Exercising the Obese Brain: Resetting the Defended Body Weight
http://www.100md.com
内分泌学杂志 2005年第4期
Neurology Service (B.E.L.), Veterans Affairs Medical Center, East Orange, New Jersey 07018; and Department of Neurology and Neurosciences (B.E.L., C.M.P.), New Jersey Medical School, Newark, New Jersey 07103
Address all correspondence and requests for reprints to: Barry E. Levin, M.D., Neurology Service (127C), Veterans Affairs Medical Center, 385 Tremont Avenue, East Orange, New Jersey 07018-1095. E-mail: levin@umdnj.edu.
In this issue of Endocrinology, Bi et al. (1) demonstrate that voluntary wheel running selectively reduces carcass adiposity in genetically obese Otsuka-Long-Evans-Tokushima Fatty (OLETF) rats, which lack cholecystokinin-A receptors. Two features of this reduced adiposity are of particular note. First, despite reductions in plasma leptin levels, which should stimulate feeding (2), exercising rats failed to increase their energy intake to compensate for lost adipose mass. Second, lost adiposity was only partially restored following 6 wk of exercise cessation. Although similar findings have been reported previously in this (3) and other rodent strains (4, 5, 6), these particular studies are especially noteworthy because the failure to regain lost adiposity was associated with a long-term resetting of hypothalamic neuropeptide systems involved in energy homeostasis.
Although anabolic neuropeptide Y (NPY) and catabolic proopiomelanocortin neurons in the hypothalamic arcuate nucleus are known to regulate energy homeostasis (2) (Fig. 1), Bi et al. (1) showed that corticotropin-releasing factor (CRF) and NPY in the dorsomedial hypothalamic nucleus (DMN) may be of particular importance in exercise-induced lowering of body weight. This focuses renewed attention on the DMN, which participates in the regulation of food intake (7), counterregulatory responses to hypoglycemia (8), and brown adipose tissue thermogenesis (9). Although the precise role of DMN NPY neurons in energy homeostasis is unknown, the fact that these neurons also express cholecystokinin-A receptors (10) may be an important determinant of the hyperphagia and obesity, which is corrected by exercise in the OLETEF rat. The exercise-induced elevation of DMN CRF expression may be an even more important and novel factor contributing to adipose loss.
FIG. 1. Hypothetical model of potential exercise-induced peripheral signals that alter central pathways involved in energy homeostasis (see text for explanation). Catabolic factors (C) decrease food intake (downward arrow) and/or increase thermogenesis (upward arrow). Anabolic factors (A) increase intake and/or decrease thermogenesis. Both IL-6 and -MSH released from arcuate nucleus proopiomelanocortin neurons increase (+) BDNF production. Dotted arrows represent afferent signals from the periphery, whereas solid arrows represent efferent outputs from brain sites to other brain areas or peripheral organs involved in energy homeostasis.
To date, there are only a few studies that have focused specifically on the interaction between exercise and those hypothalamic pathways that regulate energy homeostasis (5, 11, 12, 13). On the other hand, there are many studies that demonstrate an effect of exercise on other brain functions that also use neurotransmitters and trophic factors involved in energy homeostasis. These include CRF (14), norepinephrine (NE), serotonin (5HT), GABA (15), and brain-derived neurotrophic factor (BDNF) (16). Acting in the hypothalamus, NE (17) and GABA (18) have anabolic, whereas CRF (11), 5HT (19), and BDNF (20) have catabolic effects. Because BDNF has catabolic properties and enhances neuronal plasticity (16), we speculate that increased BDNF production may be a major reason why exercising rats fail to increase food intake in compensation for lost adiposity (1, 5, 6) and have persistent weight loss after exercise cessation (1, 6).
Although some exercising humans also fail to compensate for lost adiposity by increasing their food intake (21, 22), there is little evidence that humans maintain weight loss after exercise is terminated. In fact, it is unclear whether exercise even promotes weight loss in obese humans and how much exercise might be required to produce such an effect (23, 24, 25). However, high levels of exercise are reported by many obese individuals who successfully maintain long-term weight loss (26). Their success may be partly due to the fact that exercise prevents the reduction in metabolic rate, which usually accompanies chronic weight loss (27, 28). Even so, this highly motivated group represents only a small percentage of the overall population of postobese individuals who are able to successfully maintain long-term weight loss.
What then can we learn from exercise studies in rodents that can be generalized to humans? Perhaps most important would be the identity of those factors that "tell" the brain that the body is exercising. In fact, exercise generates a number of metabolic, hormonal, and neural signals that reach the brain (Fig. 1). Exercise mobilizes free fatty acids by activating the sympathetic nervous system (29). Fatty acids could produce satiety signals that are relayed by autonomic afferents to brain stem NE and 5HT neurons following metabolism in the liver (30) or by directly acting on lipid sensing neurons in the brain (31). Lactate derived from exercising muscles enters the brain and could provide an anorectic signal by acting on glucosensing neurons that use lactate as an alternate signaling molecule to regulate their activity (32, 33). Of all the candidates, IL-6 is particularly enticing because its production by exercising muscle (34) can, along with melanocortin signaling, increase BDNF expression (35, 36). Finally, corticosteroids produced during exercise can feed back to alter CRF expression in the paraventricular nucleus (15) and possibly the DMN.
Thus, there are many potential exercise-induced signals from the periphery that might alter the function of central regulatory pathways involved in energy intake, expenditure, and storage. Even if the effects of exercise in rodents do not completely mimic those seen in humans, the ability to assess simultaneously peripheral and central components of exercise-induced changes in energy homeostasis may lead to the identification of new pharmacological targets for the treatment of obesity.
References
Bi S, Scott KA, Hyun J, Ladenheim EE, Moran TH 2005 Running wheel activity prevents hyperphagia and obesity in Otsuka Long-Evans Tokushima Fatty rats: role of hypothalamic signaling. Endocrinology 146:1676–1685
Schwartz MW, Woods SC, Porte Jr D, Seeley RJ, Baskin DG 2000 Central nervous system control of food intake. Nature 404:661–671
Shima K, Shi K, Mizuno A, Sano T, Ishida K, Noma Y 1996 Exercise training has a long-lasting effect on prevention of non-insulin-dependent diabetes mellitus in Otsuka-Long-Evans-Tokushima Fatty rats. Metabolism 45:475–480
Mayer J, Marshall NB, Vitale JJ, Christensen JH, Mashayekhi MB, Stare FJ 1954 Exercise, food intake and body weight in normal rats and genetically obese adult mice. Am J Physiol 177:544–548[Free Full Text]
Levin BE, Dunn-Meynell AA 2004 Chronic exercise lowers the defended body weight gain and adiposity in diet-induced obese rats. Am J Physiol 286:R771–R778
Patterson C, Levin BE 2004 Post-weaning exercise prevents obesity in obesity-prone rats even after exercise termination. Obes Res 12(Suppl):A22
Bernardis LL, Bellinger LL 1976 Production of weanling rat ventromedial and dorsomedial hypothalamic syndromes by electrolytic lesions with platinum-iridium electrodes. Neuroendocrinology 22:97–106
Evans SB, Wilkinson CW, Gronbeck P, Bennett JL, Zavosh A, Taborsky Jr GJ, Figlewicz DP 2004 Inactivation of the DMH selectively inhibits the ACTH and corticosterone responses to hypoglycemia. Am J Physiol Regul Integr Comp Physiol 286:R123–R128
Zaretskaia MV, Zaretsky DV, Shekhar A, DiMicco JA 2002 Chemical stimulation of the dorsomedial hypothalamus evokes non-shivering thermogenesis in anesthetized rats. Brain Res 928:113–125
Bi S, Scott KA, Kopin AS, Moran TH 2004 Differential roles for cholecystokinin receptors in energy balance in rats and mice. Endocrinology 145:3873–3880
Rivest S, Richard D 1990 Involvement of corticotropin-releasing factor in the anorexia induced by exercise. Brain Res Bull 25:169–172
Bovetto S, Richard D 1995 Lesion of central nucleus of amygdala promotes fat gain without preventing effect of exercise on energy balance. Am J Physiol 269:2–6
Levin BE, Dunn-Meynell AA, McMinn JE, Cunningham-Bussel A, Chua Jr SC 2003 A new obesity-prone, glucose intolerant rat strain (F.DIO). Am J Physiol 285:R1184–R1191
Timofeeva E, Huang Q, Richard D 2003 Effects of treadmill running on brain activation and the corticotropin-releasing hormone system. Neuroendocrinology 77:388–405
Dishman RK 1997 Brain monoamines, exercise, and behavioral stress: animal models. Med Sci Sports Exerc 29:63–74
Neeper SA, Gomez-Pinilla F, Choi J, Cotman CW 1996 Physical activity increases mRNA for brain-derived neurotrophic factor and nerve growth factor in rat brain. Brain Res 726:49–56
Leibowitz SF, Roissin P, Rosenn M 1984 Chronic norepinephrine injection into the hypothalamic paraventricular nucleus produces hyperphagia and increased body weight in the rat. Pharmacol Biochem Behav 21:801–808
Kelly J, Alheid GF, Newberg A, Grossman SP 1977 GABA stimulation and blockade in the hypothalamus and midbrain: effects on feeding and locomotor activity. Pharmacol Biochem Behav 7:537–541
Waldbillig RJ, Bartness TJ, Stanley BG 1981 Increased food intake, body weight, and adiposity in rats after regional neurochemical depletion of serotonin. J Comp Physiol Psychol 95:391–405
Lyons WE, Mamounas LA, Ricaurte GA, Coppola V, Reid SW, Bora SH, Wihler C, Koliatsos VE, Tessarollo L 1999 Brain-derived neurotrophic factor-deficient mice develop aggressiveness and hyperphagia in conjunction with brain serotonergic abnormalities. Proc Natl Acad Sci USA 96:15239–15244
Woo R, Garrow JS, Pi-Sunyer FX 1982 Voluntary food intake during prolonged exercise in obese women. Am J Clin Nutr 36:478–484
Blundell JE, Stubbs RJ, Hughes DA, Whybrow S, King NA 2003 Cross talk between physical activity and appetite control: does physical activity stimulate appetite? Proc Nutr Soc 62:651–661
Donnelly JE, Hill JO, Jacobsen DJ, Potteiger J, Sullivan DK, Johnson SL, Heelan K, Hise M, Fennessey PV, Sonko B, Sharp T, Jakicic JM, Blair SN, Tran ZV, Mayo M, Gibson C, Washburn RA 2003 Effects of a 16-month randomized controlled exercise trial on body weight and composition in young, overweight men and women: the Midwest Exercise Trial. Arch Intern Med 163:1343–1350
Doucet E, Imbeault P, Almeras N, Tremblay A 1999 Physical activity and low-fat diet: is it enough to maintain weight stability in the reduced-obese individual following weight loss by drug therapy and energy restriction? Obes Res 7:323–333
Frey-Hewitt B, Vranizan KM, Dreon DM, Wood PD 1990 The effect of weight loss by dieting or exercise on resting metabolic rate in overweight men. Int J Obes 14:324–334
Klem ML, Wing RR, McGuire MT, Hill JO 1997 A descriptive study of individuals successful at long-term maintenance of substantial weight loss. Am J Clin Nutr 66:239–246
Leibel RL, Hirsch J 1984 Diminished energy requirements in reduced-obese patients. Metabolism 33:164–170
Wyatt HR, Grunwald GK, Seagle HM, Klem ML, McGuire MT, Wing RR, Hill JO 1999 Resting energy expenditure in reduced-obese subjects in the National Weight Control Registry. Am J Clin Nutr 69:1189–1193
Jenkins RR, Lamb DR 1982 Effects of physical training on hypothalamic obesity in rats. Eur J Appl Physiol Occup Physiol 48:355–359
Friedman MI, Tordoff MG 1986 Fatty acid oxidation and glucose utilization interact to control food intake in rats. Am J Physiol 251:R840–R845
Obici S, Feng Z, Morgan K, Stein D, Karkanias G, Rossetti L 2002 Central administration of oleic acid inhibits glucose production and food intake. Diabetes 51:271–275
Song Z, Routh VH 2005 Differential effects of glucose and lactate on glucosensing neurons in the ventromedial hypothalamic nucleus. Diabetes 54:15–22
Nagase H, Bray GA, York DA 1996 Effects of pyruvate and lactate on food intake in rat strains sensitive and resistant to dietary obesity. Physiol Behav 59:555–560
Pedersen BK, Steensberg A, Fischer C, Keller C, Keller P, Plomgaard P, Febbraio M, Saltin B 2003 Searching for the exercise factor: is IL-6 a candidate? J Muscle Res Cell Motil 24:113–119
Murphy PG, Borthwick LA, Altares M, Gauldie J, Kaplan D, Richardson PM 2000 Reciprocal actions of interleukin-6 and brain-derived neurotrophic factor on rat and mouse primary sensory neurons. Eur J Neurosci 12:1891–1899
Xu B, Goulding EH, Zang K, Cepoi D, Cone RD, Jones KR, Tecott LH, Reichardt LF 2003 Brain-derived neurotrophic factor regulates energy balance downstream of melanocortin-4 receptor. Nat Neurosci 6:736–742(Barry E. Levin and Christ)
Address all correspondence and requests for reprints to: Barry E. Levin, M.D., Neurology Service (127C), Veterans Affairs Medical Center, 385 Tremont Avenue, East Orange, New Jersey 07018-1095. E-mail: levin@umdnj.edu.
In this issue of Endocrinology, Bi et al. (1) demonstrate that voluntary wheel running selectively reduces carcass adiposity in genetically obese Otsuka-Long-Evans-Tokushima Fatty (OLETF) rats, which lack cholecystokinin-A receptors. Two features of this reduced adiposity are of particular note. First, despite reductions in plasma leptin levels, which should stimulate feeding (2), exercising rats failed to increase their energy intake to compensate for lost adipose mass. Second, lost adiposity was only partially restored following 6 wk of exercise cessation. Although similar findings have been reported previously in this (3) and other rodent strains (4, 5, 6), these particular studies are especially noteworthy because the failure to regain lost adiposity was associated with a long-term resetting of hypothalamic neuropeptide systems involved in energy homeostasis.
Although anabolic neuropeptide Y (NPY) and catabolic proopiomelanocortin neurons in the hypothalamic arcuate nucleus are known to regulate energy homeostasis (2) (Fig. 1), Bi et al. (1) showed that corticotropin-releasing factor (CRF) and NPY in the dorsomedial hypothalamic nucleus (DMN) may be of particular importance in exercise-induced lowering of body weight. This focuses renewed attention on the DMN, which participates in the regulation of food intake (7), counterregulatory responses to hypoglycemia (8), and brown adipose tissue thermogenesis (9). Although the precise role of DMN NPY neurons in energy homeostasis is unknown, the fact that these neurons also express cholecystokinin-A receptors (10) may be an important determinant of the hyperphagia and obesity, which is corrected by exercise in the OLETEF rat. The exercise-induced elevation of DMN CRF expression may be an even more important and novel factor contributing to adipose loss.
FIG. 1. Hypothetical model of potential exercise-induced peripheral signals that alter central pathways involved in energy homeostasis (see text for explanation). Catabolic factors (C) decrease food intake (downward arrow) and/or increase thermogenesis (upward arrow). Anabolic factors (A) increase intake and/or decrease thermogenesis. Both IL-6 and -MSH released from arcuate nucleus proopiomelanocortin neurons increase (+) BDNF production. Dotted arrows represent afferent signals from the periphery, whereas solid arrows represent efferent outputs from brain sites to other brain areas or peripheral organs involved in energy homeostasis.
To date, there are only a few studies that have focused specifically on the interaction between exercise and those hypothalamic pathways that regulate energy homeostasis (5, 11, 12, 13). On the other hand, there are many studies that demonstrate an effect of exercise on other brain functions that also use neurotransmitters and trophic factors involved in energy homeostasis. These include CRF (14), norepinephrine (NE), serotonin (5HT), GABA (15), and brain-derived neurotrophic factor (BDNF) (16). Acting in the hypothalamus, NE (17) and GABA (18) have anabolic, whereas CRF (11), 5HT (19), and BDNF (20) have catabolic effects. Because BDNF has catabolic properties and enhances neuronal plasticity (16), we speculate that increased BDNF production may be a major reason why exercising rats fail to increase food intake in compensation for lost adiposity (1, 5, 6) and have persistent weight loss after exercise cessation (1, 6).
Although some exercising humans also fail to compensate for lost adiposity by increasing their food intake (21, 22), there is little evidence that humans maintain weight loss after exercise is terminated. In fact, it is unclear whether exercise even promotes weight loss in obese humans and how much exercise might be required to produce such an effect (23, 24, 25). However, high levels of exercise are reported by many obese individuals who successfully maintain long-term weight loss (26). Their success may be partly due to the fact that exercise prevents the reduction in metabolic rate, which usually accompanies chronic weight loss (27, 28). Even so, this highly motivated group represents only a small percentage of the overall population of postobese individuals who are able to successfully maintain long-term weight loss.
What then can we learn from exercise studies in rodents that can be generalized to humans? Perhaps most important would be the identity of those factors that "tell" the brain that the body is exercising. In fact, exercise generates a number of metabolic, hormonal, and neural signals that reach the brain (Fig. 1). Exercise mobilizes free fatty acids by activating the sympathetic nervous system (29). Fatty acids could produce satiety signals that are relayed by autonomic afferents to brain stem NE and 5HT neurons following metabolism in the liver (30) or by directly acting on lipid sensing neurons in the brain (31). Lactate derived from exercising muscles enters the brain and could provide an anorectic signal by acting on glucosensing neurons that use lactate as an alternate signaling molecule to regulate their activity (32, 33). Of all the candidates, IL-6 is particularly enticing because its production by exercising muscle (34) can, along with melanocortin signaling, increase BDNF expression (35, 36). Finally, corticosteroids produced during exercise can feed back to alter CRF expression in the paraventricular nucleus (15) and possibly the DMN.
Thus, there are many potential exercise-induced signals from the periphery that might alter the function of central regulatory pathways involved in energy intake, expenditure, and storage. Even if the effects of exercise in rodents do not completely mimic those seen in humans, the ability to assess simultaneously peripheral and central components of exercise-induced changes in energy homeostasis may lead to the identification of new pharmacological targets for the treatment of obesity.
References
Bi S, Scott KA, Hyun J, Ladenheim EE, Moran TH 2005 Running wheel activity prevents hyperphagia and obesity in Otsuka Long-Evans Tokushima Fatty rats: role of hypothalamic signaling. Endocrinology 146:1676–1685
Schwartz MW, Woods SC, Porte Jr D, Seeley RJ, Baskin DG 2000 Central nervous system control of food intake. Nature 404:661–671
Shima K, Shi K, Mizuno A, Sano T, Ishida K, Noma Y 1996 Exercise training has a long-lasting effect on prevention of non-insulin-dependent diabetes mellitus in Otsuka-Long-Evans-Tokushima Fatty rats. Metabolism 45:475–480
Mayer J, Marshall NB, Vitale JJ, Christensen JH, Mashayekhi MB, Stare FJ 1954 Exercise, food intake and body weight in normal rats and genetically obese adult mice. Am J Physiol 177:544–548[Free Full Text]
Levin BE, Dunn-Meynell AA 2004 Chronic exercise lowers the defended body weight gain and adiposity in diet-induced obese rats. Am J Physiol 286:R771–R778
Patterson C, Levin BE 2004 Post-weaning exercise prevents obesity in obesity-prone rats even after exercise termination. Obes Res 12(Suppl):A22
Bernardis LL, Bellinger LL 1976 Production of weanling rat ventromedial and dorsomedial hypothalamic syndromes by electrolytic lesions with platinum-iridium electrodes. Neuroendocrinology 22:97–106
Evans SB, Wilkinson CW, Gronbeck P, Bennett JL, Zavosh A, Taborsky Jr GJ, Figlewicz DP 2004 Inactivation of the DMH selectively inhibits the ACTH and corticosterone responses to hypoglycemia. Am J Physiol Regul Integr Comp Physiol 286:R123–R128
Zaretskaia MV, Zaretsky DV, Shekhar A, DiMicco JA 2002 Chemical stimulation of the dorsomedial hypothalamus evokes non-shivering thermogenesis in anesthetized rats. Brain Res 928:113–125
Bi S, Scott KA, Kopin AS, Moran TH 2004 Differential roles for cholecystokinin receptors in energy balance in rats and mice. Endocrinology 145:3873–3880
Rivest S, Richard D 1990 Involvement of corticotropin-releasing factor in the anorexia induced by exercise. Brain Res Bull 25:169–172
Bovetto S, Richard D 1995 Lesion of central nucleus of amygdala promotes fat gain without preventing effect of exercise on energy balance. Am J Physiol 269:2–6
Levin BE, Dunn-Meynell AA, McMinn JE, Cunningham-Bussel A, Chua Jr SC 2003 A new obesity-prone, glucose intolerant rat strain (F.DIO). Am J Physiol 285:R1184–R1191
Timofeeva E, Huang Q, Richard D 2003 Effects of treadmill running on brain activation and the corticotropin-releasing hormone system. Neuroendocrinology 77:388–405
Dishman RK 1997 Brain monoamines, exercise, and behavioral stress: animal models. Med Sci Sports Exerc 29:63–74
Neeper SA, Gomez-Pinilla F, Choi J, Cotman CW 1996 Physical activity increases mRNA for brain-derived neurotrophic factor and nerve growth factor in rat brain. Brain Res 726:49–56
Leibowitz SF, Roissin P, Rosenn M 1984 Chronic norepinephrine injection into the hypothalamic paraventricular nucleus produces hyperphagia and increased body weight in the rat. Pharmacol Biochem Behav 21:801–808
Kelly J, Alheid GF, Newberg A, Grossman SP 1977 GABA stimulation and blockade in the hypothalamus and midbrain: effects on feeding and locomotor activity. Pharmacol Biochem Behav 7:537–541
Waldbillig RJ, Bartness TJ, Stanley BG 1981 Increased food intake, body weight, and adiposity in rats after regional neurochemical depletion of serotonin. J Comp Physiol Psychol 95:391–405
Lyons WE, Mamounas LA, Ricaurte GA, Coppola V, Reid SW, Bora SH, Wihler C, Koliatsos VE, Tessarollo L 1999 Brain-derived neurotrophic factor-deficient mice develop aggressiveness and hyperphagia in conjunction with brain serotonergic abnormalities. Proc Natl Acad Sci USA 96:15239–15244
Woo R, Garrow JS, Pi-Sunyer FX 1982 Voluntary food intake during prolonged exercise in obese women. Am J Clin Nutr 36:478–484
Blundell JE, Stubbs RJ, Hughes DA, Whybrow S, King NA 2003 Cross talk between physical activity and appetite control: does physical activity stimulate appetite? Proc Nutr Soc 62:651–661
Donnelly JE, Hill JO, Jacobsen DJ, Potteiger J, Sullivan DK, Johnson SL, Heelan K, Hise M, Fennessey PV, Sonko B, Sharp T, Jakicic JM, Blair SN, Tran ZV, Mayo M, Gibson C, Washburn RA 2003 Effects of a 16-month randomized controlled exercise trial on body weight and composition in young, overweight men and women: the Midwest Exercise Trial. Arch Intern Med 163:1343–1350
Doucet E, Imbeault P, Almeras N, Tremblay A 1999 Physical activity and low-fat diet: is it enough to maintain weight stability in the reduced-obese individual following weight loss by drug therapy and energy restriction? Obes Res 7:323–333
Frey-Hewitt B, Vranizan KM, Dreon DM, Wood PD 1990 The effect of weight loss by dieting or exercise on resting metabolic rate in overweight men. Int J Obes 14:324–334
Klem ML, Wing RR, McGuire MT, Hill JO 1997 A descriptive study of individuals successful at long-term maintenance of substantial weight loss. Am J Clin Nutr 66:239–246
Leibel RL, Hirsch J 1984 Diminished energy requirements in reduced-obese patients. Metabolism 33:164–170
Wyatt HR, Grunwald GK, Seagle HM, Klem ML, McGuire MT, Wing RR, Hill JO 1999 Resting energy expenditure in reduced-obese subjects in the National Weight Control Registry. Am J Clin Nutr 69:1189–1193
Jenkins RR, Lamb DR 1982 Effects of physical training on hypothalamic obesity in rats. Eur J Appl Physiol Occup Physiol 48:355–359
Friedman MI, Tordoff MG 1986 Fatty acid oxidation and glucose utilization interact to control food intake in rats. Am J Physiol 251:R840–R845
Obici S, Feng Z, Morgan K, Stein D, Karkanias G, Rossetti L 2002 Central administration of oleic acid inhibits glucose production and food intake. Diabetes 51:271–275
Song Z, Routh VH 2005 Differential effects of glucose and lactate on glucosensing neurons in the ventromedial hypothalamic nucleus. Diabetes 54:15–22
Nagase H, Bray GA, York DA 1996 Effects of pyruvate and lactate on food intake in rat strains sensitive and resistant to dietary obesity. Physiol Behav 59:555–560
Pedersen BK, Steensberg A, Fischer C, Keller C, Keller P, Plomgaard P, Febbraio M, Saltin B 2003 Searching for the exercise factor: is IL-6 a candidate? J Muscle Res Cell Motil 24:113–119
Murphy PG, Borthwick LA, Altares M, Gauldie J, Kaplan D, Richardson PM 2000 Reciprocal actions of interleukin-6 and brain-derived neurotrophic factor on rat and mouse primary sensory neurons. Eur J Neurosci 12:1891–1899
Xu B, Goulding EH, Zang K, Cepoi D, Cone RD, Jones KR, Tecott LH, Reichardt LF 2003 Brain-derived neurotrophic factor regulates energy balance downstream of melanocortin-4 receptor. Nat Neurosci 6:736–742(Barry E. Levin and Christ)