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Polyunsaturated fatty acids in cancer and their influence on biochemical and metabolic events and body composition
Nutrition 31 (2015) 582–584
Contents lists available at ScienceDirect
Nutrition journal homepage: www.nutritionjrnl.com
Editorial
Polyunsaturated fatty acids in cancer and their influence on biochemical and metabolic events and body composition Cancer is associated with alterations in several systemic and local biochemical events that could have profound consequences in the carbohydrate, protein, and lipid metabolism of the subject. These metabolic alterations produce significant alterations in the body composition of subjects with cancer. Some of these changes include loss of appetite (anorexia), weight loss, decrease in muscle mass and strength, osteoporosis, and innumerable changes in the function of various organs and systems, in particular, the musculoskeletal and immune systems. Sarcopenia is one dominant feature seen in those with cancer. Anorexia, sarcopenia, osteoporosis, loss of body weight, changes in body composition and metabolic alterations, and immune dysfunction seen in those with cancer have been attributed to increased production of proinflammatory cytokines and their both local and systemic actions. But paradoxically, many of these pathologic events cannot be reversed completely by anticytokine antibodies against proinflammatory cytokines such as tumor necrosis factor-a and interleukin-6 (IL-6), suggesting there are other unidentified pathways that, could be responsible for these changes. Of all the changes in the body because of cancer, anorexia and musculoskeletal changes seem to have a significant effect on the patient. Anorexia may lead to decreased nutrient intake, and consequently the patient may become malnourished leading to immune dysfunction and significant musculoskeletal weakness that may affect the quality of life and eventually lead to profound morbidity and ultimately mortality. Anorexia, cachexia, and sarcopenia are the most common systemic manifestations seen in patients with cancer and other diseases such as congestive cardiac failure (CCF). Cachexia is characterized by weight loss with atrophy of fat and skeletal muscle [1]. Importantly, cachexia is more than just anorexia. Patients with cachexia may ingest less food, but they also have negative energy balance that seems to be resistant to nutritional supplementation [1–3]. Cachexia causes frailty in patients with cancer and CCF and often prevents them from undergoing further therapy. Cachexia may lessen with shrinkage of tumors, but currently there are no effective therapies for cancer cachexia. Elevated levels of proinflammatory cytokines have been reported in patients with cachexia because of cancer and CCF, but anticytokine therapies are ineffective [4,5]. One possibility is there is undue activation of brown fat in cachexia that leads to dissipation of chemical energy in the form of heat leads to negative energy balance. But the exact mechanism as to how http://dx.doi.org/10.1016/j.nut.2014.12.003 0899-9007/Ó 2015 Elsevier Inc. All rights reserved.
tumors induce thermogenesis in brown fat and how this leads to wasting of fat and skeletal muscle is not known. Several possibilities for the occurrence of cancer cachexia have been suggested some of which include: changes in the expression of myostatin and activin and their receptors; neuroendocrine changes that may encompass changes in circulating glucocorticoids; melanocortin signaling; leptin and elevated levels of free fatty acids because of lipolysis; and finally alterations in the expression of GLUT-4, inhibition of insulinstimulated phosphorylation of IRS-1 that is seen in these patients in the form of insulin resistance [1]. Despite these advances, there is no reliable treatment available for cancer cachexia. This can be ascribed to the heterogeneity in the clinical presentation of cachexia, variations in the host genotype, genetic variation in immunity and associated signaling pathways, single nucleotide polymorphisms in the IL-1, IL-6, IL-10, and TGF-b genes. Despite these lacunae in our understanding of the exact pathophysiology of cancer cachexia, some studies suggested u-3 polyunsaturated fatty acids (PUFAs) could be of some benefit in this and other related conditions. Pappalardo et al. [6] have reviewed and presented a summary of the current status of the role of u-3 PUFA eicosapentaneoic acid (EPA) on body composition and its role in the prevention and management of cancer associated anorexia, cachexia, and its modulatory influence on the action of chemotherapy [6]. Despite the fact, to a limited extent and in some, but not all, that patients with cancer, EPA could be of benefit reason why it is not helpful in all and the reasons for is not clear. Could be attributed to the fact that our knowledge of the pathogenesis of anorexia and cancer cachexia is limited; incomplete knowledge about the metabolism of EPA in normal and tumor cells and lack of sufficient data as to how EPA and its various metabolites interact with neurotransmitters that regulate appetite and satiety and expression of genes concerned with carbohydrate, lipid, and protein metabolism. In this context, it is interesting to note u-PUFAs (including both EPA and docosahexaenoic acid, [DHA]) and their products such as prostaglandins, resolvins, protectins, and maresins (resolvins are formed from EPA and DHA; protectins and maresins are formed from DHA) seem to possess modulatory influence on pituitary-hypothalamic axis that may be relevant to obesity, anorexia, and consequently cachexia. This modulatory effect of EPA/DHA may, in part, be by altering hypothalamic inflammation. It has been shown that hypothalamic inflammation occurs in obesity that could be mediated by
Editorial / Nutrition 31 (2015) 582–584
proinflammatory prostaglandins. EPA/DHA by virtue of their antiinflammatory action could suppress such hypothalamic inflammation and thus, mitigate obesity [7,8]. But, it is not clear whether the same set of events in the opposite direction will lead to anorexia and cachexia. Furthermore, several of these studies have been performed in experimental animals and it is not certain how much these results could be extrapolated to the human situation. This is so because supplementation with EPA/DHA is of no significant benefit in reversing obesity in humans though they are certainly beneficial in the management of hyperlipidemia. The lack of significant benefit of EPA/ DHA in mitigating cancer cachexia despite their antiinflammatory actions indicates further studies are warranted to understand why they are not useful. One reason could be the failure of EPA/DHA to reach the target tissues such as the hypothalamus in sufficient amounts to modulate the pituitaryhypothalamic axis, insufficient formation of the most effective metabolites (they could be prostaglandins, lipoxins, resolvins, protectins, and maresins), and their relatively short half-life. This argument derives support from the observation that hypothalamic infusion of oleic acid (monounsaturated fatty acid) is able to reverse obesity and type 2 diabetes mellitus in experimental animals by decreasing food intake and increasing insulin sensitivity [9]. But, it is not known whether continuous infusion of oleic acid and other PUFAs for long periods can produce anorexia and consequently cachexia. One molecule that may have a role in anorexia and cancer cachexia which has not been well investigated is BDNF (brainderived neurotrophic factor) [10]. It is known that BDNF is secreted by several tissues in the body including brain and gut. In fact, the gut produces almost 80% of the total body BDNF [8]. Studies showed administration of BDNF subcutaneously, intramuscularly, and as infusion in to the hypothalamus produced decreased food intake, significant loss of weight, amelioration of hyperglycemia in diabetic animals and restoration of normoglycemia [8,11]. In a case-control study in 1142 Caucasian patients with eating disorders from five European countries (France, Germany, Italy, Spain, and UK) it was found that the Met66 variant is strongly associated to all eating disorder subtypes including anorexia nervosa and binge-eating/purging, and the 270 C BDNF variant has an effect on bulimia nervosa and late age at onset of weight loss [12] supporting a role for BDNF to aberrant eating behaviors. Furthermore, it was reported that activation of melanocortin (MC4 R) leads to an acute release of BDNF in the hypothalamus. This release was found to be a prerequisite for MC4 Rinduced effects on appetite, body temperature and cardiovascular function suggesting BDNF is an important downstream mediator of the MC4 R pathway [13]. In addition, it was noted that vagal nerve stimulation rapidly activated BDNF receptor TrkB in the brain [14], whereas vagal nerve stimulation reduces body weight and fat mass in experimental animals [15]. Acetylcholine, the principal vagal neurotransmitter and a master regulator of the secretion and actions of other neurotransmitters such as serotonin, dopamine and catecholamines, is a potent antiinflammatory molecule [16]. Thus, there is a close interaction among BDNF, vagus, inflammation, and anorexia. In this context, it is interesting to note that u-3 PUFAs enhance acetylcholine levels in the brain [17] and BDNF and u-3 PUFAs interact with each other to potentiate each other’s action [18]. These results imply that one mechanism by which u-PUFAs and antiinflammatory products of arachidonic acid (such as lipoxin A4) suppress inflammation is by
583
enhancing the action of BDNF and augmenting acetylcholine levels in the target tissues. A recent study revealed that tumor-derived parathyroid hormone-related protein (PTHrP) has an important role in wasting through driving the expression of genes involved in thermogenesis in adipose tissue and muscle wasting [19]. PTHrP is secreted by many tumors and can cause hypercalcemia seen in some patients with cancer. There appears to be a role for other tumor-derived molecules to bring about the muscle wasting produced by PTHrP, the identity of which is not yet known. It is possible some of these collaborating factors could be PUFAs-derived prostaglandins, BDNF and cytokines, though at present it is only conjectural. Based on the preceding discussion, it is evident that a better understanding of the role of various neurotransmitters such as serotonin, dopamine, melanocortins, catecholamines, and acetylcholine in the control of appetite and satiety is important in order to better understand their role in anorexia and cancer cachexia. Furthermore, a study of interaction(s) among various neurotransmitters, cytokines, insulin, GLUT receptors, leptin, PUFAs and BDNF is essential to improve our understanding of cancer cachexia. Because cachexia also occurs in diseases, such as CCF, tuberculosis, chronic malaria, sepsis, and other chronic diseases the knowledge gained from such studies may have therapeutic implications for these diseases as well. References [1] Fearon KC, Glass DJ, Guttridge DC. Cancer cachexia; mediators, signaling and metabolic pathways. Cell Metab 2012;16:153–66. [2] Ovesen L, Allingstrup L, Hannibal J, Mortensen EL, Hansen OP. Effect of dietary counseling on food intake, body weight, response rate, survival, and quality of life in cancer patients undergoing chemotherapy: A prospective, randomized study. J Clin Oncol 1993;11:2043–9. [3] Tisdale MJ. Mechanisms of cancer cachexia. Physiol Rev 2009;89:381–410. [4] Penna F, Minero VG, Costamagna D, Bonelli G, Baccino FM, Costelli P. Anticytokine strategies for the treatment of cancer-related anorexia and cachexia. Expert Opin Biol Ther 2010;10:1241–50. [5] Fearon K, Arends J, Baracos V. Understanding mechanisms and treatment options in cancer cachexia. Nature Rev Clin Oncol 2013;10:90–9. [6] Pappalardo G, Almeida A, Ravasco P. Eicosapentaenoic acid in cancer: Does it improve body composition and modulate metabolism? Nutrition 2015; 31:549–55. [7] Shewchuk BM. Prostaglandins and n-3 polyunsaturated fatty acids in the regulation of the hypothalamic–pituitary axis. Prostaglandins Leukot Essent Fatty Acids 2014;91:277–87. [8] Das UN. Obesity: Genes, brain, gut, and environment. Nutrition 2010;26: 459–73. [9] Obici S, Feng Z, Morgan K, Stein D, Karkanias G, Rossetti L. Central administration of oleic acid inhibits glucose production and food intake. Diabetes 2002;51:271–5. [10] Plata-Salam an CR. Central nervous system mechanisms contributing to the cachexia-anorexia syndrome. Nutrition 2000;16:1009–12. [11] Cao L, Lin EJ, Cahill MC, Wang C, Liu X, During MJ. Molecular therapy of obesity and diabetes by a physiological autoregulatory approach. Nat Med 2009;15:447–54. s M, Grataco s M, Ferna ndez-Aranda F, Bellodi L, Boni C, Anderluh M, [12] Ribase et al. Association of BDNF with anorexia, bulimia and age of onset of weight loss in six European populations. Hum Mol Genet 2004;13:1205–12. [13] Nicholson JR, Peter JC, Lecourt AC, Barde YA, Hofbauer KG. Melanocortin-4 receptor activation stimulates hypothalamic brain-derived neurotrophic factor release to regulate food intake, body temperature and cardiovascular function. J Neuroendocrinol 2007;19:974–82. [14] Furmaga H, Carreno FR, Frazer A. Vagal nerve stimulation rapidly activates brain-derived neurotrophic factor receptor TrkB in rat brain. PLoS One 2012;7:E34844. [15] Banni S, Carta G, Murru E, Cordeddu L, Giordano E, Marrosu F, et al. Vagus nerve stimulation reduces body weight and fat mass in rats. PLoS One 2012;7:E44813. [16] Pavlov VA, Tracey KJ. The cholinergic antiinflammatory pathway. Brain Behav Immun 2005;19:493–9. [17] Aïd S, Vancassel S, Linard A, Lavialle M, Guesnet P. Dietary docosahexaenoic acid [22: 6(n-3)] as a phospholipid or a triacylglycerol enhances the potassium chloride-evoked release of acetylcholine in rat hippocampus. J Nutr 2005;135:1008–13.
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Editorial / Nutrition 31 (2015) 582–584
[18] Vetrivel U, Ravichandran SB, Kuppan K, Mohanlal J, Das UN, Narayanasamy A. Agonistic effect of polyunsaturated fatty acids (PUFAs) and its metabolites on brain-derived neurotrophic factor (BDNF) through molecular docking simulation. Lipids Health Dis 2012;11: 109. [19] Kir S, White JP, Kleiner S, Kazak L, Cohen P, Baracos VE, et al. Tumor-derived PTH-related protein triggers adipose tissue browning and cancer cachexia. Nature 2014;513:100–4.
Undurti N. Das, M.D., F.A.M.S., F.R.S.C. UND Life Sciences, Federal Way, WA; Department of Medicine and BioScience Research Centre, GVP Hospital GVP College of Engineering Campus Visakhapatnam, India E-mail address: [email protected]
Contents lists available at ScienceDirect
Nutrition journal homepage: www.nutritionjrnl.com
Editorial
Polyunsaturated fatty acids in cancer and their influence on biochemical and metabolic events and body composition Cancer is associated with alterations in several systemic and local biochemical events that could have profound consequences in the carbohydrate, protein, and lipid metabolism of the subject. These metabolic alterations produce significant alterations in the body composition of subjects with cancer. Some of these changes include loss of appetite (anorexia), weight loss, decrease in muscle mass and strength, osteoporosis, and innumerable changes in the function of various organs and systems, in particular, the musculoskeletal and immune systems. Sarcopenia is one dominant feature seen in those with cancer. Anorexia, sarcopenia, osteoporosis, loss of body weight, changes in body composition and metabolic alterations, and immune dysfunction seen in those with cancer have been attributed to increased production of proinflammatory cytokines and their both local and systemic actions. But paradoxically, many of these pathologic events cannot be reversed completely by anticytokine antibodies against proinflammatory cytokines such as tumor necrosis factor-a and interleukin-6 (IL-6), suggesting there are other unidentified pathways that, could be responsible for these changes. Of all the changes in the body because of cancer, anorexia and musculoskeletal changes seem to have a significant effect on the patient. Anorexia may lead to decreased nutrient intake, and consequently the patient may become malnourished leading to immune dysfunction and significant musculoskeletal weakness that may affect the quality of life and eventually lead to profound morbidity and ultimately mortality. Anorexia, cachexia, and sarcopenia are the most common systemic manifestations seen in patients with cancer and other diseases such as congestive cardiac failure (CCF). Cachexia is characterized by weight loss with atrophy of fat and skeletal muscle [1]. Importantly, cachexia is more than just anorexia. Patients with cachexia may ingest less food, but they also have negative energy balance that seems to be resistant to nutritional supplementation [1–3]. Cachexia causes frailty in patients with cancer and CCF and often prevents them from undergoing further therapy. Cachexia may lessen with shrinkage of tumors, but currently there are no effective therapies for cancer cachexia. Elevated levels of proinflammatory cytokines have been reported in patients with cachexia because of cancer and CCF, but anticytokine therapies are ineffective [4,5]. One possibility is there is undue activation of brown fat in cachexia that leads to dissipation of chemical energy in the form of heat leads to negative energy balance. But the exact mechanism as to how http://dx.doi.org/10.1016/j.nut.2014.12.003 0899-9007/Ó 2015 Elsevier Inc. All rights reserved.
tumors induce thermogenesis in brown fat and how this leads to wasting of fat and skeletal muscle is not known. Several possibilities for the occurrence of cancer cachexia have been suggested some of which include: changes in the expression of myostatin and activin and their receptors; neuroendocrine changes that may encompass changes in circulating glucocorticoids; melanocortin signaling; leptin and elevated levels of free fatty acids because of lipolysis; and finally alterations in the expression of GLUT-4, inhibition of insulinstimulated phosphorylation of IRS-1 that is seen in these patients in the form of insulin resistance [1]. Despite these advances, there is no reliable treatment available for cancer cachexia. This can be ascribed to the heterogeneity in the clinical presentation of cachexia, variations in the host genotype, genetic variation in immunity and associated signaling pathways, single nucleotide polymorphisms in the IL-1, IL-6, IL-10, and TGF-b genes. Despite these lacunae in our understanding of the exact pathophysiology of cancer cachexia, some studies suggested u-3 polyunsaturated fatty acids (PUFAs) could be of some benefit in this and other related conditions. Pappalardo et al. [6] have reviewed and presented a summary of the current status of the role of u-3 PUFA eicosapentaneoic acid (EPA) on body composition and its role in the prevention and management of cancer associated anorexia, cachexia, and its modulatory influence on the action of chemotherapy [6]. Despite the fact, to a limited extent and in some, but not all, that patients with cancer, EPA could be of benefit reason why it is not helpful in all and the reasons for is not clear. Could be attributed to the fact that our knowledge of the pathogenesis of anorexia and cancer cachexia is limited; incomplete knowledge about the metabolism of EPA in normal and tumor cells and lack of sufficient data as to how EPA and its various metabolites interact with neurotransmitters that regulate appetite and satiety and expression of genes concerned with carbohydrate, lipid, and protein metabolism. In this context, it is interesting to note u-PUFAs (including both EPA and docosahexaenoic acid, [DHA]) and their products such as prostaglandins, resolvins, protectins, and maresins (resolvins are formed from EPA and DHA; protectins and maresins are formed from DHA) seem to possess modulatory influence on pituitary-hypothalamic axis that may be relevant to obesity, anorexia, and consequently cachexia. This modulatory effect of EPA/DHA may, in part, be by altering hypothalamic inflammation. It has been shown that hypothalamic inflammation occurs in obesity that could be mediated by
Editorial / Nutrition 31 (2015) 582–584
proinflammatory prostaglandins. EPA/DHA by virtue of their antiinflammatory action could suppress such hypothalamic inflammation and thus, mitigate obesity [7,8]. But, it is not clear whether the same set of events in the opposite direction will lead to anorexia and cachexia. Furthermore, several of these studies have been performed in experimental animals and it is not certain how much these results could be extrapolated to the human situation. This is so because supplementation with EPA/DHA is of no significant benefit in reversing obesity in humans though they are certainly beneficial in the management of hyperlipidemia. The lack of significant benefit of EPA/ DHA in mitigating cancer cachexia despite their antiinflammatory actions indicates further studies are warranted to understand why they are not useful. One reason could be the failure of EPA/DHA to reach the target tissues such as the hypothalamus in sufficient amounts to modulate the pituitaryhypothalamic axis, insufficient formation of the most effective metabolites (they could be prostaglandins, lipoxins, resolvins, protectins, and maresins), and their relatively short half-life. This argument derives support from the observation that hypothalamic infusion of oleic acid (monounsaturated fatty acid) is able to reverse obesity and type 2 diabetes mellitus in experimental animals by decreasing food intake and increasing insulin sensitivity [9]. But, it is not known whether continuous infusion of oleic acid and other PUFAs for long periods can produce anorexia and consequently cachexia. One molecule that may have a role in anorexia and cancer cachexia which has not been well investigated is BDNF (brainderived neurotrophic factor) [10]. It is known that BDNF is secreted by several tissues in the body including brain and gut. In fact, the gut produces almost 80% of the total body BDNF [8]. Studies showed administration of BDNF subcutaneously, intramuscularly, and as infusion in to the hypothalamus produced decreased food intake, significant loss of weight, amelioration of hyperglycemia in diabetic animals and restoration of normoglycemia [8,11]. In a case-control study in 1142 Caucasian patients with eating disorders from five European countries (France, Germany, Italy, Spain, and UK) it was found that the Met66 variant is strongly associated to all eating disorder subtypes including anorexia nervosa and binge-eating/purging, and the 270 C BDNF variant has an effect on bulimia nervosa and late age at onset of weight loss [12] supporting a role for BDNF to aberrant eating behaviors. Furthermore, it was reported that activation of melanocortin (MC4 R) leads to an acute release of BDNF in the hypothalamus. This release was found to be a prerequisite for MC4 Rinduced effects on appetite, body temperature and cardiovascular function suggesting BDNF is an important downstream mediator of the MC4 R pathway [13]. In addition, it was noted that vagal nerve stimulation rapidly activated BDNF receptor TrkB in the brain [14], whereas vagal nerve stimulation reduces body weight and fat mass in experimental animals [15]. Acetylcholine, the principal vagal neurotransmitter and a master regulator of the secretion and actions of other neurotransmitters such as serotonin, dopamine and catecholamines, is a potent antiinflammatory molecule [16]. Thus, there is a close interaction among BDNF, vagus, inflammation, and anorexia. In this context, it is interesting to note that u-3 PUFAs enhance acetylcholine levels in the brain [17] and BDNF and u-3 PUFAs interact with each other to potentiate each other’s action [18]. These results imply that one mechanism by which u-PUFAs and antiinflammatory products of arachidonic acid (such as lipoxin A4) suppress inflammation is by
583
enhancing the action of BDNF and augmenting acetylcholine levels in the target tissues. A recent study revealed that tumor-derived parathyroid hormone-related protein (PTHrP) has an important role in wasting through driving the expression of genes involved in thermogenesis in adipose tissue and muscle wasting [19]. PTHrP is secreted by many tumors and can cause hypercalcemia seen in some patients with cancer. There appears to be a role for other tumor-derived molecules to bring about the muscle wasting produced by PTHrP, the identity of which is not yet known. It is possible some of these collaborating factors could be PUFAs-derived prostaglandins, BDNF and cytokines, though at present it is only conjectural. Based on the preceding discussion, it is evident that a better understanding of the role of various neurotransmitters such as serotonin, dopamine, melanocortins, catecholamines, and acetylcholine in the control of appetite and satiety is important in order to better understand their role in anorexia and cancer cachexia. Furthermore, a study of interaction(s) among various neurotransmitters, cytokines, insulin, GLUT receptors, leptin, PUFAs and BDNF is essential to improve our understanding of cancer cachexia. Because cachexia also occurs in diseases, such as CCF, tuberculosis, chronic malaria, sepsis, and other chronic diseases the knowledge gained from such studies may have therapeutic implications for these diseases as well. References [1] Fearon KC, Glass DJ, Guttridge DC. Cancer cachexia; mediators, signaling and metabolic pathways. Cell Metab 2012;16:153–66. [2] Ovesen L, Allingstrup L, Hannibal J, Mortensen EL, Hansen OP. Effect of dietary counseling on food intake, body weight, response rate, survival, and quality of life in cancer patients undergoing chemotherapy: A prospective, randomized study. J Clin Oncol 1993;11:2043–9. [3] Tisdale MJ. Mechanisms of cancer cachexia. Physiol Rev 2009;89:381–410. [4] Penna F, Minero VG, Costamagna D, Bonelli G, Baccino FM, Costelli P. Anticytokine strategies for the treatment of cancer-related anorexia and cachexia. Expert Opin Biol Ther 2010;10:1241–50. [5] Fearon K, Arends J, Baracos V. Understanding mechanisms and treatment options in cancer cachexia. Nature Rev Clin Oncol 2013;10:90–9. [6] Pappalardo G, Almeida A, Ravasco P. Eicosapentaenoic acid in cancer: Does it improve body composition and modulate metabolism? Nutrition 2015; 31:549–55. [7] Shewchuk BM. Prostaglandins and n-3 polyunsaturated fatty acids in the regulation of the hypothalamic–pituitary axis. Prostaglandins Leukot Essent Fatty Acids 2014;91:277–87. [8] Das UN. Obesity: Genes, brain, gut, and environment. Nutrition 2010;26: 459–73. [9] Obici S, Feng Z, Morgan K, Stein D, Karkanias G, Rossetti L. Central administration of oleic acid inhibits glucose production and food intake. Diabetes 2002;51:271–5. [10] Plata-Salam an CR. Central nervous system mechanisms contributing to the cachexia-anorexia syndrome. Nutrition 2000;16:1009–12. [11] Cao L, Lin EJ, Cahill MC, Wang C, Liu X, During MJ. Molecular therapy of obesity and diabetes by a physiological autoregulatory approach. Nat Med 2009;15:447–54. s M, Grataco s M, Ferna ndez-Aranda F, Bellodi L, Boni C, Anderluh M, [12] Ribase et al. Association of BDNF with anorexia, bulimia and age of onset of weight loss in six European populations. Hum Mol Genet 2004;13:1205–12. [13] Nicholson JR, Peter JC, Lecourt AC, Barde YA, Hofbauer KG. Melanocortin-4 receptor activation stimulates hypothalamic brain-derived neurotrophic factor release to regulate food intake, body temperature and cardiovascular function. J Neuroendocrinol 2007;19:974–82. [14] Furmaga H, Carreno FR, Frazer A. Vagal nerve stimulation rapidly activates brain-derived neurotrophic factor receptor TrkB in rat brain. PLoS One 2012;7:E34844. [15] Banni S, Carta G, Murru E, Cordeddu L, Giordano E, Marrosu F, et al. Vagus nerve stimulation reduces body weight and fat mass in rats. PLoS One 2012;7:E44813. [16] Pavlov VA, Tracey KJ. The cholinergic antiinflammatory pathway. Brain Behav Immun 2005;19:493–9. [17] Aïd S, Vancassel S, Linard A, Lavialle M, Guesnet P. Dietary docosahexaenoic acid [22: 6(n-3)] as a phospholipid or a triacylglycerol enhances the potassium chloride-evoked release of acetylcholine in rat hippocampus. J Nutr 2005;135:1008–13.
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Editorial / Nutrition 31 (2015) 582–584
[18] Vetrivel U, Ravichandran SB, Kuppan K, Mohanlal J, Das UN, Narayanasamy A. Agonistic effect of polyunsaturated fatty acids (PUFAs) and its metabolites on brain-derived neurotrophic factor (BDNF) through molecular docking simulation. Lipids Health Dis 2012;11: 109. [19] Kir S, White JP, Kleiner S, Kazak L, Cohen P, Baracos VE, et al. Tumor-derived PTH-related protein triggers adipose tissue browning and cancer cachexia. Nature 2014;513:100–4.
Undurti N. Das, M.D., F.A.M.S., F.R.S.C. UND Life Sciences, Federal Way, WA; Department of Medicine and BioScience Research Centre, GVP Hospital GVP College of Engineering Campus Visakhapatnam, India E-mail address: [email protected]