White Adipose Tissue, Inert No More!
http://www.100md.com
内分泌学杂志 2005年第5期
Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky College of Medicine, Lexington, Kentucky 40536
Address all correspondence and requests for reprints to: Dr. Joe McGillis, Department of Microbiology, Immunology and Molecular Genetics, MS415, University of Kentucky College of Medicine, Lexington, Kentucky 40536. E-mail: jpmcgi01@uky.edu.
When many of us first learned about white adipose tissue (WAT, fat cells) in the classroom, we learned that it was a place to store energy. Thus, if you consume more calories than you burn they are converted into lipids and stored in fat cells (our inevitable fate). Conversely, if you burn more calories than you consume, lipids are retrieved from fat cells to balance the energy deficit (our elusive goal). For many of us not highly interested in energy metabolism, we retained these facts because of a disposition toward the former metabolic state—increasing energy storage in that pesky WAT. As a society with growing tendency toward obesity (1), we have become more sensitive to the increased health risk associated with excess WAT energy storage. This has led in part to increased scientific interest in WAT. In recent years, we have become more aware of the fact that fat cells are metabolically active—they produce adipokines, soluble hormone-like substances including adiponectin, and leptin that have a wide range of metabolic effects (2). Targets of these mediators now seem to include immune and inflammatory systems (2, 3).
Over the last decade, the immune system and inflammatory processes have been implicated in many diseases where their involvement had not previously been appreciated. Diabetes, a serious metabolic disease, and Alzheimer’s disease, a neurodegenerative disorder, are but two examples (4, 5). We also have recognized that the immune system, once considered by many to function independently of outside influence, is subject to regulatory actions of both neural and endocrine systems (6, 7). Now a study by Sennello et al. (8) in this issue adds an important piece of evidence to the growing list suggesting that WAT and its soluble products adiponectin and leptin influence immune and inflammatory functions
Leptin was first discovered by characterization of the gene defect in the ob/ob mouse (9). The ob/ob mouse, which does not make leptin, is a model for morbid obesity. Besides leading to characterization of leptin’s role in energy homeostasis, it was observed that the ob/ob mouse has impaired T-cell functions that can be reversed by administration of leptin (10, 11, 12, 13). These are manifested in a reduced susceptibility to autoimmune encephalomyelitis, experimental arthritis, and intestinal inflammation. Previous work by this group and others has found that ob/ob mice are resistant to experimental autoimmune hepatitis induced by administration of the T-cell mitogen Concanavalin (Con A) (12, 13). In wild-type (WT) mice, induction of autoimmune hepatitis is associated with an elevation of the proinflammatory cytokines TNF and IL-18, a reduction in natural killer (NK) cells in liver, and an increase in activated T cells in liver (12, 13), as summarized in Fig. 1. This protection was interpreted in part as being due to the lack of leptin in the ob/ob mouse. In other words, the ob/ob mouse is not as susceptible to a T cell-mediated autoimmune condition because of either the leptin-associated T-cell deficiencies or some acute effect of leptin on T-cell functions.
FIG. 1. Susceptibility and resistance to Con A-induced hepatitis in ob/ob and LD mice. When WT mice are injected iv with the T-cell mitogen Con A, they develop an autoimmune hepatitis. The autoimmune hepatitis is associated with an increase in proinflammatory cytokines, a reduction in the antiinflammatory cytokine IL-10, a decrease in NK T cells in liver and an increase in activated T cells. ob/ob Mice have elevated levels of adiponectin (ADP) and no leptin (LEP). They are resistant to Con A-induced hepatitis and the associated changes in proinflammatory cytokines are reduced relative to WT mice, as are activated T cells in liver. In contrast, IL-10 is elevated in ob/ob mice. LD mice have highly reduced or nondetectable levels of adiponectin and leptin. When treated with Con A, LD mice have changes in proinflammatory cytokines and IL-10 that are similar to ob/ob mice. However, they do have an increase in activated T cells in liver, and unlike ob/ob mice they develop liver disease. When LD mice are infused with adiponectin replacement for 7 d, their cytokine and T-cell changes are similar to ob/ob mice and they are resistant to the hepatotoxic effects of Con A. When mice are infused with adiponectin and leptin (or leptin alone, not shown), cytokine responses are restored to WT levels, activated T cells are elevated in liver and the mice are susceptible to liver disease.
In the study reported in this issue, Sennello et al. (8) examined Con A-induced hepatitis in an additional model for WAT function, liypodystropic (LD) mice. They used the aP2-nSREBP-1c transgenic mouse, an animal that lacks WAT (14). In addition, they also used a model where WAT tissue is depleted by chronic administration of leptin (15). The LD mouse is similar to the ob/ob mouse in that it also has very low levels of leptin. In the Con A-induced hepatitis model, the response in the LD mouse is very similar to that in ob/ob mice (8). TNF, IL-4, IL-6, and IL-18 are reduced and IL-10 is elevated. Also, like the ob/ob mouse the reduction in NK T cells is much lower than WT as is the increase in activated T cells. However, there is one major difference between ob/ob and LD mice. LD mice develop hepatitis (summarized in Fig. 1).
Because of reduced leptin levels and similar cytokine, NK, and T-cell changes after con A injection, it was predicted that LD mice would be resistant to Con A-induced hepatitis, like ob/ob mice. Clearly, LD mice are not resistant. So why are LD mice susceptible and not ob/ob mice? Two possibilities are that there are factors other than those already observed in ob/ob mice that make them resistant, or that the associated differences in cytokine and cellular responses already identified in ob/ob mice are not important for the differences in disease susceptibility between ob/ob and WT mice. The remaining studies by Sennello et al. suggest that there are other WAT-dependent factors involved, and that the differences in cytokine and cellular responses between LD or ob/ob and WT mice are involved in susceptibility or resistance to hepatitis induction (8).
The first difference between ob/ob and LD that the authors document is that adiponectin is elevated in ob/ob mice relative to WT mice and that adiponectin levels are markedly reduced in LD mice. This leads to the question of whether administration of adiponectin can protect LD mice from Con A-induced hepatitis, and the answer is yes. LD mice infused with adiponectin for 7 d are resistant to hepatitis, similar to ob/ob mice that have endogenously elevated adiponectin. However, here is where the mechanism gets a little more complex. LD mice infused with leptin for the same period are actually more susceptible to liver damage than vehicle-treated LD mice, as are animals that are infused with both adiponectin and leptin. The pattern of cytokine production in LD mice replaced with continuous adiponectin or adiponectin and leptin infusions is consistent with disease susceptibility. TNF is reduced in adiponectin-replaced LD animals relative to vehicle controls, whereas both TNF and IL-4 are elevated in leptin or leptin and adiponectin-replaced animals. This suggests that potential immune and inflammatory effects of leptin in this model outweigh those of adiponectin under these specific treatment conditions (Fig. 1). From these results, the authors surmise that TNF is part of the Con A-dependent mechanism for liver toxicity in LD mice and that adiponectin acts to protect hepatocytes.
To test the first question the authors treated LD mice with a soluble form of the TNF receptor, sTNFRp55, that neutralizes TNF by preventing its binding to cell surface receptors. sTNFp55 blocks increased liver toxicity in Con A-treated LD mice, confirming TNF’s role. These in vivo results were confirmed using another model, administration of + D-gal and TNF which sensitizes hepatocytes to TNF’s hepatotoxic effects (16). In this case, LD mice were more sensitive than WT mice to the combined effects of + D-gal and TNF. To confirm the protective effect of adiponectin, the authors examined the ability of adiponectin to protect cultured hepatocytes from TNF-induced cell death. Adiponectin had a protective effect, alone or in combination with leptin, whereas leptin had no effect by itself on TNF-induced cell death. These data support the authors’ suggestion that adiponectin exerts its protective effects by acting directly on the hepatocyte to decrease the toxic effects of TNF. An additional study that would have strengthened these arguments would have been to treat LD mice with + D-gal, TNF, and adiponectin to confirm adiponectin’s protective effect in the in vivo model.
The current studies suggest that WAT’s influences on development of autoimmune conditions are more complicated than previously thought. On one side, leptin clearly seems to be necessary for development of normal T-cell functions. On the other, adiponectin clearly has protective effects during induction of autoimmunity. In these studies, the authors argue that leptin’s effects seem to be dominant based on the studies using adiponectin and leptin replacement in LD mice. However, it must be kept in mind that these studies used an artificial disease model and a very limited range of time and concentration treatments. It seems more likely that the interplay between leptins, adiponectins, and other as yet unidentified WAT products in the development of autoimmune disease are probably more complex. Nonetheless, the results suggest that these mediators may be viable candidates for therapeutic approaches to certain autoimmune conditions.
Clearly, more detailed studies will be necessary to determine the cellular targets of adipokines and the underlying biochemical and cellular mechanisms by which they influence development of autoimmune disease. The LD mouse should be a very valuable model for pursuing these goals. For those not directly working in this field as scientists but interested if for no other reason than our personal battle with WAT, the ever-expanding role of WAT in metabolism, homeostasis and disease gives us something new to contemplate during those hours spent on the treadmill.
References
Flegal KM, Carroll MD, Ogden CL, Johnson CL 2002 Prevalence and trends in obesity among US adults, 1999–2000. JAMA 288:1723–1727
Rajala MW, Scherer PE 2003 Minireview: the adipocyte—at the crossroads of energy homeostasis, inflammation, and atherosclerosis. Endocrinology 144:3765–3773
Fantuzzi G, Faggioni R 2000 Leptin in the regulation of immunity, inflammation, and hematopoiesis. J Leukoc Biol 68:437–446
Donath MY, Storling J, Maedler K, Mandrup-Poulsen T 2003 Inflammatory mediators and islet ?-cell failure: a link between type 1 and type 2 diabetes. J Mol Med 84:455–470
Weiner HL, Selkoe DJ 2002 Inflammation and therapeutic vaccination in CNS diseases. Nature 420:879–884
McGillis JP, Fernandez S, Knopf MA 2001 Regulation of immune and inflammatory reactions in local microenvironments by sensory neuropeptides. In: Ader B, Cohen C, Felten D, eds. Psychoneuroimmunology. 3rd ed. New York: Academic Press; 217–229
Sanders VM, Kohm AP 2002 Sympathetic nervous system interaction with the immune system. Int Rev Neurobiol 52:17–41
Sennello JA, Fayad R, Morris AM, Eckel RH, Asilmaz E, Montez J, Friedman JM, Dinarello CA, Fantuzzi G 2005 Regulation of T cell-mediated hepatic inflammation by adiponectin and leptin. Endocrinology 146:2157–2164
Zhang Y, Proenca R, Maffei M, Barone M 1994 Positional cloning of the mouse obese gene and its human homologue. Nature 372:425–432
Matarese G, Di Giacomo A, Sanna V, Lord GM, Howard JK, Di Tuoro A, Bloom SR, Lechler RI, Zappacosta S, Fontana S 2001 Requirement for leptin in the induction and progression of autoimmune encephalomyelitis. J Immunol 166:5909–5916
Busso N, So A, Chobaz-Péclat V, Morard C, Martinez-Soria E, Talabot-Ayer D, Gabay C 2002 Leptin signaling deficiency impairs humoral and cellular immune responses and attenuates experimental arthritis. J Immunol 168:875–882
Siegmund B, Lear-Kaul KC, Faggioni R, Fantuzzi G 2002 Leptin deficiency, not obesity, protects mice from Con A-induced hepatitis. Eur J Immunol 32:552–560
Faggioni R, Jones-Carson J, Reed DA, Dinarello CA, Feingold KR, Grunfeld C, Fantuzzi G 2000 Leptin-deficient (ob/ob) mice are protected from T cell-mediated hepatotoxicity: role of tumor necrosis factor and IL-18. Proc Natl Acad Sci USA 97:2367–2372
Shimomura I, Hammer RE, Richardson JA, Ikemoto S, Bashmakov Y, Goldstein JL, Brown MS 1998 Insulin resistance and diabetes mellitus in transgenic mice expressing nuclear SREBP-1c in adipose tissue: model for congenital generalized lipodystrophy. Genes Dev 12:3182–3194
Montez JM, Soukas A, Asilmaz E, Fayzikhodjaeva G, Fantuzzi G, Friedman JM 2005 Acute leptin deficiency, leptin resistance, and the physiologic response to leptin withdrawal. Proc Natl Acad Sci USA 102:2537–2542
Lehmann V, Freudenberg MA, Galanos C 1987 Lethal toxicity of lipopolysaccharide and tumor necrosis factor in normal and D-galactosamine-treated mice. J Exp Med 165:657–663(Joseph P. McGillis, Ph.D)
Address all correspondence and requests for reprints to: Dr. Joe McGillis, Department of Microbiology, Immunology and Molecular Genetics, MS415, University of Kentucky College of Medicine, Lexington, Kentucky 40536. E-mail: jpmcgi01@uky.edu.
When many of us first learned about white adipose tissue (WAT, fat cells) in the classroom, we learned that it was a place to store energy. Thus, if you consume more calories than you burn they are converted into lipids and stored in fat cells (our inevitable fate). Conversely, if you burn more calories than you consume, lipids are retrieved from fat cells to balance the energy deficit (our elusive goal). For many of us not highly interested in energy metabolism, we retained these facts because of a disposition toward the former metabolic state—increasing energy storage in that pesky WAT. As a society with growing tendency toward obesity (1), we have become more sensitive to the increased health risk associated with excess WAT energy storage. This has led in part to increased scientific interest in WAT. In recent years, we have become more aware of the fact that fat cells are metabolically active—they produce adipokines, soluble hormone-like substances including adiponectin, and leptin that have a wide range of metabolic effects (2). Targets of these mediators now seem to include immune and inflammatory systems (2, 3).
Over the last decade, the immune system and inflammatory processes have been implicated in many diseases where their involvement had not previously been appreciated. Diabetes, a serious metabolic disease, and Alzheimer’s disease, a neurodegenerative disorder, are but two examples (4, 5). We also have recognized that the immune system, once considered by many to function independently of outside influence, is subject to regulatory actions of both neural and endocrine systems (6, 7). Now a study by Sennello et al. (8) in this issue adds an important piece of evidence to the growing list suggesting that WAT and its soluble products adiponectin and leptin influence immune and inflammatory functions
Leptin was first discovered by characterization of the gene defect in the ob/ob mouse (9). The ob/ob mouse, which does not make leptin, is a model for morbid obesity. Besides leading to characterization of leptin’s role in energy homeostasis, it was observed that the ob/ob mouse has impaired T-cell functions that can be reversed by administration of leptin (10, 11, 12, 13). These are manifested in a reduced susceptibility to autoimmune encephalomyelitis, experimental arthritis, and intestinal inflammation. Previous work by this group and others has found that ob/ob mice are resistant to experimental autoimmune hepatitis induced by administration of the T-cell mitogen Concanavalin (Con A) (12, 13). In wild-type (WT) mice, induction of autoimmune hepatitis is associated with an elevation of the proinflammatory cytokines TNF and IL-18, a reduction in natural killer (NK) cells in liver, and an increase in activated T cells in liver (12, 13), as summarized in Fig. 1. This protection was interpreted in part as being due to the lack of leptin in the ob/ob mouse. In other words, the ob/ob mouse is not as susceptible to a T cell-mediated autoimmune condition because of either the leptin-associated T-cell deficiencies or some acute effect of leptin on T-cell functions.
FIG. 1. Susceptibility and resistance to Con A-induced hepatitis in ob/ob and LD mice. When WT mice are injected iv with the T-cell mitogen Con A, they develop an autoimmune hepatitis. The autoimmune hepatitis is associated with an increase in proinflammatory cytokines, a reduction in the antiinflammatory cytokine IL-10, a decrease in NK T cells in liver and an increase in activated T cells. ob/ob Mice have elevated levels of adiponectin (ADP) and no leptin (LEP). They are resistant to Con A-induced hepatitis and the associated changes in proinflammatory cytokines are reduced relative to WT mice, as are activated T cells in liver. In contrast, IL-10 is elevated in ob/ob mice. LD mice have highly reduced or nondetectable levels of adiponectin and leptin. When treated with Con A, LD mice have changes in proinflammatory cytokines and IL-10 that are similar to ob/ob mice. However, they do have an increase in activated T cells in liver, and unlike ob/ob mice they develop liver disease. When LD mice are infused with adiponectin replacement for 7 d, their cytokine and T-cell changes are similar to ob/ob mice and they are resistant to the hepatotoxic effects of Con A. When mice are infused with adiponectin and leptin (or leptin alone, not shown), cytokine responses are restored to WT levels, activated T cells are elevated in liver and the mice are susceptible to liver disease.
In the study reported in this issue, Sennello et al. (8) examined Con A-induced hepatitis in an additional model for WAT function, liypodystropic (LD) mice. They used the aP2-nSREBP-1c transgenic mouse, an animal that lacks WAT (14). In addition, they also used a model where WAT tissue is depleted by chronic administration of leptin (15). The LD mouse is similar to the ob/ob mouse in that it also has very low levels of leptin. In the Con A-induced hepatitis model, the response in the LD mouse is very similar to that in ob/ob mice (8). TNF, IL-4, IL-6, and IL-18 are reduced and IL-10 is elevated. Also, like the ob/ob mouse the reduction in NK T cells is much lower than WT as is the increase in activated T cells. However, there is one major difference between ob/ob and LD mice. LD mice develop hepatitis (summarized in Fig. 1).
Because of reduced leptin levels and similar cytokine, NK, and T-cell changes after con A injection, it was predicted that LD mice would be resistant to Con A-induced hepatitis, like ob/ob mice. Clearly, LD mice are not resistant. So why are LD mice susceptible and not ob/ob mice? Two possibilities are that there are factors other than those already observed in ob/ob mice that make them resistant, or that the associated differences in cytokine and cellular responses already identified in ob/ob mice are not important for the differences in disease susceptibility between ob/ob and WT mice. The remaining studies by Sennello et al. suggest that there are other WAT-dependent factors involved, and that the differences in cytokine and cellular responses between LD or ob/ob and WT mice are involved in susceptibility or resistance to hepatitis induction (8).
The first difference between ob/ob and LD that the authors document is that adiponectin is elevated in ob/ob mice relative to WT mice and that adiponectin levels are markedly reduced in LD mice. This leads to the question of whether administration of adiponectin can protect LD mice from Con A-induced hepatitis, and the answer is yes. LD mice infused with adiponectin for 7 d are resistant to hepatitis, similar to ob/ob mice that have endogenously elevated adiponectin. However, here is where the mechanism gets a little more complex. LD mice infused with leptin for the same period are actually more susceptible to liver damage than vehicle-treated LD mice, as are animals that are infused with both adiponectin and leptin. The pattern of cytokine production in LD mice replaced with continuous adiponectin or adiponectin and leptin infusions is consistent with disease susceptibility. TNF is reduced in adiponectin-replaced LD animals relative to vehicle controls, whereas both TNF and IL-4 are elevated in leptin or leptin and adiponectin-replaced animals. This suggests that potential immune and inflammatory effects of leptin in this model outweigh those of adiponectin under these specific treatment conditions (Fig. 1). From these results, the authors surmise that TNF is part of the Con A-dependent mechanism for liver toxicity in LD mice and that adiponectin acts to protect hepatocytes.
To test the first question the authors treated LD mice with a soluble form of the TNF receptor, sTNFRp55, that neutralizes TNF by preventing its binding to cell surface receptors. sTNFp55 blocks increased liver toxicity in Con A-treated LD mice, confirming TNF’s role. These in vivo results were confirmed using another model, administration of + D-gal and TNF which sensitizes hepatocytes to TNF’s hepatotoxic effects (16). In this case, LD mice were more sensitive than WT mice to the combined effects of + D-gal and TNF. To confirm the protective effect of adiponectin, the authors examined the ability of adiponectin to protect cultured hepatocytes from TNF-induced cell death. Adiponectin had a protective effect, alone or in combination with leptin, whereas leptin had no effect by itself on TNF-induced cell death. These data support the authors’ suggestion that adiponectin exerts its protective effects by acting directly on the hepatocyte to decrease the toxic effects of TNF. An additional study that would have strengthened these arguments would have been to treat LD mice with + D-gal, TNF, and adiponectin to confirm adiponectin’s protective effect in the in vivo model.
The current studies suggest that WAT’s influences on development of autoimmune conditions are more complicated than previously thought. On one side, leptin clearly seems to be necessary for development of normal T-cell functions. On the other, adiponectin clearly has protective effects during induction of autoimmunity. In these studies, the authors argue that leptin’s effects seem to be dominant based on the studies using adiponectin and leptin replacement in LD mice. However, it must be kept in mind that these studies used an artificial disease model and a very limited range of time and concentration treatments. It seems more likely that the interplay between leptins, adiponectins, and other as yet unidentified WAT products in the development of autoimmune disease are probably more complex. Nonetheless, the results suggest that these mediators may be viable candidates for therapeutic approaches to certain autoimmune conditions.
Clearly, more detailed studies will be necessary to determine the cellular targets of adipokines and the underlying biochemical and cellular mechanisms by which they influence development of autoimmune disease. The LD mouse should be a very valuable model for pursuing these goals. For those not directly working in this field as scientists but interested if for no other reason than our personal battle with WAT, the ever-expanding role of WAT in metabolism, homeostasis and disease gives us something new to contemplate during those hours spent on the treadmill.
References
Flegal KM, Carroll MD, Ogden CL, Johnson CL 2002 Prevalence and trends in obesity among US adults, 1999–2000. JAMA 288:1723–1727
Rajala MW, Scherer PE 2003 Minireview: the adipocyte—at the crossroads of energy homeostasis, inflammation, and atherosclerosis. Endocrinology 144:3765–3773
Fantuzzi G, Faggioni R 2000 Leptin in the regulation of immunity, inflammation, and hematopoiesis. J Leukoc Biol 68:437–446
Donath MY, Storling J, Maedler K, Mandrup-Poulsen T 2003 Inflammatory mediators and islet ?-cell failure: a link between type 1 and type 2 diabetes. J Mol Med 84:455–470
Weiner HL, Selkoe DJ 2002 Inflammation and therapeutic vaccination in CNS diseases. Nature 420:879–884
McGillis JP, Fernandez S, Knopf MA 2001 Regulation of immune and inflammatory reactions in local microenvironments by sensory neuropeptides. In: Ader B, Cohen C, Felten D, eds. Psychoneuroimmunology. 3rd ed. New York: Academic Press; 217–229
Sanders VM, Kohm AP 2002 Sympathetic nervous system interaction with the immune system. Int Rev Neurobiol 52:17–41
Sennello JA, Fayad R, Morris AM, Eckel RH, Asilmaz E, Montez J, Friedman JM, Dinarello CA, Fantuzzi G 2005 Regulation of T cell-mediated hepatic inflammation by adiponectin and leptin. Endocrinology 146:2157–2164
Zhang Y, Proenca R, Maffei M, Barone M 1994 Positional cloning of the mouse obese gene and its human homologue. Nature 372:425–432
Matarese G, Di Giacomo A, Sanna V, Lord GM, Howard JK, Di Tuoro A, Bloom SR, Lechler RI, Zappacosta S, Fontana S 2001 Requirement for leptin in the induction and progression of autoimmune encephalomyelitis. J Immunol 166:5909–5916
Busso N, So A, Chobaz-Péclat V, Morard C, Martinez-Soria E, Talabot-Ayer D, Gabay C 2002 Leptin signaling deficiency impairs humoral and cellular immune responses and attenuates experimental arthritis. J Immunol 168:875–882
Siegmund B, Lear-Kaul KC, Faggioni R, Fantuzzi G 2002 Leptin deficiency, not obesity, protects mice from Con A-induced hepatitis. Eur J Immunol 32:552–560
Faggioni R, Jones-Carson J, Reed DA, Dinarello CA, Feingold KR, Grunfeld C, Fantuzzi G 2000 Leptin-deficient (ob/ob) mice are protected from T cell-mediated hepatotoxicity: role of tumor necrosis factor and IL-18. Proc Natl Acad Sci USA 97:2367–2372
Shimomura I, Hammer RE, Richardson JA, Ikemoto S, Bashmakov Y, Goldstein JL, Brown MS 1998 Insulin resistance and diabetes mellitus in transgenic mice expressing nuclear SREBP-1c in adipose tissue: model for congenital generalized lipodystrophy. Genes Dev 12:3182–3194
Montez JM, Soukas A, Asilmaz E, Fayzikhodjaeva G, Fantuzzi G, Friedman JM 2005 Acute leptin deficiency, leptin resistance, and the physiologic response to leptin withdrawal. Proc Natl Acad Sci USA 102:2537–2542
Lehmann V, Freudenberg MA, Galanos C 1987 Lethal toxicity of lipopolysaccharide and tumor necrosis factor in normal and D-galactosamine-treated mice. J Exp Med 165:657–663(Joseph P. McGillis, Ph.D)