Medical Hypotheses 85 (2015) 380–382
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Anorexia nervosa, seasonality, and polyunsaturated fatty acids Barbara Scolnick ⇑, David I. Mostofsky Boston University, Department of Psychology, 64 Cummington Street, Boston, MA, United States
a r t i c l e
i n f o
Article history: Received 9 April 2015 Accepted 6 May 2015
a b s t r a c t Anorexia nervosa is a serious neurobehavioral disorder marked by semistarvation, extreme fear of weight gain, frequently hyperactivity, and low body temperature. The etiology remains unknown. We present a speculation that a primary causative factor is that polyunsaturated fatty acids are skewed to prevent oxidative damage in phospholipid membranes. This causes a change in the trade off of oxidation protection vs homeoviscous adaptation to lower temperatures, which sets off a metabolic cascade that leads to the rogue state of anorexia nervosa. Ó 2015 Elsevier Ltd. All rights reserved.
Introduction Anorexia nervosa is a serious neurobehavioral disorder marked by semi-starvation, extreme fear of weight gain, frequently hyperactivity. Our hypothesis is that seasonal fluxes in polyunsaturated fatty acids might play a role in causing and sustaining the disorder. Studying circannual rhythms in humans is hampered because modern humans no longer show obvious seasonal behavioral adaptations; we essentially live in a world where temperature, light and food supply are relatively constant. By studying hibernating species, and extrapolating to humans these archaic pathways become more obvious [1]. We have pursued this line of inquiry, because the epidemiology of anorexia nervosa strongly suggests that the disorder is rare in the tropics and more common in higher and lower latitudes [2,3]. While this has traditionally been viewed as evidence of ‘‘cultural bias to thinness’’ this view is being challenged as evidence points to the biologically driven nature of anorexia nervosa [4]. Preliminary evidence suggests hospital stays are longer, and body weight index is lower in patients with anorexia nervosa in the winter months compared with the summer [5]. Some studies have found improvement in weight gain when patients with anorexia nervosa are treated with heat therapy [6,7] although others have not confirmed this [8].
PUFAs and homeoviscous adaptation Polyunsaturated fatty acids (PUFA) are essential fatty acids that contain more than one double bond, as opposed to monounsaturated (MUFA) which have one double bond, or saturated fatty acids ⇑ Corresponding author. Tel.: +1 617 803 6353. E-mail addresses: [email protected] (B. Scolnick), [email protected] (D.I. Mostofsky). http://dx.doi.org/10.1016/j.mehy.2015.05.007 0306-9877/Ó 2015 Elsevier Ltd. All rights reserved.
which have no double bonds. When the carbons in the chain are numbered from the noncarboxy end of the chain (backward nomenclature compared to classic chemical naming; hence omega), these acids fall into 2 families, omega-3 in which the first double bond is on the 3rd carbon, and omega-6 in which the first double bond is on the 6th carbon. PUFAs undergo successive elongation and desaturation, and there is an innate competition in metabolism between these two families [9]. These long chain PUFAs and some long chain MUFAs have uniquely important properties when combined with phosphate groups to form phospholipids. With the long hydrophilic tail, and the short hydrophobic head they form into bilayers which are the backbone of most cell membranes. Altering the ratio of saturated fatty acids to unsaturated PUFAs, and the ratio of omega:3 to omega:6 fatty acids changes the properties of membranes, and the functioning of embedded proteins. ‘‘Homeoviscous adaptation’’ is a term coined in 1974 to refer to changes in the fatty acid concentration of cell membranes of actively growing Escherichia coli bacteria in response to ambient temperature changes [10]. These fluxes in fatty acids-increasing saturated fatty acids in higher temperature, and increasing PUFAs in lower temperatures – produce membranes whose lipids have a constant fluidity at the temperature of growth. It has become recognized that the phenomena is evolutionarily highly conserved and present in fish, in ‘‘cold blooded’’ animals, and vertebrates [11]. Although, not yet proven, our hypothesis is that homeoviscous adaptation metabolic pathways are present in humans.
Homeoviscous adaptation in hibernation A recently published experiment on free living alpine marmots found that tissue samples from liver and heart display an active circannual flux of the PUFA content of phospholipids [12]. In
B. Scolnick, D.I. Mostofsky / Medical Hypotheses 85 (2015) 380–382
autumn, as ambient temperature start to drop, and daylight shortens, but before the animal enters hibernation, n 6 PUFAs rapidly replace MUFAs in the liver, and replace both MUFAs and n 3 PUFAs in the heart. In spring, concurrent with the rising ambient temperature, the process reverses. These changes are largely independent of current dietary intake, and reflect lipids from adipose tissue. In short, for this hibernating species, omega 6 PUFAs are ‘‘preferable’’ in the phospholipid layer in the cold months, and omega 3 PUFAs are ‘‘preferable’’ in the warmer months. There is a strong relationship between increased omega-6:omega:3 ratio in cardiac phospholipids and the activity of a key enzyme that controls cardiac contraction in the cold. Yet, with an increased omega-6; omega:3 phospholipid cell membrane ratio there is a well described adverse effect of increased susceptibility to oxidative degradation from reactive radicals. Thus, in short, there is a trade off—more omega-6 PUFAs in phospholipids improve cold adaptation; more omega-3 PUFAs in phospholipids decrease the risk of oxidation. Serum lipid studies in patients with anorexia nervosa Our hypothesis is that this tradeoff is skewed in patients with AN, thus adversely affecting their ability to alter cell membranes in colder ambient temperatures. This causes a cascade of metabolic effects, and patients essentially become ‘‘stuck’’ in a physiologic rogue state marked by low body temperature, hypometabolism, semistarvation, and paradoxically frequently hyperexercise. If the hypothesis is correct, we should see evidence that the phospholipids of patients with anorexia nervosa show an increased tendency for oxidative degradation, and hence a decreased ability to effectively cold adapt. Although subtle, there is such evidence. Several studies of serum lipid profile changes in patients with anorexia nervosa have shown a deep alterations in chemical/physical properties in the serum PUFAs [13–16] This is partially nutritional, as patients tend to avoid fatty foods, and prefer the greens and salads rich in omega-3, as opposed to nuts and oils richer in omega-6. In 1995, Holman et al. studied 8 patients with anorexia nervosa, compared to 19 controls, and measured serum fatty acid composition of phospholipids, nonesteried fatty acids, triglycerides and cholesterol esters [17]. The most striking differences were in the phospholipid category and showed lower n 6 and n 3 elongation and desaturation products and elevated short chain saturated, short chain monounsaturated, branched chain, and the odd-chain fatty acids. This differed from simple malnutrition which showed lowered content of all n 6 and n 3 fatty acids and an increase in 20:3(n 9) [18]. Furthermore, Holman measured the mean melting point of the phospholipid component and found the melting point value for the AN group was significantly elevated over the controls. He interpreted these findings as showing PUFA deficiencies (may be partially nutritional), evidence of elongation enzyme ‘‘difficulties’’ and abnormal phospholipid fluidity marked by elevated melting points. A recent (2015) study by Shih et al. compared free (nonesterified) and total (esterified) forms of fatty acids in the serum of 30 ill patients with anorexia nervosa, 30 recovered patients, and 36 controls [19]. Generally, the patients with anorexia nervosa showed elevated n 3 PUFAs reflected in n 3:n 6 ratios, compared to healthy controls. The recovered patients fell in between, more closely resembling the patients. These authors also compared 10 ill anorexia nervosa to 10 recovered patients to 38 controls, with a targeted metabolomics assay. They focused on the substrate and product levels of one specific enzyme; soluble epoxide hydrolase (sEH). This analysis was done because an earlier gene sequencing discovery study had found suggestive evidence that epoxide hydrolase 2 gene
381
(EPHX2) which codes for this specific enzyme harbors rare variants that were associated with anorexia nervosa [20]. Ratios of product:substrate were elevated in anorexia nervosa compared to controls, implying increase sEH activity. The recovered patients fell in between, more toward the controls, implying recovery leads to more normal sEH activity. Soluble EH sits at an important cross roads in lipid metabolism because it metabolizes epoxy-fatty acids to the corresponding 1,2dihyoxy-fatty acids (diols). The epoxy-fatty acids, in turn were derived from 20 carbon PUFAs, notable arachidonic acid (C20; 4; n 6) a major precursor of the epoxy-fatty acids. Vignini et al. compared the amount of nitric oxide (NO) produced in vitro from a human astrocytoma cell line incubated with serum lipids obtained from 25 patients with anorexia nervosa and 20 healthy controls [21]. NO is a simple molecule with diverse and potent biological effects, and has been implicated as a measure of oxidative stress. They noted that serum lipids from patients with anorexia nervosa have increased capability to induce oxidative stress compared to lipids of healthy controls. This evidence suggests that serum lipids in patients with anorexia nervosa have an slightly increased risk of oxidation compared to serum lipids in healthy controls. If so, the homeoviscous adaptation will be skewed to protect oxidation at the expense of cold adaptation. Rhythm of retinoids in the brain While the major signaling pathway to initiate hibernation remains unknown, there are several pathways that are thought to be involved, including thyroid hormone signaling, neuronal cilia, melatonin, and retinoic acid [22]. Retinoic acid, a fat soluble compound is a derivative of retinol (vitamin A), and has profound effects on embryogenesis and on vision, Through its receptors families, the retinoic acid pathways has been shown to oscillate in response to photoperiod (hours of daylight) thus it is a prime candidate for initiating seasonal changes [23]). Mammals are not able to produce retinoic acid de novo, and so it is essential—derived either from animal sources as a fat soluble retinyl ester, or from plant sources from the closely related beta-carotene, which can be cleaved to retinaldehyde. In the hibernating species, thirteen-lined ground squirrel, the hypothalamus showed differences in retinoic acid signaling related genes across the circannual cycle. [24]. Clinically, it has been recognized for decades that patients with anorexia nervosa often have a yellowish hue, and several small studies have examined the serum beta carotene, retinyl esters, retinol, and retinoic acids. Robboy et al. compared these levels in healthy controls, patients with anorexia nervosa, postmenarchal women, pregnant women, women on birth control pills, women with irregular menses, normal weight who were attending a fertility clinic, and patients with cachexia from cancer or other terminal medical illness [25]. Interestingly, they found both beta carotene, retinyl esters, rand retinoic acid were most skewed in the cachectic patients and those with anorexia nervosa—being universally depressed in cachexia and elevated in anorexia nervosa. It is possible this is nutritional, as patients with anorexia nervosa, have less anxiety eating vegetables and fruits which are rich in beta carotene, although the limited diet history did not confirm that. The retinoic pathways, being fat soluble are intimately involved with lipid metabolism.
Implications Although this analysis is highly speculative, we think some approaches can clarify the proposed relationship between
382
B. Scolnick, D.I. Mostofsky / Medical Hypotheses 85 (2015) 380–382
seasonality, altered PUFAs, vitamin A metabolism and anorexia nervosa. They include: 1. Including basal body temperature and information on seasonality in subsequent analyses of lipid profiles in anorexia nervosa. 2. Animal studies either in the rat and mouse model, or, ideally some hibernating species (Broad Institute of MIT and Harvard http://www.broad.mit.edu has sequenced the genomes of four hibernating mammals in the last decade: thirteen-line ground squirrel; little brown bat, big brown bat, and the common hedgehog) that explore whether PUFA pathways and ambient temperature affect metabolic systems thought to be involved in the pathogenesis of anorexia nervosa. Recent findings suggest the melanocortin system is intimately involved in feeding behavior and associated with obsessive compulsive behavior, and thus is a prime suspect in the etiology of anorexia nervosa [26–28]. Gutierrez et al. has demonstrated, using an animal model of activity based anorexia, that high ambient temperature ‘‘rescued’’ the animal from self-starvation, and normalized the melanocortin system [29]. It would be interesting to study the PUFA changes in these animals in the serum, liver, muscle, heart, and brain. 3. Trials of omega-3:omega-6 supplementation in AN are warranted, but the analogy from hibernation suggests that nutritional component of PUFAs, while important in effecting torpor is limited [30]. Because of the pressing and urgent need for better treatment, it might make sense to go ahead with rigorous targeted supplements, but also to inject common sense into finding new treatments. In 1994, Ralph Holman, the lipid researcher who noted the ‘‘magic’’ of lipid families when the carbons were labeled in a backward manner, and thus started the field of omega 3/omega PUFAs, noted
‘‘The fundamental changes in membrane structure. . . may well be closer to the cause of anorexia than are the inanition and psychological aberrations associated with it. . . Treatment programs should include dietary management. . . Organ meats and fish are recommended as sources.’’ [17] 4. Additional nutritional trials should include foods with very high PUFA content. Malnutrition treatment has been revolutionized by the development of Ready to Use Therapeutic Foods (RUTF)s, and especially PlumpyNutÒ by Nutriset [31,32]. The dramatic recoveries from malnutrition seen in the third world, often in war ravaged areas, have been attributed to the gel mix of peanut butter and other lipids that requires no refrigeration nor addition of water. Obviously those factors are immaterial in the West, but it is possible that the recoveries are also due to the very high PUFA content of the gels. The most significant outcome from advancing this hypothesis, would be if barriers between different academic fields would be erased, and basic scientists, physicians treating patients with anorexia nervosa, researchers in hibernation, and public health malnutrition experts would pool their expertise to develop effective approaches to the treatment of anorexia nervosa. Conflict of interest statement None. References [1] Scolnick B, Mostofsky DI. Anorexia nervosa: a rogue hibernation. Med Hypotheses 2014;82(2):231–5.
[2] Carrera O, Adan RAH, Gutierrez E, Danner UN, Hoeck HW, Van Elburg AA, Kas MJH. Hyperactivity in anorexia nervosa: warming up not just burning off calories. PLoS ONE 2012:e41851. [3] Vasquea R, Carrera O, Birmingham I, Gutierrez E. Exploring the association between anorexia nervosa and geographical latitude. Eat Weight Disord 2006;11:1–8. [4] Njenga FG, Kangethe RN. Anorexia nervosa in Kenya. East Afr Med J 2004;81(4):188–93. [5] Fraga A, Caggianesse V, Carrera O, Graell M, Morande G, Gutierrez E. Seasonal BMI differences between restrictive and purging anorexia nervosa subtypes. J Eat Disord 2015;48(1):35–41. [6] Bergh C, Brodin U, Lindberg G, Sodersten P. Randomized controlled trial of a treatment for anorexia and bulimia nervosa. Proc Natl Acad Sci USA 2002;99:9486–94. [7] Gutierrez E, Vazquez R. Heat in the treatment of patients with anorexia nervosa. Eat Weight Disord 2001;6:49–52. [8] Birmingham CL, Butierrez E, Jonat L, Beumont P. Randomized controlled trial of warming in anorexia nervosa. Int J Eat Disord 2004;35(2):234–8. [9] Holman RT. The slow discovery of the importance of omega-3 essential fatty acids in human health. J Nutr 1998;128:427S–33S. [10] Sinensky M. Homeoviscous adaptation: a homeostatic process that regulates the viscosity of membrane lipids in Escherichia coli. Proc Natl Acad Sci USA 1974;71:522–5. [11] Ruf T, Arnold W. Effects of polyunsaturated fatty acids on hibernation and torpor: a review and hypothesis. Am J Physiol Reg Integr Comp Physiol 2008;294:R1044–52. [12] Arnold W, Ruf T, Frey-Roos F, Bruns U. Diet-independent remodeling of cellular membranes precedes seasonally changing body temperature in a hibernator. PLoS ONE 2011;6(4):e18641. [13] Zak A, Vecka M, Twrzicka E, Hruby M, Novak F, Papezova H, et al. Composition of plasma fatty acids and non-cholesterol sterols in anorexia nervosa. Physiol Res 2005;54:443–51. [14] Swenne I, Rosling A, Tenglad S, Bessby B. Essential fatty acid status in teenage girls with eating disorders and weight loss. Acta Paediatr 2011;100:1610–5. [15] Halmi K, Fry M. Serum lipids in anorexia nervosa. Biol Psychiatry 1974;8(2):159–67. [16] Curatola G, Camilloni MA, Vignini A, Nanetti L, Boscaro M, Mazzanti L. Chemical–physical properties of lipoproteins in anorexia nervosa. Eur J Clin Invest 2004;34:747–51. [17] Homan RT, Adams CE, Nelson RA, Grater SJE, Jaskiewica JA, Johnson S, Erdman JW. Patients with anorexia nervosa demonstrate deficiencies of selected essential fatty acids, compensator changes in nonessential fatty acids and decreased fluidity of plasma lipids. J Nutr 1995;125:901–7. [18] Holman RT, Johnson SB, Mercuri O, Itarte HJ, Rodrigo MA, De Tomas ME. Essential fatty acid deficiency in malnourished children. Am J Clin Nutr 1981;34:1534–9. [19] Shih PB, Yang J, Morisseau C, German JB, Scott-Van Zeeland AA, Armando AM, et al. Dysregulation of soluble epoxide hydrolase and lipidomic profiles in anorexia nervosa. Mol Psychiatry 2015:1–10. [20] Scott-Van Zeeland AA, Bloss CS, Twehey R, Bansal V, Torkamani A, Libiger O, et al. Evidence for the role of EPHX2 gene variants in anorexia nervosa. Mol Psychiatry 2014;19:724–32. [21] Vigini A, Canibus P, Nanetti L, Montecchhiani G, Faloia E, Caster AM, et al. Lipoproteins obtained from anorexia nervosa patients induce higher oxidative stress in U373MG Astrocytes through nitric oxide production. NeuroMol Med 2008;10:17–23. [22] Schwartz C, Andrews MT. Circannual transitions in gene expression: lessons from seasonal adaptations. Curr Top Dev Biol 2013;105:247–73. [23] Ransom J, Morgan PJ, McCaffery PJ, Stoney PN. The rhythm of retinoids in the brain. J Neurochem 2014;129:366–76. [24] Schwartz C, Hampton M, Andrews MT. Seasonal and regional differences in gene expression in the brain of a hibernating mammals. PLoS ONE 2013;8:e58427. [25] Robboy MS, Sato AS, Schwabe AD. The hypercarotenemia in anorexia nervosa: a comparison of vitamin A and carotene levels in various forms of menstrual dysfunction and cachexia. Am J Clin Nutr 1974:363–7. [26] Xu P, Grueter BA, Britt JK, McDaniel L, Huntington PJ, Hodge R, Tran S, Mason BL, Lee C, Vong L, Lowell BB, Malenka RC, Lutter M, Pieper AA. Double deletion of melanocortin 4 receptors and SAPAP3 corrects compulsive behavior and obesity in mice. Proc Natl Acad Sci USA 2014;110(26):10758–64. [27] Dietrich MO, Zimmer MR, Bober J, Horvath TL. Hypothalamic AGRp neurons drive stereotypic behaviors beyond feeding. Cell 2015;160(6):1222–32. [28] Liu J, Garza JC, Li W, Lu XY. Melanocortin 4 receptor in the medial amygdala regulates emotional stress induced anxiety like behavior, anorexia, and corticosterone secretion. Int J Neuropsychopharmacol 2013;16(1):105–20. [29] Gutierrez, Gutierrez E, Churruca I, Zarate J, Carrera O, Portillo MP, Cerrato M, Vazquez R, Echevarria E. High ambient temperature reverses hypothalamic MC4 receptor overexpression in an animal model of anorexia nervosa. Psychoneuroendocrinology 2009;34:420–9. [30] Munro D, Thomas DW. The role of polyunsaturated fatty acids in the expression of torpor by mammals: a review. Zoology 2004;107:29–48. [31] Collins S. Changing the way we address severe malnutrition during famine. The Lancet 2001;358:498–501. [32] Manary, Mark J, et al. Home based therapy for severe malnutrition with readyto-use therapeutic food. Arch Dis Child 2004;89:557–61.
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Anorexia nervosa, seasonality, and polyunsaturated fatty acids Barbara Scolnick ⇑, David I. Mostofsky Boston University, Department of Psychology, 64 Cummington Street, Boston, MA, United States
a r t i c l e
i n f o
Article history: Received 9 April 2015 Accepted 6 May 2015
a b s t r a c t Anorexia nervosa is a serious neurobehavioral disorder marked by semistarvation, extreme fear of weight gain, frequently hyperactivity, and low body temperature. The etiology remains unknown. We present a speculation that a primary causative factor is that polyunsaturated fatty acids are skewed to prevent oxidative damage in phospholipid membranes. This causes a change in the trade off of oxidation protection vs homeoviscous adaptation to lower temperatures, which sets off a metabolic cascade that leads to the rogue state of anorexia nervosa. Ó 2015 Elsevier Ltd. All rights reserved.
Introduction Anorexia nervosa is a serious neurobehavioral disorder marked by semi-starvation, extreme fear of weight gain, frequently hyperactivity. Our hypothesis is that seasonal fluxes in polyunsaturated fatty acids might play a role in causing and sustaining the disorder. Studying circannual rhythms in humans is hampered because modern humans no longer show obvious seasonal behavioral adaptations; we essentially live in a world where temperature, light and food supply are relatively constant. By studying hibernating species, and extrapolating to humans these archaic pathways become more obvious [1]. We have pursued this line of inquiry, because the epidemiology of anorexia nervosa strongly suggests that the disorder is rare in the tropics and more common in higher and lower latitudes [2,3]. While this has traditionally been viewed as evidence of ‘‘cultural bias to thinness’’ this view is being challenged as evidence points to the biologically driven nature of anorexia nervosa [4]. Preliminary evidence suggests hospital stays are longer, and body weight index is lower in patients with anorexia nervosa in the winter months compared with the summer [5]. Some studies have found improvement in weight gain when patients with anorexia nervosa are treated with heat therapy [6,7] although others have not confirmed this [8].
PUFAs and homeoviscous adaptation Polyunsaturated fatty acids (PUFA) are essential fatty acids that contain more than one double bond, as opposed to monounsaturated (MUFA) which have one double bond, or saturated fatty acids ⇑ Corresponding author. Tel.: +1 617 803 6353. E-mail addresses: [email protected] (B. Scolnick), [email protected] (D.I. Mostofsky). http://dx.doi.org/10.1016/j.mehy.2015.05.007 0306-9877/Ó 2015 Elsevier Ltd. All rights reserved.
which have no double bonds. When the carbons in the chain are numbered from the noncarboxy end of the chain (backward nomenclature compared to classic chemical naming; hence omega), these acids fall into 2 families, omega-3 in which the first double bond is on the 3rd carbon, and omega-6 in which the first double bond is on the 6th carbon. PUFAs undergo successive elongation and desaturation, and there is an innate competition in metabolism between these two families [9]. These long chain PUFAs and some long chain MUFAs have uniquely important properties when combined with phosphate groups to form phospholipids. With the long hydrophilic tail, and the short hydrophobic head they form into bilayers which are the backbone of most cell membranes. Altering the ratio of saturated fatty acids to unsaturated PUFAs, and the ratio of omega:3 to omega:6 fatty acids changes the properties of membranes, and the functioning of embedded proteins. ‘‘Homeoviscous adaptation’’ is a term coined in 1974 to refer to changes in the fatty acid concentration of cell membranes of actively growing Escherichia coli bacteria in response to ambient temperature changes [10]. These fluxes in fatty acids-increasing saturated fatty acids in higher temperature, and increasing PUFAs in lower temperatures – produce membranes whose lipids have a constant fluidity at the temperature of growth. It has become recognized that the phenomena is evolutionarily highly conserved and present in fish, in ‘‘cold blooded’’ animals, and vertebrates [11]. Although, not yet proven, our hypothesis is that homeoviscous adaptation metabolic pathways are present in humans.
Homeoviscous adaptation in hibernation A recently published experiment on free living alpine marmots found that tissue samples from liver and heart display an active circannual flux of the PUFA content of phospholipids [12]. In
B. Scolnick, D.I. Mostofsky / Medical Hypotheses 85 (2015) 380–382
autumn, as ambient temperature start to drop, and daylight shortens, but before the animal enters hibernation, n 6 PUFAs rapidly replace MUFAs in the liver, and replace both MUFAs and n 3 PUFAs in the heart. In spring, concurrent with the rising ambient temperature, the process reverses. These changes are largely independent of current dietary intake, and reflect lipids from adipose tissue. In short, for this hibernating species, omega 6 PUFAs are ‘‘preferable’’ in the phospholipid layer in the cold months, and omega 3 PUFAs are ‘‘preferable’’ in the warmer months. There is a strong relationship between increased omega-6:omega:3 ratio in cardiac phospholipids and the activity of a key enzyme that controls cardiac contraction in the cold. Yet, with an increased omega-6; omega:3 phospholipid cell membrane ratio there is a well described adverse effect of increased susceptibility to oxidative degradation from reactive radicals. Thus, in short, there is a trade off—more omega-6 PUFAs in phospholipids improve cold adaptation; more omega-3 PUFAs in phospholipids decrease the risk of oxidation. Serum lipid studies in patients with anorexia nervosa Our hypothesis is that this tradeoff is skewed in patients with AN, thus adversely affecting their ability to alter cell membranes in colder ambient temperatures. This causes a cascade of metabolic effects, and patients essentially become ‘‘stuck’’ in a physiologic rogue state marked by low body temperature, hypometabolism, semistarvation, and paradoxically frequently hyperexercise. If the hypothesis is correct, we should see evidence that the phospholipids of patients with anorexia nervosa show an increased tendency for oxidative degradation, and hence a decreased ability to effectively cold adapt. Although subtle, there is such evidence. Several studies of serum lipid profile changes in patients with anorexia nervosa have shown a deep alterations in chemical/physical properties in the serum PUFAs [13–16] This is partially nutritional, as patients tend to avoid fatty foods, and prefer the greens and salads rich in omega-3, as opposed to nuts and oils richer in omega-6. In 1995, Holman et al. studied 8 patients with anorexia nervosa, compared to 19 controls, and measured serum fatty acid composition of phospholipids, nonesteried fatty acids, triglycerides and cholesterol esters [17]. The most striking differences were in the phospholipid category and showed lower n 6 and n 3 elongation and desaturation products and elevated short chain saturated, short chain monounsaturated, branched chain, and the odd-chain fatty acids. This differed from simple malnutrition which showed lowered content of all n 6 and n 3 fatty acids and an increase in 20:3(n 9) [18]. Furthermore, Holman measured the mean melting point of the phospholipid component and found the melting point value for the AN group was significantly elevated over the controls. He interpreted these findings as showing PUFA deficiencies (may be partially nutritional), evidence of elongation enzyme ‘‘difficulties’’ and abnormal phospholipid fluidity marked by elevated melting points. A recent (2015) study by Shih et al. compared free (nonesterified) and total (esterified) forms of fatty acids in the serum of 30 ill patients with anorexia nervosa, 30 recovered patients, and 36 controls [19]. Generally, the patients with anorexia nervosa showed elevated n 3 PUFAs reflected in n 3:n 6 ratios, compared to healthy controls. The recovered patients fell in between, more closely resembling the patients. These authors also compared 10 ill anorexia nervosa to 10 recovered patients to 38 controls, with a targeted metabolomics assay. They focused on the substrate and product levels of one specific enzyme; soluble epoxide hydrolase (sEH). This analysis was done because an earlier gene sequencing discovery study had found suggestive evidence that epoxide hydrolase 2 gene
381
(EPHX2) which codes for this specific enzyme harbors rare variants that were associated with anorexia nervosa [20]. Ratios of product:substrate were elevated in anorexia nervosa compared to controls, implying increase sEH activity. The recovered patients fell in between, more toward the controls, implying recovery leads to more normal sEH activity. Soluble EH sits at an important cross roads in lipid metabolism because it metabolizes epoxy-fatty acids to the corresponding 1,2dihyoxy-fatty acids (diols). The epoxy-fatty acids, in turn were derived from 20 carbon PUFAs, notable arachidonic acid (C20; 4; n 6) a major precursor of the epoxy-fatty acids. Vignini et al. compared the amount of nitric oxide (NO) produced in vitro from a human astrocytoma cell line incubated with serum lipids obtained from 25 patients with anorexia nervosa and 20 healthy controls [21]. NO is a simple molecule with diverse and potent biological effects, and has been implicated as a measure of oxidative stress. They noted that serum lipids from patients with anorexia nervosa have increased capability to induce oxidative stress compared to lipids of healthy controls. This evidence suggests that serum lipids in patients with anorexia nervosa have an slightly increased risk of oxidation compared to serum lipids in healthy controls. If so, the homeoviscous adaptation will be skewed to protect oxidation at the expense of cold adaptation. Rhythm of retinoids in the brain While the major signaling pathway to initiate hibernation remains unknown, there are several pathways that are thought to be involved, including thyroid hormone signaling, neuronal cilia, melatonin, and retinoic acid [22]. Retinoic acid, a fat soluble compound is a derivative of retinol (vitamin A), and has profound effects on embryogenesis and on vision, Through its receptors families, the retinoic acid pathways has been shown to oscillate in response to photoperiod (hours of daylight) thus it is a prime candidate for initiating seasonal changes [23]). Mammals are not able to produce retinoic acid de novo, and so it is essential—derived either from animal sources as a fat soluble retinyl ester, or from plant sources from the closely related beta-carotene, which can be cleaved to retinaldehyde. In the hibernating species, thirteen-lined ground squirrel, the hypothalamus showed differences in retinoic acid signaling related genes across the circannual cycle. [24]. Clinically, it has been recognized for decades that patients with anorexia nervosa often have a yellowish hue, and several small studies have examined the serum beta carotene, retinyl esters, retinol, and retinoic acids. Robboy et al. compared these levels in healthy controls, patients with anorexia nervosa, postmenarchal women, pregnant women, women on birth control pills, women with irregular menses, normal weight who were attending a fertility clinic, and patients with cachexia from cancer or other terminal medical illness [25]. Interestingly, they found both beta carotene, retinyl esters, rand retinoic acid were most skewed in the cachectic patients and those with anorexia nervosa—being universally depressed in cachexia and elevated in anorexia nervosa. It is possible this is nutritional, as patients with anorexia nervosa, have less anxiety eating vegetables and fruits which are rich in beta carotene, although the limited diet history did not confirm that. The retinoic pathways, being fat soluble are intimately involved with lipid metabolism.
Implications Although this analysis is highly speculative, we think some approaches can clarify the proposed relationship between
382
B. Scolnick, D.I. Mostofsky / Medical Hypotheses 85 (2015) 380–382
seasonality, altered PUFAs, vitamin A metabolism and anorexia nervosa. They include: 1. Including basal body temperature and information on seasonality in subsequent analyses of lipid profiles in anorexia nervosa. 2. Animal studies either in the rat and mouse model, or, ideally some hibernating species (Broad Institute of MIT and Harvard http://www.broad.mit.edu has sequenced the genomes of four hibernating mammals in the last decade: thirteen-line ground squirrel; little brown bat, big brown bat, and the common hedgehog) that explore whether PUFA pathways and ambient temperature affect metabolic systems thought to be involved in the pathogenesis of anorexia nervosa. Recent findings suggest the melanocortin system is intimately involved in feeding behavior and associated with obsessive compulsive behavior, and thus is a prime suspect in the etiology of anorexia nervosa [26–28]. Gutierrez et al. has demonstrated, using an animal model of activity based anorexia, that high ambient temperature ‘‘rescued’’ the animal from self-starvation, and normalized the melanocortin system [29]. It would be interesting to study the PUFA changes in these animals in the serum, liver, muscle, heart, and brain. 3. Trials of omega-3:omega-6 supplementation in AN are warranted, but the analogy from hibernation suggests that nutritional component of PUFAs, while important in effecting torpor is limited [30]. Because of the pressing and urgent need for better treatment, it might make sense to go ahead with rigorous targeted supplements, but also to inject common sense into finding new treatments. In 1994, Ralph Holman, the lipid researcher who noted the ‘‘magic’’ of lipid families when the carbons were labeled in a backward manner, and thus started the field of omega 3/omega PUFAs, noted
‘‘The fundamental changes in membrane structure. . . may well be closer to the cause of anorexia than are the inanition and psychological aberrations associated with it. . . Treatment programs should include dietary management. . . Organ meats and fish are recommended as sources.’’ [17] 4. Additional nutritional trials should include foods with very high PUFA content. Malnutrition treatment has been revolutionized by the development of Ready to Use Therapeutic Foods (RUTF)s, and especially PlumpyNutÒ by Nutriset [31,32]. The dramatic recoveries from malnutrition seen in the third world, often in war ravaged areas, have been attributed to the gel mix of peanut butter and other lipids that requires no refrigeration nor addition of water. Obviously those factors are immaterial in the West, but it is possible that the recoveries are also due to the very high PUFA content of the gels. The most significant outcome from advancing this hypothesis, would be if barriers between different academic fields would be erased, and basic scientists, physicians treating patients with anorexia nervosa, researchers in hibernation, and public health malnutrition experts would pool their expertise to develop effective approaches to the treatment of anorexia nervosa. Conflict of interest statement None. References [1] Scolnick B, Mostofsky DI. Anorexia nervosa: a rogue hibernation. Med Hypotheses 2014;82(2):231–5.
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