Is decreased appetite for food a physiological consequence of alcohol consumption?

Appetite 51 (2008) 233–243

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Appetite journal homepage: www.elsevier.com/locate/appet

Research review

Is decreased appetite for food a physiological consequence of alcohol consumption? Anna Kokavec La Trobe University, School of Psychological Science, P.O. Box 199, Bendigo, 3552, Australia

A R T I C L E I N F O

A B S T R A C T

Article history: Received 31 August 2007 Received in revised form 2 March 2008 Accepted 26 March 2008

Despite the overwhelming evidence linking alcohol to the development of disease, the contribution of alcohol toxicity to ill health remains controversial. One of the major problems facing researchers is the fact that alcoholic beverages, which contribute little to the nutritional requirements of the body, are often substituted for food and nutritional deficiency alone can promote cell damage. Long-term alcohol intake can decrease the total amount of food consumed when food is freely available and the alcoholic individual is often held accountable for their irregular eating behaviour. Assessment of meal composition has highlighted that appetite for food-containing carbohydrate (in particular) is altered in moderate– heavy drinkers but at present there is insufficient biochemical evidence to confirm or deny this observation. The biochemical processes associated with appetite are many and it would be impossible to address all of these events in a single paper. Therefore, the aim of this review will be to focus on one of the major biochemical markers of appetite for carbohydrate in order to put forward the suggestion that a decreased appetite for food could be a physiological consequence of consuming some forms of alcohol. ß 2008 Elsevier Ltd. All rights reserved.

Keywords: Alcohol Cortisol DHEAS Insulin Appetite Fasting

Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hormonal regulation of food intake. . . . . . . . . . . . . . . . . Meal composition and taste preference . . . . . . . . . . . . . . Energy metabolism and utilization . . . . . . . . . . . . . . . . . Alcohol and receptor activity . . . . . . . . . . . . . . . . . . . . . Alcohol consumption prior to food . . . . . . . . . . . . . . . . . Food after alcohol. . . . . . . . . . . . . . . . . . . . . . . . . . . . . Alcohol after food. . . . . . . . . . . . . . . . . . . . . . . . . . . . . Effects of red versus white wine . . . . . . . . . . . . . . . . . . . Alcohol containing carbohydrate. . . . . . . . . . . . . . . . . . . Sugar preference in abstinent and non-abstinent alcoholics Alcohol and lipogenesis. . . . . . . . . . . . . . . . . . . . . . . . . Alteration of energy metabolism? . . . . . . . . . . . . . . . . . . Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Introduction

E-mail address: [email protected]. 0195-6663/$ – see front matter ß 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.appet.2008.03.011

Despite the overwhelming evidence linking alcohol to the development of disease, the contribution of alcohol toxicity to ill health remains controversial. One of the major obstacles researchers encounter when attempting to determine the role (if any)

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alcohol consumption has in the development of illness is that often alcoholic beverages, which contribute little to the nutritional requirements of the body, are substituted for food (Orozco & De Castro, 1991), and nutritional deficiency alone can promote cell damage (Kaplan & Pesce, 1996). Early work has shown that in some individuals, alcohol can alter appetite for food, despite food being freely available (Colditz et al., 1991; Herbeth, Didelot-Barthelemy, Lemoine, & Le Devehat, 1988; Strbak, Benicky, Macho, Jezova, & Nikodemova, 1998). Furthermore, biochemical evidence shows that alcohol can influence hormonal processes (e.g. Kokavec & Crowe, 2001a, 2001b, 2003, 2006) that have also been implicated in appetite regulation (e.g. Dallman et al., 1993; Dallman, Akana, Strack, Hanson, & Sebastian, 1995). Malnutrition is commonly associated with alcohol abuse (Victor, Adams, & Collins, 1989) and knowing whether alcohol promotes, inhibits, or has no effect on appetite for food could be of importance to health professionals involved in the treatment of alcoholic individuals. The aim of this paper is to attempt to stimulate discussion on the alcohol toxicity versus nutritional deficiency debate by exploring the possibility that one of the specific effects of alcohol toxicity may be to promote an alteration in appetite for carbohydrate. In the next few sections a minor review of the available evidence relevant to appetite and energy metabolism from human and animal studies will be presented. Then biochemical and behavioural evidence will be used to argue that under some (but not all) conditions a reduced appetite for carbohydrate combined with enhanced appetite for alcohol may be a physiological consequence of consuming specific forms of commercially available alcohol. Hormonal regulation of food intake A meal high in carbohydrate will usually promote a sudden increase in plasma glucose, which then stimulates insulin release by the b-cells in the pancreas in order to promote glycogenesis and glycolysis when glucose is plentiful (Kaplan & Pesce, 1996). Circulating insulin levels in non-diabetic individuals usually rise with feeding (Schwartz, Sipols, et al., 1992) and the level of plasma insulin remains elevated until the plasma glucose level begins to drop, which often can take several hours (Stryer, 1995). In contrast, during fasting insulin secretion is markedly reduced (Schwartz, Figlewicz, Baskin, Woods, & Porte, 1992) and cortisol, a glucocorticoid under the control of the hypothalamic-pituitary-adrenal (HPA) axis is elevated in order to reduce glucose utilization and transport and promote gluconeogenesis (Kaplan & Pesce, 1996). While the relationship between cortisol and insulin is usually antagonistic (Marieb, 1998), elevations in cortisol and insulin can occur simultaneously in response to food intake. The role of cortisol in this instance is to modulate the effects of insulin on glucose utilization in order to ensure that energy stores are replenished (Goldstein et al., 1993). Investigations have shown that feeding behaviour is largely dependent on the efficient performance of cortisol and insulin (Strack, Sebastian, Schwartz, & Dallman, 1995). Early work has demonstrated that a low-moderate level of cortisol is required to stimulate appetite (Cohn, Shrago, & Joseph, 1955), and insulin release (Rebuffe-Scrive, Walsh, McEwen, & Rodin, 1992), while a concomitant rise in insulin is necessary to stop feeding (Woods & Porte, 1975). The effects of cortisol and insulin may also be mediated, in part, through the regulation of hypothalamic neuropeptide Y (NPY), a 36-amino sequence pancreatic polypeptide (Strack et al., 1995). Glucocorticoids can increase the transcription rate of NPY mRNA (Dean & White, 1990) and a sufficient release of cortisol may be

necessary for NPY-stimulated insulin release (Wisialowski et al., 2000). NPY is synthesized by neurons in the hypothalamic arcuate nucleus (ARC) and while these neuronal axons can project to a number of areas (O’Donohue et al., 1985), projections to the paraventricular nuclei (PVN) have been strongly associated with stimulation of feeding (Muroya, Yada, Shioda, & Takigawa, 1999; Stanley, Kyrkouli, Lampert, & Leibowitz, 1986). Fasting promotes an elevation in glucocorticoids and NPY gene expression (Hanson, Levin, & Dallman, 1997). In contrast, under fasting conditions the level of insulin in non-diabetic individuals is reduced. Insulin acts locally to inhibit NPY gene expression in the ARC (Schwartz, Sipols, et al., 1992) and a decrease in food intake is observed with insulin and adrenalectomy (ADX) due to a reduction in ARC NPY mRNA levels (Tempel & Leibowitz, 1989; White, Dean, & Martin, 1990). NPY-induced feeding behaviour in the PVN appears to specifically increase carbohydrate intake (Stanley & Leibowitz, 1984), and a lack of glucocorticoids by inhibiting NPY release in the PVN notably decreases carbohydrate intake (Tempel & Leibowitz, 1989). The ARC contains glucose-sensitive NPY-containing neurons and the purpose of these neurons is to detect a reduction in the glucose concentration in the brain and subsequently stimulate NPY-induced feeding (Muroya et al., 1999). There is little evidence to suggest that NPY administration can alter the plasma glucose level (Wisialowski et al., 2000). Thus, it is likely that glucose utilization constitutes an important signal, either direct or indirect, in the modulation of NPY production in the hypothalamus (Akabayashi, Zeia, Silva, Chae, & Leibowitz, 1993). Neuropeptide Y has been strongly implicated in alcohol reinforcement and it is well accepted that activation of NPY Y5 receptors will promote alcohol self-administration (Schroeder, Overstreet, & Hodge, 2005). Genetic linkage studies have identified a chromosomal region that incorporates the NPY gene in alcoholpreferring rodents. NPY-deficient animals show a greater preference for alcohol when compared to rodents that over-express the NPY gene in neurons. Thus, alcohol consumption and resistance could be inversely related to NPY levels in the brain (Badia-Elder, Stewart, Powrozek, Murphy, & Li, 2003; Thiele & Badia-Elder, 2003; Thiele, Marsh, Marie, Bernstein, & Palmiter, 1998). Meal composition and taste preference Assessment of the behavioural effects of alcohol on appetite has often included some investigation of meal size (e.g. Poppitt, Eckhardt, McGonagle, Murgatroyd, & Prentice, 1996; Strbak et al., 1998) and meal composition (e.g. Colditz et al., 1991; Herbeth et al., 1988). It appears that while short-term alcohol intake has little effect on meal size (Poppitt et al., 1996), longterm alcohol consumption can decrease the total amount of food consumed when food is freely available (Strbak et al., 1998). Further assessment of meal composition has highlighted that moderate–heavy alcohol drinkers when compared to controls consume significantly less food containing carbohydrate (Colditz et al., 1991), and more food containing fat and protein (Herbeth et al., 1988), and fat and salt (Caton, Ball, Ahern, & Hetherington, 2004). Voluntary alcohol intake is influenced by the macronutrient content of food (for review, see Forsander, 1998). Furthermore, it is well accepted that a high-carbohydrate/low-protein meal can decrease alcohol intake when compared to a low-carbohydrate/ high-protein meal (Forsander & Sinclair, 1988). Carbohydrate and non-carbohydrate artificial sweeteners such as saccharin may attenuate alcohol intake by promoting insulin release (KampovPolevoy, Garbutt, & Janowsky, 1999). Therefore, an inverse

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relationship between alcohol intake and appetite for sugar could exist (Colditz et al., 1991). A significant relationship between preference for sweet solutions and alcohol dependence was initially reported (Kampov-Polevoy, Garbutt, & Janowski, 1997; Kampov-Polevoy, Garbutt, Davis, & Janowsky, 1998). However, this theory failed to gain support as sweet preference can also be a consequence of heavy drinking, poor nutrition (Kranzler, Sandstrom, & Van Kirk, 2001) or due to an alcohol-induced impairment in olfactory ability (Hirsch, 2002). More recent findings revealed that heightened sweet preference in alcoholics is more likely to be associated with a paternal family history of alcoholism (Kampov-Polevoy, Eick, Boland, Khalitov, & Crews, 2004) and this has since been confirmed by others (Pepino & Mennella, 2007). Therefore, sweet preference or reactivity to other gustatory stimuli (e.g. monosodium glutamate), while being linked to a genetic vulnerability for alcoholism on its own is insufficient to predict alcohol dependency (Kampov-Polevoy et al., 2004; Wrobel et al., 2005; Wronski et al., 2007). Alcohol may directly stimulate neural pathways related to sweet taste (Lemon, Brasser, & Smith, 2004), suggesting that alcohol may activate areas of the brain associated with reinforcement and reward. It has been shown that both dopamine (McQuade, Xu, Woods, Seeley, & Benoit, 2003; Noble, 1996) and opioids (Herz, 1997) may mediate alcohol reward and intake (Blednov, Walker, Martinez, & Harris, 2006). In rodents, alcohol self-administration can directly increase dopamine in the nucleus accumbens in line with the stimulus properties of the alcohol (Doyon et al., 2003). Alcohol preferring rodents have demonstrated poor control over reinforcing substances such as saccharin and sucrose suggesting some impairment in serotonin regulation (KampovPolevoy & Rezvani, 1997). Consuming sweets can produce a hedonic response, which could contribute to impaired control over eating sweet food and elevation in mood (Kampov-Polevoy, Alterman, Khalitov, & Garbutt, 2006). Furthermore, a combination of saccharin and alcohol may condition alcohol-preferring rodents to consume even more alcohol (Tampier & Quintanilla, 2005). Although, merely concluding that there is a positive relationship between sweet preference and alcohol consumption may, on its own, be too simplistic (Goodwin & Amit, 1998). Sweet taste can elicit cephalic phase insulin release (CPIR) and the main characteristic of CPIR is that it occurs prior to any elevation in plasma glucose. It has been shown that in some cases sucrose will promote CPIR while starch, which lacks a sweet taste, does not promote CPIR. Saccharin despite not having any nutritional value may also promote CPIR, suggesting that sweetness information and not nutritional value provides the necessary information for promoting CPIR (Tonosaki, Hori, Shimizu, & Tonosaki, 2007). In contrast, others have failed to reproduce these findings (e.g. Ambrus, Ambrus, Shields, Mink, & Cleveland, 1976; Teff, Devine, & Engelman, 1995). Similarly, magnetic resonance imaging data has shown that only glucose can promote CPIR confirming that a combination of sweet taste and energy content is required to trigger a sensory signal (Smeets, de Graaf, Stafleu, van Osch, & van der Grond, 2005). Genetic mapping has revealed a chromosomal locus, with links to both alcohol ingestion and saccharin preference (Bachmanov et al., 2002), containing the gene for T1R3, a previously unidentified taste receptor involved in sweet taste reception (Damak et al., 2003; Max et al., 2001; Montmayeur, Liberles, Matsunami, & Buck, 2001; Nelson et al., 2001; Zhao et al., 2003). Deletion of genes involved in detection of sweet taste can promote a significant decrease in alcohol ingestion in the absence of any alteration in the pharmacological actions of alcohol (Blednov et al.,

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2008). Therefore, when this is considered together with the conditional taste aversion data (e.g. Blizard & McClearn, 2000; Di Lorenzo, Kiefer, Rice, & Garcia, 1986; Kiefer & Mahadevan, 1993) it is possible that alcohol possesses a sweet taste component (Lemon et al., 2004), and/or is linked in some way to sugar. Energy metabolism and utilization It has been reported that ‘energy’ ingested as alcohol calories, does not result in a compensatory reduction in food intake, therefore ‘energy intake’ is increased when alcohol is consumed (Poppitt et al., 1996; Yeomans & Phillips, 2002). Furthermore, researchers have claimed that self-report data has confirmed this is due to an alcohol-induced increase in appetite (Caton et al., 2004; Hetherington, Cameron, Wallis, & Pirie, 2001; Yeomans & Phillips, 2002; Yeomans et al., 1999). However, a recent review of the literature has found little difference in appetite ratings between alcohol and no alcohol preload groups, which appears to be at odds with these anecdotal claims (Gee, 2006). In addition, from a biochemical perspective, these claims are difficult to substantiate as it is unknown whether calories derived from alcohol can be converted to metabolic energy by the known human energy pathways. Metabolic energy in humans is produced by the tricarboxylic acid (TCA) cycle and the entry of substrates into the TCA cycle is dependent on activation of the pyruvate dehydrogenase complex (Stryer, 1995). We have previously outlined why it is unlikely that alcohol promotes energy metabolism via this route (for review, see Kokavec & Crowe, 2002). However, alcohol being a dead-end of energy metabolism formed from pyruvate in yeast and other microorganisms (Stryer, 1995) is indeed linked to carbohydrate. The conversion of glucose to alcohol is an anaerobic process (Burton, 1992) and to plants and other anaerobic organisms alcohol represents a form of stored energy. When alcohol is metabolised in the body acetaldehyde cannot be converted back to pyruvate and instead is converted to acetate by aldehyde dehydrogenase primarily in the mitochondria before final oxidization into carbon dioxide and water (Agarwal & Goedde, 1989; Diamond & Messing, 1994; Lieber, 1989). Acetaldehyde is converted to acetate because bacteria and plants are able to grow on acetate by making use of the glyoxylate cycle (Stryer, 1995), a gluconeogenic pathway responsible for the conversion of fat into carbohydrate (Masters, 1997). Alcohol and receptor activity NPY-induced feeding in the hypothalamus could be dependent on activation of N-methyl-D-aspartate (NMDA) glutamate receptors (Lee & Stanley, 2005) as NPY protein and mRNA levels are increased by glutamatergic stimulation (Kim, Kwon, Shin, & Choe, 2000). Moreover, activation of NMDA receptors can promote the release of g-aminobutyric acid (GABA) and NPY (Belhage, Hansen, & Schousboe, 1993; Gemignani, Marchese, Fontana, & Raiteri, 1997). Neurons of the ARC release glutamate from local synaptic terminals and an absence of glutamatergic neurons have been noted in the PVN, which contains a large number of GABAergic neurons. In the absence of glutamate excitation, NPY in the ARC has little influence on hypothalamic neuronal activity but instead has a modulatory role by either reducing glutamate release at presynaptic terminals or modulating the postsynaptic response to glutamate (Belousov & van den Pol, 1997). Recent evidence suggests that chronic ethanol exposure can produce a significant reduction in NPY protein levels (Roy & Pandey, 2002), and suppress NPY gene expression in the ARC (Kinoshita et al., 2000). Thus, this supports the accepted view that acute alcohol administration

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impairs functioning of excitatory NMDA glutamate receptors (Lustig, Chan, & Greenberg, 1992) and potentiates the function of inhibitory GABAA receptors (Givens & Breese, 1990; Mehta & Ticku, 1988). Steroid hormones such as cortisol and dehydroepiandrosterone sulfate (DHEAS), in the brain can act as modulators of synaptic events Majewska (1992). Cortisol may alter the binding of GABA to inhibitory GABAA receptors in a biphasic fashion (Majewska, Bisserbe, & Eskay, 1985) and an increase in glucocorticoid activity can inhibit glucose transport and glutamate uptake in astrocytes (Virgin et al., 1991). In contrast, the role of DHEAS may be to modulate the action of cortisol and as a GABA antagonist at the GABAA receptor (Demirgoren, Majewska, & Spivak, 1991; Majewska, Demirgoren, Spivak, & London, 1990) DHEAS can potentiate NMDA receptor activity (Baulieu, 1996). Fasting can increase NPY in ARC neurons that specifically send axons to the PVN but this effect may be dependent on low ambient insulin levels (Schwartz, Figlewicz, et al., 1992). Glucocorticoids will increase and insulin can decrease NPY gene expression in the ARC. The insulin-mediated inhibition of NPY gene expression in the ARC may be mediated through GABAergic systems (Sato et al., 2005). There is co-localization of NPY and GABA in various brain areas (Aoki & Pickel, 1990; Deller & Leranth, 1990) and NPY can inhibit potassium-stimulated glutamate release (Greber, Schwarzer, & Sperk, 1994; Wang, 2005). Alternatively, NPY protein and mRNA levels are increased by glutamatergic stimulation (Kim et al., 2000). An antagonistic relationship exists between DHEAS and insulin (Baulieu, 1996), which is consistent with the suggestion that DHEAS, a known GABA antagonist (Demirgoren et al., 1991; Majewska et al., 1990) can promote activation of NMDA receptors via inhibition of GABA (Baulieu, 1996). Alcohol consumption prior to food Plasma cortisol and DHEAS is significantly elevated under fasting conditions (Akanji, Ezenwaka, Adejuwon, & Osotimehin, 1990; Lane, Ingram, Bal, & Roth, 1997; Tegelman, Lindeskog, Carlstrom, Pousette, & Blomstrand, 1986; Vance & Thorner, 1989). Similarly, an elevation in salivary cortisol and DHEAS has been noted following a six hour fast (Kokavec & Crowe, 2001a). It has been shown that the amount of cortisol in saliva is highly correlated with the level of plasma free cortisol (Akanji et al., 1990; Read, Riad Fahmy, Walker, & Griffiths, 1976; Umeda et al., 1981; Vining, McGinley, Maksujtis, & Yho, 1983). Moreover, the level of steroids in saliva is highly correlated with levels in cerebrospinal fluid (CSF). Therefore, salivary steroids may offer an easy, convenient, and reliable sampling method for assessment of neurosteroids (Guazzo, Kirkpatrick, Goodyer, Shiers, & Herbert, 1996). The consumption of white wine significantly decreases salivary cortisol and DHEAS when consumed alone under fasting conditions (Kokavec & Crowe, 2001a). While an absence of cortisol in CNS could indicate that glucose transport and glutamate uptake is promoted in astrocytes (Virgin et al., 1991) the significant reduction in DHEAS highlights that NMDA receptor activity is not promoted. Moreover, as NPY protein and mRNA levels in the ARC are increased by glutamatergic stimulation (Kim et al., 2000) the steroid data could support previous claims that an alcoholinduced reduction in NPY mRNA in ARC (Kinoshita et al., 2000) and NPY in PVN (Roy & Pandey, 2002) occurs. During fasting insulin is usually reduced in order to promote feeding and insulin administration during fasting may prevent the fasting-induced increase in NPY in PVN and NPY mRNA in ARC (Schwartz, Sipols, et al., 1992). White wine prior to food does not increase plasma insulin (Kokavec & Crowe, 2006) and ketone

production is maintained (Kokavec, 2000). Taken together this would suggest that white wine prior to food does not promote an elevation in plasma glucose and raises the possibility that an increase in NPY mRNA in ARC could occur under these conditions. The expression of NPY in the ARC is influenced by both feeding and hydration factors. Moreover, a combination of ADX and chronic osmotic stimulation can increase NPY mRNA expression in neurons of the ARC (Larsen, Mikkelsen, Jessop, Lightman, & Chowdrey, 1993). Similarly, a combination of ADX and fasting can increase NPY gene expression in the medial basal hypothalamus (Hanson et al., 1997) and an increase in ARC NPY mRNA has also been observed in food (Johnstone, Srisawat, Kumarnsit, & Leng, 2005) and calorie (Shimokawa et al., 2003) restricted animals Chronic osmotic stimulation can deactivate the HPA axis (Jessop, Chowdrey, & Lightman, 1990) and alcohol may promote the development of a dehydration condition (Linkola, Fyhrquist, & Ylikahri, 1979), as evidenced by fluid and salt retention (Ragland, 1990) and an increase in renin (Nieminen, Linkola, Fyhrquist, Tikkanen, & Forslund, 1985; Inder, Joyce, Ellis, et al., 1995; Inder, Joyce, Wells, et al., 1995). Similarly, we noted a significant alcoholinduced reduction in urinary Na+ and K+ excretion and reduced urine flow when white wine is consumed prior to food (Kokavec, 2000). However, when we compared the level of urinary K+ and urinary Na+ in our study with urinary electrolyte data collected after several days fasting in non-obese individuals (Elia, Crozier, & Neale, 1984), we were surprised to find that the electrolyte data was very similar after 40 g alcohol despite participants being only mildly fasted prior to alcohol consumption. Both alcohol and cortisol can promote the release of K+ from intracellular stores although the K+ loss induced by alcohol was noted to be much larger (Streeton & Solomon, 1954). Moreover, the lack of cell shrinkage observed in experiments demonstrates that the release of K+ from intracellular stores is compensated by a Na+ gain that more than doubles the glucose consumption by cells at higher alcohol concentrations (Nelson, 1944; Ponder, 1946). Researchers have proposed that the alcohol-induced increase in K+ efflux is probably due to extracellular K+ directly antagonising the intoxicating effect of alcohol in the CNS (Israel, Kalant, & Laufer, 1965). Glucose is required for cellular K+ influx and efflux, and it is noteworthy that the alcohol-induced increase in K+ efflux is associated with double the demand for glucose by cells (Streeton & Solomon, 1954). An increased movement of K+ into the extracellular compartment can promote GABA release by astrocytes in order to reduce brain excitability (Albrecht, Bender, & Norenberg, 1998). A decrease in cortisol and deactivation of the HPA axis is thus beneficial as under these circumstances this would increase glucose availability for glia (Kandel, Schwartz, & Jessell, 1991), and protect against excessive potassium-induced neuronal depolarization (Hamberger, Nystrom, Sellstrom, & Woiler, 1976). Consuming white wine prior to food, despite promoting a significant reduction in steroid hormones (Kokavec & Crowe, 2001a), may therefore due to impaired salt and water balance (for review see Kokavec & Crowe, 2001b) increase NPY mRNA in the ARC. Although, inactivation of NMDA receptors could prevent NPY in the ARC from influencing hypothalamic neuronal activity and instead may reduce glutamate release at presynaptic terminals and/or promote glutamate resistance. Therefore, the DHEAS and insulin data together may suggest modulation of NPY in PVN due to glutamate resistance, and the PVN is where a large concentration of GABAergic neurons are located (Belousov & van den Pol, 1997). While fasting can increase the palatability and consumption of alcohol (Hansen, Fahlke, Soderpalm, & Hard, 1995; Soderpalm & Hansen, 1999), ADX can significantly decrease alcohol intake under fasting conditions (Fahlke, Hard, & Hansen, 1996; Hansen et al., 1995). An alcohol-induced increase in K+ efflux (Streeton &

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Solomon, 1954) could potentially increase NPY release in PVN (Stricker-Krongrad et al., 1993). Therefore, it is possible that deactivation of the HPA axis occurs (Kokavec & Crowe, 2001a, 2001b) in order to inhibit NPY activity in PVN (White et al., 1990) and subsequently inhibit alcohol consumption. NPY-induced feeding behaviour in the PVN appears to be specifically related to appetite for carbohydrate (Stanley & Leibowitz, 1984) and while a lack of glucocorticoids will notably decrease carbohydrate intake (Tempel & Leibowitz, 1989), an absence of NPY in PVN will also reduce ethanol self-administration (Kelley, Nannini, Bratt, & Hodge, 2001). Thus, under fasting conditions the consumption of white wine may reduce appetite for carbohydrate but alcohol self-administration is also not promoted.

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The alcohol-induced elevation in DHEAS by inhibiting GABA uptake at the GABAA receptor could promote an increase in NPY mRNA in ARC and NPY level in PVN via potentiation of NMDA receptors (Kim et al., 2000). Moreover, a significant decrease in insulin (Kokavec & Crowe, 2003) adds further support for an alcohol-induced increase in NPY mRNA in ARC. However, a significant alcohol-induced decrease in cortisol was also observed (Kokavec & Crowe, 2001b), which could modulate the transcription of NPY in ARC (Dean & White, 1990) and reduce the level of NPY in PVN (Ponsalle, Srivastava, Uht, & White, 1992; Sato et al., 2005; Savontaus, Conwell, & Wardlaw, 2002; Strack et al., 1995). Therefore, white wine consumption after a meal probably does not promote appetite for food or alcohol self-administration. Effects of red versus white wine

Food after alcohol The consumption of food after white wine can significantly reduce DHEAS and promote an increase in salivary cortisol concentration (Kokavec & Crowe, 2001a). Laboratory investigations have demonstrated that ethanol administration prior to ingestion of a glucose load (McMonagle & Felig, 1975) can potentiate the glucose stimulating properties of insulin and promote a rapid release of insulin (O’Keefe & Marks, 1977). Similarly, we observed a significant elevation in plasma insulin when food was consumed after a moderate amount of white wine had already been ingested (Kokavec, 2000). The rapid release of insulin that was noted when food is consumed after white wine (Kokavec, 2000) could reduce NPY gene transcription in ARC (Schwartz, Sipols, et al., 1992). Furthermore, the significantly reduced level of DHEAS that was observed when food is consumed after white wine (Kokavec & Crowe, 2001a) could promote a cascade of events commencing with increased GABA uptake at the GABAA receptor and then may involve inhibition of NPY in the ARC on hypothalamic neuronal activity, reduced glutamate release, and promotion of glutamate resistance (Belousov & van den Pol, 1997). Therefore, the DHEAS and insulin data could be highlighting that an NPY deficient state develops when food is consumed after white wine. Alcohol consumption and resistance may be inversely related to NPY levels in the brain (Badia-Elder et al., 2003; Thiele et al., 1998; Thiele & Badia-Elder, 2003). Furthermore, a food-induced increase in cortisol may encourage alcohol consumption (Fahlke & Eriksson, 2000; Fahlke et al., 1996; Hansen et al., 1995). Thus, the white wine hormonal data suggests that when food is consumed after white wine appetite for carbohydrate could be inhibited and alcohol selfadministration promoted. Alcohol after food The effect of white wine on steroid hormones and glucose utilization and metabolism may be dependent on the prior nutritional status of the individual. Consuming white wine alone after a meal can promote a significant elevation in DHEAS together with a significant decrease in cortisol (Kokavec & Crowe, 2001a), plasma insulin (Kokavec & Crowe, 2003), urinary K+ excretion (Kokavec, 2000) and a trend for a lowering of plasma glucose (Kokavec & Crowe, 2003). Our findings are consistent with rodent studies where it has been shown that ethanol treatment following glucose administration can promote a marked inhibition of glucose-induced insulin secretion (Holley, Bagby, & Curry, 1981; Tiengo, Valerio, Molinari, Meneghel, & Lapolla, 1981). Therefore, this together could highlight that white wine may alter glucose utilization and metabolism.

The effect of alcohol on the HPA axis may be dependent on the type of alcoholic beverage consumed. In the past, we have assessed a number of commercially available alcoholic beverages and found that the consumption of red wine and white wine under similar experimental conditions does not necessarily produce the same effect on the HPA axis. The effect of alcohol on the HPA axis may be dependent on not only the prior nutritional status of the individual but also the nutritional content of the alcoholic product being tested. While most alcoholic beverages contain varying amounts of histamine (Lonvaud-Funel, 2001), red wine is unique in that red wine contains a higher level of histamine when compared to other alcoholic products (Wantke, Gotz, & Jarisch, 1994) and (unlike other alcoholic beverages) can also promote histamine release (Intorre et al., 1996). Therefore, given that histamine can promote ACTH release (Knigge, Alsbjorn, Thuesen, Siemssen, & Christiansen, 1988), the precursor for steroidgenesis (Endoh, Kristiansen, Casson, Buster, & Hornsby, 1996) it would not be unreasonable to assume that red wine may also influence the HPA axis differently to other alcoholic beverages. When we assessed the effect of red wine on the HPA axis prior to food intake it became clear that the amount of red wine being ingested was a very important factor. We observed that consumption of <15 g alcohol can produce a highly variable increase in salivary cortisol, an immediate decrease in salivary DHEAS, and ketone production is maintained. In contrast, ingestion of 2–3 standard units of red wine (20–30 g alcohol) can decrease cortisol concentration, significantly increase salivary DHEAS, promote an increase in urine flow, and halt ketone production in all participants. After ingestion of four standard units of red wine (40 g alcohol) the concentration of salivary cortisol increases slightly, DHEAS remains significantly elevated, urine flow remains unaltered, and ketone bodies are not produced (Lindner, 2006). Thus, the red wine data suggests that glucose transport and utilization in astrocytes (Virgin et al., 1991) is initially reduced and activation of GABAA receptors is promoted (Demirgoren et al., 1991; Majewska et al., 1990). Alternatively, ingestion of 2–3 standard units of red wine (20–30 g alcohol) may increase glucose transport and utilization in astrocytes and promote activation of NMDA receptors due to inhibition of GABA. Following ingestion of four standard units of red wine (40 g alcohol) activation of NMDA receptors may continue to be promoted and NPY mRNA in ARC and NPY release in PVN may increase (Kim et al., 2000). Increased activity of brain histamine may suppress food intake (Sakata, Kurokawa, Oohara, & Yoshimatsu, 1994; Sakata, Tamari, Kang, & Yoshimatsu, 1994) in the VMH and PVN (Fukagawa et al., 1989; Ookuma et al., 1993) and may alter glucose metabolism (Nishibori, Oishi, Itoh, & Saeki, 1987). The role of histamine in the brain is to enhance the supply of glucose to cells when the

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organism is presented with a metabolic challenge (Thomas et al., 1995). Activation of hypothalamic histamine in response to glucoprivation may modulate homeostatic control of energy supply in the brain by activating glycogenolysis during energy depletion. Thus, histamine in response to an energy deficit may play an essential role in glucose utilization through glycogenolytic processes in the hypothalamus (Sakata, Kurokawa, et al., 1994; Sakata, Tamari, et al., 1994). We observed that ketone production stopped in nearly all participants when red wine is consumed (>30 g alcohol) despite participants not having eaten any food for at least 8 h. Thus, the ketone data suggests that the energy needs of the brain are being met by some other means when red wine is consumed. Fasting increases the palatability and consumption of alcohol (Hansen et al., 1995; Soderpalm & Hansen, 1999). Moreover, glucocorticoids promote alcohol consumption in alcohol preferring rodents (Fahlke et al., 1996; Fahlke & Eriksson, 2000; Hansen et al., 1995) and an elevation of NPY levels in the PVN potently increases ethanol self-administration in rodents (Kelley et al., 2001). Therefore, the red wine data could suggest caution when consuming red wine prior to food with more than three standard units of red wine (>30 g alcohol) prior to food possibly increasing the palatability of red wine and subsequently encouraging more red wine to be consumed. Alcohol containing carbohydrate Consuming beer, a product containing alcohol, various minerals, and approximately 8 g carbohydrate (Borushek, 1998), prior to food can promote a significant elevation in the level of fasting salivary DHEAS after only one standard unit of regular beer (i.e. 10 g alcohol) is ingested. Cortisol was immediately lowered and an increase in cortisol was only observed after 40 g alcohol had been consumed. An inverse relationship was observed when the level of DHEAS was compared under beer and high carbohydrate placebo conditions. Although, (unlike white wine), ketones were not produced in any participant after 30 g alcohol was consumed (Ryan, 2007). The initial alcohol-induced elevation in DHEAS by inhibiting GABA uptake at the GABAA receptor could promote an increase in NPY mRNA in ARC and NPY level in PVN via potentiation of NMDA receptors (Kim et al., 2000). However, an alcohol-induced decrease in cortisol could modulate the transcription of NPY in ARC (Dean & White, 1990) and reduce the level of NPY in PVN (Savontaus et al., 2002; Ponsalle et al., 1992; Strack et al., 1995; Sato et al., 2005). Therefore, consuming one standard unit of beer (10 g alcohol) probably does not promote appetite for carbohydrate or alcohol self-administration. Simultaneous administration of ethanol and glucose can decrease the insulin response (Singh, Patel, & Snyder, 1980). Alternatively, consuming alcohol with carbohydrate (Marks, 1978) can elevate insulin (O’Keefe & Marks, 1977). An antagonistic relationship is known to exist between insulin and DHEAS (Kaplan & Pesce, 1996) and it may be that as more beer is consumed the carbohydrate content of beer could be sufficient to exert some influence on the level of fasting insulin. The significant decrease in DHEAS observed after 30 g alcohol suggests this may be the case (Ryan, 2007). Thus, the steroid data when combined with early insulin findings could imply that consuming 20–30 g alcohol containing carbohydrate decreases NPY gene expression in ARC, which could promote NPY deficiency by subsequently reducing NPY in PVN (Schwartz, Sipols, et al., 1992). However, an increase in cortisol was noted after 40 g alcohol, which could suggest an increase in the transcription rate of NPY mRNA (Dean & White, 1990) and subsequent increase in alcohol self administration

(Kelley et al., 2001). Therefore, the effect of beer on appetite for food and alcohol may be dependent on the amount of beer being consumed. Sugar preference in abstinent and non-abstinent alcoholics Preference for a high concentration of sucrose is often observed in alcoholics compared to controls (Kampov-Polevoy et al., 1998). Alcohol intoxication can significantly blunt the ACTH/cortisol response to CRF administration (Waltman, Blevins, Boyd, & Wand, 1993) in males with a family history of alcoholism (Waltman, McCaul, & Wand, 1994) and this may be due to decreased pituitary responsiveness to CRF (Inder, Joyce, Ellis, et al., 1995; Inder, Joyce, Wells, et al., 1995). Moreover, deactivation of the HPA axis can increase consumption of sweet solutions containing sucrose but not saccharin. Glucocorticoids inhibit (Laugero, Bell, Bhatnagar, Soriano, & Dallman, 2001) and ADX increases (Fuxe, Hokfelt, Jonnson, Levine, & Lofstrom, 1973; Watts & Sanchez-Watts, 1995) expression of CRF a known precursor of ACTH, in the PVN. Furthermore, the behavioural effects of ADX include a reduction in food intake, depression of lipogenesis, and disruption of drinking behaviour (Bell et al., 2000; Bhatnagar et al., 2000). ADX animals do not voluntarily consume very much saccharin and ingestion of saccharin does not correct the imbalances associated with the absence of steroids (Bhatnagar et al., 2000). In contrast, ingestion of sucrose can normalize CRF expression in hypothalamus (Laugero et al., 2001), correct ACTH secretion (Bell et al., 2000), and restore insulin (Laugero et al., 2001) in ADX rats. Thus, sucrose has the ability to restore the energy imbalance caused by an absence of cortisol. Clinical reports indicate that abstinent alcoholics consume significantly more sucrose in the first 30 days during detoxification when compared to those who do not remain alcohol free (Yung, Gordis, & Holt, 1983). Eating sweets can promote sobriety in recovering alcoholics (Farkas & Dwyer, 1984). Therefore, given that a link between sucrose and activity of the HPA axis has been reported (Laugero et al., 2001) it is possible that the increased sucrose intake is associated with the emergence of pseudo-Cushing’s syndrome (Kapcala, 1987) in the 3–4 weeks following alcohol abstinence (Proto, Barberi, & Bertolissi, 1985; Willenbring et al., 1984). Acute administration of alcohol has often been shown to increase plasma cortisol. Evidence has been presented which shows that alcohol can promote a decreased binding to albumin and cortisol-binding globulin, which could lead to an increase in the plasma unbound component and decreased transport to target areas including the brain. Alcohol stimulates the HPA axis by increasing ACTH secretion and this has been attributed to alcohol promoting a cortisol resistant state. Alcohol can decrease binding of cortisol to glucocorticoid receptors, which would render cortisol relatively ineffective in cortisol-responsive cells and over time the deficiency of cortisol will result in the organism increasing the number of glucocorticoid receptors (Hiramatsu & Nisula, 1989). Alcohol abstinence initially could thus be associated with hypercortisolism until sufficient time has elapsed allowing for the organism to adapt to the lack of alcohol. Similarly, during fasting the organism can compensate for the lack of carbohydrate by increasing the number of NPY receptors in PVN (White et al., 1990). Moreover, consuming alcohol under certain conditions may alter NPY mRNA in ARC, NPY level in the PVN, and the way the organism uses energy. Therefore, I would like to suggest that sugar preference may be due to over activation of an abnormally large number of glucocorticoid and NPY receptors. In contrast, alcohol consumption does not promote appetite for sugar due to under activation of glucocorticoids receptors and cortisolresistance.

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Alcohol and lipogenesis Recently there have been many claims in the media that alcohol does not promote weight gain and may even contribute to weight loss. The pentose phosphate pathway is an energy pathway related to lipid synthesis and glucose-6-phosphate dehydrogenase (G6PDH) is the rate-limiting enzyme of the oxidative branch of the pentose phosphate pathway (Ayene et al., 2002). Animal studies have shown that ethanol administration can promote a significant reduction in G6PDH (Buyukokuroglu, Altikat, & Ciftci, 2002), under fasting and feeding conditions (Oh, Kim, Chun, & Park, 1998). Insulin is a known inducer of G6PDH activity (Stapleton et al., 1993) and we have already observed that some forms of alcohol when consumed under fasting conditions will not elevate plasma insulin (Kokavec & Crowe, 2006). Moreover, alcohol immediately following a meal may promote a significant decrease in the level of plasma insulin (Kokavec & Crowe, 2003), supporting the conclusion that G6PDH activity (Buyukokuroglu et al., 2002; Oh et al., 1998) and lipogenesis is not promoted when alcohol is consumed. Transcription of the G6PDH gene is usually elevated following ingestion of a high-carbohydrate diet and mRNA stability is also increased (Prostko, Fritz, & Kletzien, 1989). During fasting, when carbohydrate intake is low, glucocorticoids alone have little effect on the rate of G6PDH activity (Stumpo & Kletzien, 1985). The role of glucocorticoids on G6PDH mRNA is a permissive one with glucocorticoids amplifying the insulin effect on G6PDH synthesis (Manos, Nakayama, & Holten, 1991; Stumpo, Prostko, & Kletzien, 1985), which implies that the amount of G6PDH mRNA is modulated by these two hormones (Fritz, Stumpo, & Kletzien, 1986). A direct effect of DHEAS is the inhibition of G6PDH (Ursini, Parrella, Rosa, Salzano, & Martini, 1997). Thus, a significant decrease in DHEAS can promote lipogenesis. A low level of DHEAS in the past has been linked to obesity (Jakubowicz, Beer, Beer, & Nestler, 1995) and it is possible that consuming >15 g alcohol in the form of beer prior to food, or food after wine could promote lipogenesis. Alteration of energy metabolism? In the past, we have drawn attention to the fact that alcohol may not be a food for the human body (for review see Kokavec & Crowe, 2002). The known human energy systems are not able to utilize alcohol as an energy source because pyruvate cannot be produced from alcohol. In contrast, plants and anaerobic organisms are able to utilize the stored energy in alcohol via activation of the glyoxylate cycle, a gluconeogenic pathway responsible for the conversion of fat into carbohydrate (Stryer, 1995). The TCA cycle and the glyoxylate cycle compete for a common substrate and the metering of flux between these two pathways is determined by the presence or absence of glucose (LaPorte, Walsh, & Koshland, 1984). Alcohol-induced increase in K+ efflux is associated with double the demand for glucose by cells (Streeton & Solomon, 1954) and acetate in addition to glucose may be metabolised by astrocytes in order to increase the amount of energy available to glial cells. Astrocytes preferentially oxidize acetate and the rate of acetate oxidization is similar to glucose (Dienel & Cruz, 2006). The glyoxylate cycle is very active during steady growth on acetate and flow through the pathway is regulated by inhibitory phosphorylation of isocitrate dehydrogenase (LaPorte et al., 1984). While the TCA and glyoxylate cycles may at first appear similar a major difference between the two energy pathways is that the glyoxylate cycle omits the steps in the TCA cycle requiring activation of thiamine dependent enzymes (Stryer, 1995). When alcohol enters the body the ability of cells to maintain the store of thiamine is severely compromised (Thomson, Baker, & Leevy, 1970; Zimatkin &

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Zimatkina, 1996). Furthermore, extended periods of alcohol consumption can cause thiamine deficiency (Martin et al., 1985), even in well-nourished individuals (Rathanaswami & Sundaresan, 1991). Thus, given that thiamine is required for the biosynthesis of insulin and alcohol can promote thiamine deficiency (Rathanaswami & Sundaresan, 1991; Thomson et al., 1970; Zimatkin & Zimatkina, 1996), an alcohol-induced alteration in insulin may occur when alcohol is consumed alone (Kokavec & Crowe, 2003). The glyoxylate cycle may have a role in intermediary metabolism in the human liver (Holmes & Assimos, 1998). The key enzymes associated with the glyoxylate cycle can become active in the human liver after 3–4 days fasting (Masters, 1997), allowing lipid to be converted into carbohydrate. When white wine is consumed under fasting conditions we observed a significant alteration in urinary electrolytes (Kokavec, 2000) similar to what has previously been observed in non-obese individuals after several days fasting (Elia et al., 1984). It is well known that alcohol can elevate serum triglycerides in alcoholics (Lieber, 1989) and the glyoxylate hypothesis offers an explanation for the liver problems and thiamine deficiency often observed in alcoholic individuals. Moreover, it can explain the malnutrition and the lack of appetite for carbohydrate as the body is producing its own from lipid. It has already been suggested that activation of the glyoxylate cycle may contribute to the development of diabetes (Song, 2000). DHEAS is influenced by heredity factors (Baulieu, 1996) and a decrease in DHEAS can increase the risk of diabetes (Small, Gray, Beastall, & MacCuish, 1989) and immune dysregulation (Daynes, Dudley, & Araneo, 1990; Hennebold & Daynes, 1994), suggesting the consumption of some form of alcohol under specific conditions may place some individuals at increased risk. Summary The aim of this paper was to attempt to stimulate discussion on the alcohol toxicity versus nutritional deficiency debate by proposing that one of the specific effects of alcohol toxicity may be to discourage carbohydrate intake. From the evidence presented above it would appear that an alteration in appetite for carbohydrate may occur but this could be dependent on certain conditions being met. Furthermore, enhanced appetite for carbohydrate may be a feature of detoxification due to the effect of alcohol on hormonal processes. It is tempting to conclude that consuming white wine under fasting conditions would be (more) likely than other commercially available alcohol products to activate the glyoxylate cycle (if at all). However, what is clear is that consuming commercially available alcohol alone prior to a meal should not be encouraged. The material presented in this review is by no means extensive and has merely focussed on some of the more established biochemical aspects of carbohydrate intake regulation. There are several other biochemical factors associated with food intake (e.g. cholecystokinin, leptin, ghrelin) that have not been mentioned, and probably many more factors that remain to be discovered. However, this review serves as a good starting point to perhaps make us start to question the initial cause of the malnutrition commonly observed in alcoholics. It is possible that a consequence of alcohol consumption under certain conditions may be to promote an alteration in biochemical processes such that carbohydrate intake is discouraged and a malnourished state is encouraged. References Agarwal, D. P., & Goedde, H. W. (1989). Enzymology of alcohol degradation. In H. W. Goedde & D. P. Agarwal (Eds.), Alcoholism: Biomedical and genetic aspects. New York: Pergamon Press Inc.

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