
terone and dihydrotestosterone. Methods for investigating these results, including measurement of lipoprotein lipase activity and of radiolabeled fat uptake and turnover, are described and discussed. Mayo Clin Proc. 2000;75(suppl):S65-S69
T
he relationship between androgen levels and fat distribution differs between women and men. In women, elevated levels of androgens are associated with a central or visceral obesity, whereas in men the opposite is the case-testosterone levels and abdominal visceral fat bear an inverse relationship. Evans et ali reported a positive correlation between an increasing waist-hip ratio (WHR) (a measure of central fat distribution) and high levels of free testosterone in premenopausal women. A similar relationship was seen with increasing body weight. At higher degrees of obesity, there is an increasing proportion of free testosterone. The authors ofthis study report that these effects are additive.' In the same study, a measure of insulin action was obtained by measuring the steady-state plasma glucose response to a fixed insulin and glucose infusion. Results showed that in women, the higher the level of free testosterone, the higher the blood glucose value during this test, suggesting a greater degree of insulin resistance. Therefore, with higher levels of free testosterone, a central fat distribution and insulin resistance appear to be grouped together in women. The opposite effect has been reported in men: decreasing levels of free testosterone are associated with greater amounts of visceral fat.? Men with the lowest levels of free testosterone have the most visceral fat, and those with higher levels of free testosterone have lower visceral fat. The literature on this topic is conclusive: lower andro-
gen levels in men are associated with increasing abdominal and visceral adiposity. However, it is unclear whether there is a cause-and-effect relationship to this finding; that is, whether the visceral obesity may somehow have central effects, lowering testosterone, or vice versa. The opposite situation occurs in women. Increasing abdominal visceral adiposity is associated with higher androgen levels. Here, too, the cause-and-effect relationships are unclear. BODY FAT DISTRIBUTION AND EFFECTS ON HEALTH In both sexes, there are effects on health from body fat distribution. Upper body or central obesity is associated with hyperinsulinemia, insulin resistance, hypertension, coagulation abnormalities, glucose intolerance, dyslipidemia, and cardiovascular death.> More recently it has been suggested that visceral adiposity is more of a metabolic hazard than subcutaneous obesity; that is, fat distributed within the abdominal cavity, as shown in Figure 1, tends to be worse than the same amount of fat under the skin.4 ,5 This suggestion is not without controversy, however, and this singular focus on visceral fat may be too simplistic. Other investigators have examined the relationship between a variety of fat indices and insulin regulation of glucose metabolism. In one such study, Abate et al6 found that abdominal subcutaneous fat mass was more strongly related to insulin resistance than was visceral fat. It sometimes is difficult to dissociate the potential effects of subcutaneous vs visceral fat, however. In many instances, there is a strong relationship between the amount of subcutaneous abdominal fat and the intraperitoneal fat mass-it is not common for individuals to have the clearly isolated effect of either predominantly subcutaneous or predominantly visceral fat as shown in Figure 1.
From the Division of Endocrinology, Metabolism, Nutrition, and Internal Medicine, Mayo Clinic Rochester, Rochester, Minn. This work was supported by research grant AR27065 from the National Institute of Arthritis, Musculoskeletal and Skin Diseases. Presented at Symposium on Testosterone Replacement in Elderly Men, Palm Springs, Calif, March 18-20, 1999.
Mayo Clin Proc. 2000;75(suppl):S65-S69
S65
© 2000 Mayo Foundation for Medical Education and Research
S66
Mayo Clin Proc, January 2000, Vol 75 (Supplement)
Androgen Effect on Body Composition and Fat Metabolism
35
•P
~
..
Dli :!!.
30
.i! f
.i! ~
.0
~
25
20 testosterone
placebo
testosterone
placebo
Figure 2. Androgen treatment of obese men. Filled bars depict baseline values and open bars depict posttreatment values. Adapted from Marin et aJ.7
was no appreciable change in total body fat with either testosterone or placebo treatment, but at 8 months, visceral fat had significantly decreased in response to testosterone replacement compared with placebo. These investigators also found an increased glucose disposal rate during insulin clamp in the testosteronetreated subjects but not in the placebo-treated individuals.' From this preliminary study, it was concluded that testosterone replacement might have a selective effect on visceral fat, and that it probably increases insulin action.
Effects of Testosterone vs Dihydrotestosterone
Figure I. The top panel is a computed tomographic scan showing predominantly intra-abdominal fat, and the bottom panel is a computed tomographic scan showing predominantly subcutaneous fat.
EFFECTS OF ANDROGEN TREATMENT ON BODY FAT DISTRIBUTION
Against the background that upper body fat in general and visceral fat in particular, are bad for health, a question arises concerning their relationship with androgens. As noted, in men, there is a relationship between low testosterone and increased incidence of visceral and abdominal subcutaneous fat, but the cause-and-effect relationship is still unclear. Clinical studies have attempted to show what happens when these men undergo testosterone replacement.
Effects of Testosterone Figure 2 summarizes data from one of the early studies to examine this issue'? Marin et al evaluated the effects of testosterone replacement vs placebo on total body fat and visceral fat as measured by computed tomography. There
To address the question of whether the effects of testosterone might be mediated via aromatization-created compounds, the same investigators designed a study in which effects from testosterone treatment were compared with those from dihydrotestosterone (DHT) treatment.f Neither testosterone nor DHT had an effect on total body fat. Interestingly, however, the testosterone-treated men had a reduction in WHR, a finding that is consistent with the reduction in visceral fat found in the other study. The DHT-treated men had no reduction in their WHR. The testosterone-treated group also had a 17% increase in their glucose response to insulin, whereas the DRT· treated men did not. These results represent a second finding or additional clinical evidence that testosterone treatment may have effects on both fat distribution and insulin action. The lack of effect of DHT may indicate that testosterone effects are mediated by a compound created via the aromatization process.
Effects of Extended Treatment With Testosterone vs DHT The same group? compared 9 months of treatment with transdermal testosterone, transdermal DHT, or transdermal placebo in obese, middle-aged men. Again, there was
Mayo Clin Proc, January 2000, Vol 75 (Supplement)
Androgen Effect on Body Composition and Fat Metabolism
no change in lean body mass or total body fat in any group. Visceral fat decreased in the testosterone group, increased in the DHT group (a surprising result), and did not change in the placebo group. Glucose disposal, cholesterol and triglyceride levels, and diastolic blood pressure improved only in the testosterone-treatment group. There was further analysis because the research design did not call for inclusion or exclusion based on baseline testosterone values. The relationship between serum testosterone values before testosterone treatment and the improvement seen in glucose disposal rate was explored. Results showed that in the men with the lowest baseline testosterone levels, testosterone treatment produced the greatest increase in glucose disposal rate. In contrast, subjects with the highest preintervention testosterone levels had the least improvement in glucose disposal. This suggested an effect primarily in the men with lower testosterone levels at baseline.
radiotracer. After waiting 24 hours, when all the food has been either stored or oxidized, it is possible to take fat biopsies from different regions. The extent to which radioactivity is concentrated in the different biopsy regions indicates preferential uptake of fat in that region. In one such study, a fatty acid radiotracer lipid meal was administered to men I day before intra-abdominal surgery.t- Analysis of biopsies of abdominal subcutaneous, omental, and retroperitoneal fat revealed greater lipid uptake relative to the amount of fat tissue in omental and retroperitoneal fat than in abdominal subcutaneous fat. These results imply that in men dietary fat is preferentially stored in the intra-abdominal site. The same investigators next directed their attention to androgen effects on adipose tissue depot, using the same paradigm but administering testosterone 5 days prior to surgery. 10 Testosterone appeared to reduce meal fatty acid uptake by intra-abdominal adipose tissue.
POSSIBLE EXPLANATIONS FOR THE EFFECTS OF ANDROGEN TREATMENT
Fat Thrnover Measured The same investigators studied whether, by taking serial biopsies, it is possible to learn how quickly the fat is turning over in an area. An initial biopsy, done I day to I month after the radiolabeled meal, provides an indication of how readily the meal fat is taken up; then by doing serial biopsies over time and measuring the decrease in radioactivity half-life, it is possible to assess the turnover of fat, which provides an integrated look at both lipolysis and fat storage over time. The shorter the turnover time, the more rapid the rates of net lipolysis and fatty acid mobilization.!' Treatment with testosterone, but not DHT or placebo, tended to decrease the half-life of fatty acids in the abdominal adipose tissue depot, suggesting greater integrated lipolysis. There was no treatment effect on fatty acid half-life in femoral adipose tissue.
How might this redistribution of fat occur in response to androgen treatment? There are at least 2 possibilities. Fat may be selectively stored in different locations, and it is possible to change either the regional fat uptake, rate of fat mobilization, or both. These issues are the focus of several published studies. 10-12 Lipoprotein Lipase Activity With respect to fat storage, the focus has been on lipoprotein lipase (LPL), which is considered to be the rate-limiting factor for storage of fat in different adipose tissue regions. LPL activity was measured in abdominal and femoral adipose tissue before a single dose of testosterone in men and I week following that dose.P At both sites, there was a tendency for decreased LPL activity I week after a testosterone injection; however, at neither site was the difference statistically significant. The same researchers then proceeded to administer 6 weeks of testosterone treatment and make the same measurements in a different group of men.':' These results showed a significant decrease in LPL activity in abdominal subcutaneous adipose tissue, whereas there was no significant change in LPL activity in the femoral region. These results suggested that perhaps testosterone is having effects on the storage side of the equation, where fat is deposited in men. Fat Uptake Traced A more physiologic method for tracking fat storage is to administer a lipid-labeled meal containing a fatty acid
S67
Confirming Data About Androgen Effects on Adiopocytes With regard to lipolysis, the half-life data on fatty acids measured in the previous study!' indicated there may be an increase in turnover with testosterone treatment, a possible indication of an increase in lipolysis in abdominal adipose tissue. In a study of adipocytes cultured in vitro, testosterone was added to assess effects on lipolysis.t? Although there was no change in the basal rate of lipolysis, testosterone increased the responsiveness of the adipocytes to 2 cyclic AMP-mediated lipolysis stimulators, isoproterenol and forskolin. SUMMARY
Low testosterone in men is associated with visceral
S68
Androgen Effect on Body Composition and Fat Metabolism
obesity and its complications. Several studies have shown that testosterone replacement decreases visceral fat without decreasing total body fat in obese men with low baseline testosterone levels. The improvements in metabolic function seen with testosterone replacement are consistent with its effects on visceral fat mass. Testosterone appears to alter meal triglyceride uptake by visceral and abdominal adipose tissue, although there are some inconsistencies with the results. Testosterone may influence adipose tissue lipolysis, but this has never been examined in vivo. There is no reliable information regarding testosterone's effects on energy expenditure or fat oxidation in older men with low normal testosterone levels. Replacing testosterone in obese men with subnormal serum testosterone levels may result in beneficial changes in body fat distribution, but it does not appear to have an effect on total body fat. Whether the risks of testosterone replacement offset these benefits is currently unknown. REFERENCES I.
Evans D1, Hoffmann RG, Kalkhoff RK, et al. Relationship of androgenic activity to body fat topography, fat cell morphology, and metabolic aberrations in premenopausal women. J Clin Endocrinol Metab. 1983;57:304-310.
2.
Seidell1C, Bjomtorp L, Sjostrom L, et al. Visceral fat accumulation in men is positively associated with insulin, glucose, and Cpeptide levels, but negatively with testosterone levels. Metabolism. 1990;39:897-901.
3.
Kissebah AH, Peiris AN. Biology of regional fat distribution: relationship to non-insulin-dependent diabetes mellitus. Diabetes Metab Rev. 1989;5:83-109.
4. 5.
6. 7. 8. 9. 10.
11.
12. 13.
Fujioka S, Matsuzawa Y,Tokunaga K, et al. Contribution of intraabdominal fat accumulation to the impairment of glucose and lipid metabolism in human obesity. Metabolism. 1987;36:54-59. Despres JP, Nadeau A, Tremblay A, et al. Role of deep abdominal fat in the association between regional adipose tissue distribution and glucose tolerance in obese women. Diabetes. 1989;38:304309. Abate N, Garg A, Peshock RM, et al. Relationships of generalized and regional adiposity to insulin sensitivity in men. J Clin Invest. 1995;96:88-98. Marin P, Homang S, Jonsson L, et al. The effects of testosterone treatment on body composition and metabolism in middle-aged obese men.lnr J Obes. 1992;16:991-997. Marin P, Krotkiewski M, Bjorntorp P. Androgen treatment of middle-aged, obese men: effects on metabolism, muscle and adipose tissue. Eur J Med. 1992;I:329-336. Marin P, Holmang S, Gustafsson C, et al. Androgen treatment of abdominally obese men. Obes Res. 1993;I:245-251. Marin P, Oden B, Olbe L, et al. Assimilation of triglycerides in subcutaneous and intraabdominal adipose tissues in vivo in men: effects of testosterone. J Clin Endocrinol Me/ab. 1996;81:10181022. Marin P, Oden B, Bjorntorp P. Assimilation and mobilization of triglycerides in subcutaneous abdominal and femoral adipose tissue in vivo in men: effects of androgens. J Clin Endocrinol Metab. 1995;80:239-243. Xu X, De Pergola G, Bjomtorp P. The effects of androgens on the regulation of lipolysis in adipose precursor cells. Endocrinology. 1990; 126:1229-1234. Rebuffe-Scrive M, Marin P, Bjorntorp P. Effect of testosterone on
Mayo Clin Proc, January 2000, Vol 75 (Supplement)
•
14.
abdominal adipose tissue in men. Int J Obes. 1991;/5:791-795. Marin P, Anderson B, Ottosson M, et al. The morphology ami metabolism of intraabdominal adipose tissue in men. Me/abolisnIJ 1992;41:1 2 4 2 - 1 2 4 8 . '
DISCUSSION OF PRESENTATION
Dr Bhasin: What is visceral fat? I have difficulty with the way it is defined, through use of computed tomography or magnetic resonance imaging. Some calculations are done by computing the subcutaneous fat area and then subtracting that from total abdominal fat, while others alse take out the retroperitoneal fat, or the perirenal fat. Dr Jensen: The definition of visceral fat would probably be that fat which drains into the portal vein: omental and mesenteric fat. Unfortunately, our imaging techniques, are not good enough to always clearly isolate retroperitoneal fat, but it is typically a small component, and failure to do so will not likely influence results. If total intraabdominal fat is calculated using the abdominal wall muscles and the lumbar spine, that measurement is probably not too far off. Dr Bhasin: Testosterone effects on body fat are not uniform across studies, even in well-defined androgendeficient populations. Some studies show a decrease in fat mass; others show no change. Age, pretreatment body composition (ie, fat mass), and treatment duration may have something to do with these discrepancies. Studiesof shorter duration (12 to 26 weeks) tend not to show an effect, whereas those following treatment for 6 months or longer do. Dr Khosla: Differences in the study population, thatis, changes in activity or eating patterns, probably have a much greater effect than the treatment. Dr Nair: How much of the change in intra-abdominal fat may be related to exercise? Dr Jensen: Most studies do not control for exercise. The closest approximation appears to be something along the lines of "we told our patients not to change their exercise level." Question: Gender differences in fat distribution are so striking that there must be a physiologic or at least a cellular mechanism. Since it is relatively easy to study adipocytes in culture, has that been done to examine whether adipocytes from the buttocks behave differently from adipocytes in the abdominal cavity? For example, to test for differences in androgen receptor (AR) and estrogen receptor (ER) concentrations in those tissues, and their responsiveness to ER and AR in vitro? Dr Jensen: There are differences in cell types, but no differences that I can recall in the AR and ER. One of the difficulties has to do with examining a lipid label in a lipid-laden cell. There is a huge amount of "noise" when
Mayo Clin Proc, January 2000, Vol 75 (Supplement)
Androgen Effect on Body Composition and Fat Metabolism
that measurement is attempted in a fat cell; it is much more difficult than doing so in a bone cell, for example. Question: Are there any peripheral measures of visceral obesity, such as TNF-a? Dr Jensen: There is quite a bit of controversy regarding the TNF-a measurement, with some groups saying that it goes up with obesity and other saying that it does
not. Nobody has been able to sort out differences in production in vivo, and results from in vitro studies also are contradictory. Probably the simplest anthropometric marker of visceral obesity is to measure the height of the abdomen while one is lying down. That technique is simple and inexpensive and a reasonably good predictor of visceral fat mass.
S69
Androgen Effect on Body Composition and Fat Metabolism MICHAEL
D. JENSEN, MD
Recognizing the adverse metabolic effects of predominantly visceral body fat distribution associated with low testosterone levels, researchers have investigated the effects of androgen treatment on body fat distribution in men. This presentation reviews the results of research on acute and longer-term effects of treatment with testos-
terone and dihydrotestosterone. Methods for investigating these results, including measurement of lipoprotein lipase activity and of radiolabeled fat uptake and turnover, are described and discussed. Mayo Clin Proc. 2000;75(suppl):S65-S69
T
he relationship between androgen levels and fat distribution differs between women and men. In women, elevated levels of androgens are associated with a central or visceral obesity, whereas in men the opposite is the case-testosterone levels and abdominal visceral fat bear an inverse relationship. Evans et ali reported a positive correlation between an increasing waist-hip ratio (WHR) (a measure of central fat distribution) and high levels of free testosterone in premenopausal women. A similar relationship was seen with increasing body weight. At higher degrees of obesity, there is an increasing proportion of free testosterone. The authors ofthis study report that these effects are additive.' In the same study, a measure of insulin action was obtained by measuring the steady-state plasma glucose response to a fixed insulin and glucose infusion. Results showed that in women, the higher the level of free testosterone, the higher the blood glucose value during this test, suggesting a greater degree of insulin resistance. Therefore, with higher levels of free testosterone, a central fat distribution and insulin resistance appear to be grouped together in women. The opposite effect has been reported in men: decreasing levels of free testosterone are associated with greater amounts of visceral fat.? Men with the lowest levels of free testosterone have the most visceral fat, and those with higher levels of free testosterone have lower visceral fat. The literature on this topic is conclusive: lower andro-
gen levels in men are associated with increasing abdominal and visceral adiposity. However, it is unclear whether there is a cause-and-effect relationship to this finding; that is, whether the visceral obesity may somehow have central effects, lowering testosterone, or vice versa. The opposite situation occurs in women. Increasing abdominal visceral adiposity is associated with higher androgen levels. Here, too, the cause-and-effect relationships are unclear. BODY FAT DISTRIBUTION AND EFFECTS ON HEALTH In both sexes, there are effects on health from body fat distribution. Upper body or central obesity is associated with hyperinsulinemia, insulin resistance, hypertension, coagulation abnormalities, glucose intolerance, dyslipidemia, and cardiovascular death.> More recently it has been suggested that visceral adiposity is more of a metabolic hazard than subcutaneous obesity; that is, fat distributed within the abdominal cavity, as shown in Figure 1, tends to be worse than the same amount of fat under the skin.4 ,5 This suggestion is not without controversy, however, and this singular focus on visceral fat may be too simplistic. Other investigators have examined the relationship between a variety of fat indices and insulin regulation of glucose metabolism. In one such study, Abate et al6 found that abdominal subcutaneous fat mass was more strongly related to insulin resistance than was visceral fat. It sometimes is difficult to dissociate the potential effects of subcutaneous vs visceral fat, however. In many instances, there is a strong relationship between the amount of subcutaneous abdominal fat and the intraperitoneal fat mass-it is not common for individuals to have the clearly isolated effect of either predominantly subcutaneous or predominantly visceral fat as shown in Figure 1.
From the Division of Endocrinology, Metabolism, Nutrition, and Internal Medicine, Mayo Clinic Rochester, Rochester, Minn. This work was supported by research grant AR27065 from the National Institute of Arthritis, Musculoskeletal and Skin Diseases. Presented at Symposium on Testosterone Replacement in Elderly Men, Palm Springs, Calif, March 18-20, 1999.
Mayo Clin Proc. 2000;75(suppl):S65-S69
S65
© 2000 Mayo Foundation for Medical Education and Research
S66
Mayo Clin Proc, January 2000, Vol 75 (Supplement)
Androgen Effect on Body Composition and Fat Metabolism
35
•P
~
..
Dli :!!.
30
.i! f
.i! ~
.0
~
25
20 testosterone
placebo
testosterone
placebo
Figure 2. Androgen treatment of obese men. Filled bars depict baseline values and open bars depict posttreatment values. Adapted from Marin et aJ.7
was no appreciable change in total body fat with either testosterone or placebo treatment, but at 8 months, visceral fat had significantly decreased in response to testosterone replacement compared with placebo. These investigators also found an increased glucose disposal rate during insulin clamp in the testosteronetreated subjects but not in the placebo-treated individuals.' From this preliminary study, it was concluded that testosterone replacement might have a selective effect on visceral fat, and that it probably increases insulin action.
Effects of Testosterone vs Dihydrotestosterone
Figure I. The top panel is a computed tomographic scan showing predominantly intra-abdominal fat, and the bottom panel is a computed tomographic scan showing predominantly subcutaneous fat.
EFFECTS OF ANDROGEN TREATMENT ON BODY FAT DISTRIBUTION
Against the background that upper body fat in general and visceral fat in particular, are bad for health, a question arises concerning their relationship with androgens. As noted, in men, there is a relationship between low testosterone and increased incidence of visceral and abdominal subcutaneous fat, but the cause-and-effect relationship is still unclear. Clinical studies have attempted to show what happens when these men undergo testosterone replacement.
Effects of Testosterone Figure 2 summarizes data from one of the early studies to examine this issue'? Marin et al evaluated the effects of testosterone replacement vs placebo on total body fat and visceral fat as measured by computed tomography. There
To address the question of whether the effects of testosterone might be mediated via aromatization-created compounds, the same investigators designed a study in which effects from testosterone treatment were compared with those from dihydrotestosterone (DHT) treatment.f Neither testosterone nor DHT had an effect on total body fat. Interestingly, however, the testosterone-treated men had a reduction in WHR, a finding that is consistent with the reduction in visceral fat found in the other study. The DHT-treated men had no reduction in their WHR. The testosterone-treated group also had a 17% increase in their glucose response to insulin, whereas the DRT· treated men did not. These results represent a second finding or additional clinical evidence that testosterone treatment may have effects on both fat distribution and insulin action. The lack of effect of DHT may indicate that testosterone effects are mediated by a compound created via the aromatization process.
Effects of Extended Treatment With Testosterone vs DHT The same group? compared 9 months of treatment with transdermal testosterone, transdermal DHT, or transdermal placebo in obese, middle-aged men. Again, there was
Mayo Clin Proc, January 2000, Vol 75 (Supplement)
Androgen Effect on Body Composition and Fat Metabolism
no change in lean body mass or total body fat in any group. Visceral fat decreased in the testosterone group, increased in the DHT group (a surprising result), and did not change in the placebo group. Glucose disposal, cholesterol and triglyceride levels, and diastolic blood pressure improved only in the testosterone-treatment group. There was further analysis because the research design did not call for inclusion or exclusion based on baseline testosterone values. The relationship between serum testosterone values before testosterone treatment and the improvement seen in glucose disposal rate was explored. Results showed that in the men with the lowest baseline testosterone levels, testosterone treatment produced the greatest increase in glucose disposal rate. In contrast, subjects with the highest preintervention testosterone levels had the least improvement in glucose disposal. This suggested an effect primarily in the men with lower testosterone levels at baseline.
radiotracer. After waiting 24 hours, when all the food has been either stored or oxidized, it is possible to take fat biopsies from different regions. The extent to which radioactivity is concentrated in the different biopsy regions indicates preferential uptake of fat in that region. In one such study, a fatty acid radiotracer lipid meal was administered to men I day before intra-abdominal surgery.t- Analysis of biopsies of abdominal subcutaneous, omental, and retroperitoneal fat revealed greater lipid uptake relative to the amount of fat tissue in omental and retroperitoneal fat than in abdominal subcutaneous fat. These results imply that in men dietary fat is preferentially stored in the intra-abdominal site. The same investigators next directed their attention to androgen effects on adipose tissue depot, using the same paradigm but administering testosterone 5 days prior to surgery. 10 Testosterone appeared to reduce meal fatty acid uptake by intra-abdominal adipose tissue.
POSSIBLE EXPLANATIONS FOR THE EFFECTS OF ANDROGEN TREATMENT
Fat Thrnover Measured The same investigators studied whether, by taking serial biopsies, it is possible to learn how quickly the fat is turning over in an area. An initial biopsy, done I day to I month after the radiolabeled meal, provides an indication of how readily the meal fat is taken up; then by doing serial biopsies over time and measuring the decrease in radioactivity half-life, it is possible to assess the turnover of fat, which provides an integrated look at both lipolysis and fat storage over time. The shorter the turnover time, the more rapid the rates of net lipolysis and fatty acid mobilization.!' Treatment with testosterone, but not DHT or placebo, tended to decrease the half-life of fatty acids in the abdominal adipose tissue depot, suggesting greater integrated lipolysis. There was no treatment effect on fatty acid half-life in femoral adipose tissue.
How might this redistribution of fat occur in response to androgen treatment? There are at least 2 possibilities. Fat may be selectively stored in different locations, and it is possible to change either the regional fat uptake, rate of fat mobilization, or both. These issues are the focus of several published studies. 10-12 Lipoprotein Lipase Activity With respect to fat storage, the focus has been on lipoprotein lipase (LPL), which is considered to be the rate-limiting factor for storage of fat in different adipose tissue regions. LPL activity was measured in abdominal and femoral adipose tissue before a single dose of testosterone in men and I week following that dose.P At both sites, there was a tendency for decreased LPL activity I week after a testosterone injection; however, at neither site was the difference statistically significant. The same researchers then proceeded to administer 6 weeks of testosterone treatment and make the same measurements in a different group of men.':' These results showed a significant decrease in LPL activity in abdominal subcutaneous adipose tissue, whereas there was no significant change in LPL activity in the femoral region. These results suggested that perhaps testosterone is having effects on the storage side of the equation, where fat is deposited in men. Fat Uptake Traced A more physiologic method for tracking fat storage is to administer a lipid-labeled meal containing a fatty acid
S67
Confirming Data About Androgen Effects on Adiopocytes With regard to lipolysis, the half-life data on fatty acids measured in the previous study!' indicated there may be an increase in turnover with testosterone treatment, a possible indication of an increase in lipolysis in abdominal adipose tissue. In a study of adipocytes cultured in vitro, testosterone was added to assess effects on lipolysis.t? Although there was no change in the basal rate of lipolysis, testosterone increased the responsiveness of the adipocytes to 2 cyclic AMP-mediated lipolysis stimulators, isoproterenol and forskolin. SUMMARY
Low testosterone in men is associated with visceral
S68
Androgen Effect on Body Composition and Fat Metabolism
obesity and its complications. Several studies have shown that testosterone replacement decreases visceral fat without decreasing total body fat in obese men with low baseline testosterone levels. The improvements in metabolic function seen with testosterone replacement are consistent with its effects on visceral fat mass. Testosterone appears to alter meal triglyceride uptake by visceral and abdominal adipose tissue, although there are some inconsistencies with the results. Testosterone may influence adipose tissue lipolysis, but this has never been examined in vivo. There is no reliable information regarding testosterone's effects on energy expenditure or fat oxidation in older men with low normal testosterone levels. Replacing testosterone in obese men with subnormal serum testosterone levels may result in beneficial changes in body fat distribution, but it does not appear to have an effect on total body fat. Whether the risks of testosterone replacement offset these benefits is currently unknown. REFERENCES I.
Evans D1, Hoffmann RG, Kalkhoff RK, et al. Relationship of androgenic activity to body fat topography, fat cell morphology, and metabolic aberrations in premenopausal women. J Clin Endocrinol Metab. 1983;57:304-310.
2.
Seidell1C, Bjomtorp L, Sjostrom L, et al. Visceral fat accumulation in men is positively associated with insulin, glucose, and Cpeptide levels, but negatively with testosterone levels. Metabolism. 1990;39:897-901.
3.
Kissebah AH, Peiris AN. Biology of regional fat distribution: relationship to non-insulin-dependent diabetes mellitus. Diabetes Metab Rev. 1989;5:83-109.
4. 5.
6. 7. 8. 9. 10.
11.
12. 13.
Fujioka S, Matsuzawa Y,Tokunaga K, et al. Contribution of intraabdominal fat accumulation to the impairment of glucose and lipid metabolism in human obesity. Metabolism. 1987;36:54-59. Despres JP, Nadeau A, Tremblay A, et al. Role of deep abdominal fat in the association between regional adipose tissue distribution and glucose tolerance in obese women. Diabetes. 1989;38:304309. Abate N, Garg A, Peshock RM, et al. Relationships of generalized and regional adiposity to insulin sensitivity in men. J Clin Invest. 1995;96:88-98. Marin P, Homang S, Jonsson L, et al. The effects of testosterone treatment on body composition and metabolism in middle-aged obese men.lnr J Obes. 1992;16:991-997. Marin P, Krotkiewski M, Bjorntorp P. Androgen treatment of middle-aged, obese men: effects on metabolism, muscle and adipose tissue. Eur J Med. 1992;I:329-336. Marin P, Holmang S, Gustafsson C, et al. Androgen treatment of abdominally obese men. Obes Res. 1993;I:245-251. Marin P, Oden B, Olbe L, et al. Assimilation of triglycerides in subcutaneous and intraabdominal adipose tissues in vivo in men: effects of testosterone. J Clin Endocrinol Me/ab. 1996;81:10181022. Marin P, Oden B, Bjorntorp P. Assimilation and mobilization of triglycerides in subcutaneous abdominal and femoral adipose tissue in vivo in men: effects of androgens. J Clin Endocrinol Metab. 1995;80:239-243. Xu X, De Pergola G, Bjomtorp P. The effects of androgens on the regulation of lipolysis in adipose precursor cells. Endocrinology. 1990; 126:1229-1234. Rebuffe-Scrive M, Marin P, Bjorntorp P. Effect of testosterone on
Mayo Clin Proc, January 2000, Vol 75 (Supplement)
•
14.
abdominal adipose tissue in men. Int J Obes. 1991;/5:791-795. Marin P, Anderson B, Ottosson M, et al. The morphology ami metabolism of intraabdominal adipose tissue in men. Me/abolisnIJ 1992;41:1 2 4 2 - 1 2 4 8 . '
DISCUSSION OF PRESENTATION
Dr Bhasin: What is visceral fat? I have difficulty with the way it is defined, through use of computed tomography or magnetic resonance imaging. Some calculations are done by computing the subcutaneous fat area and then subtracting that from total abdominal fat, while others alse take out the retroperitoneal fat, or the perirenal fat. Dr Jensen: The definition of visceral fat would probably be that fat which drains into the portal vein: omental and mesenteric fat. Unfortunately, our imaging techniques, are not good enough to always clearly isolate retroperitoneal fat, but it is typically a small component, and failure to do so will not likely influence results. If total intraabdominal fat is calculated using the abdominal wall muscles and the lumbar spine, that measurement is probably not too far off. Dr Bhasin: Testosterone effects on body fat are not uniform across studies, even in well-defined androgendeficient populations. Some studies show a decrease in fat mass; others show no change. Age, pretreatment body composition (ie, fat mass), and treatment duration may have something to do with these discrepancies. Studiesof shorter duration (12 to 26 weeks) tend not to show an effect, whereas those following treatment for 6 months or longer do. Dr Khosla: Differences in the study population, thatis, changes in activity or eating patterns, probably have a much greater effect than the treatment. Dr Nair: How much of the change in intra-abdominal fat may be related to exercise? Dr Jensen: Most studies do not control for exercise. The closest approximation appears to be something along the lines of "we told our patients not to change their exercise level." Question: Gender differences in fat distribution are so striking that there must be a physiologic or at least a cellular mechanism. Since it is relatively easy to study adipocytes in culture, has that been done to examine whether adipocytes from the buttocks behave differently from adipocytes in the abdominal cavity? For example, to test for differences in androgen receptor (AR) and estrogen receptor (ER) concentrations in those tissues, and their responsiveness to ER and AR in vitro? Dr Jensen: There are differences in cell types, but no differences that I can recall in the AR and ER. One of the difficulties has to do with examining a lipid label in a lipid-laden cell. There is a huge amount of "noise" when
Mayo Clin Proc, January 2000, Vol 75 (Supplement)
Androgen Effect on Body Composition and Fat Metabolism
that measurement is attempted in a fat cell; it is much more difficult than doing so in a bone cell, for example. Question: Are there any peripheral measures of visceral obesity, such as TNF-a? Dr Jensen: There is quite a bit of controversy regarding the TNF-a measurement, with some groups saying that it goes up with obesity and other saying that it does
not. Nobody has been able to sort out differences in production in vivo, and results from in vitro studies also are contradictory. Probably the simplest anthropometric marker of visceral obesity is to measure the height of the abdomen while one is lying down. That technique is simple and inexpensive and a reasonably good predictor of visceral fat mass.
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