Cost-based anorexia: A novel framework to model anorexia nervosa.

Anorexia nervosa (AN) is an eating disorder that is thought to emerge through biological predisposition(s) within sociocultural context(s). Practical and ethical concerns limit study of the etiology of this disorder in humans, and in particular the biological aspects. Laboratory animal models have a pivotal role in advancing our understanding of the neurobiological, physiological and behavioral aspects of this disorder, and developing new treatment strategies. One shortcoming of animal models, including activity based anorexia (ABA) in rodents, is that they cannot fully capture the contextual aspects of AN. In this article we discuss the merits of an alternate approach, cost-based anorexia (CBA). CBA is conceptually founded in behavioral economics and its magnitude is influenced by several relevant contextual aspects of feeding.

Effects of Opioid Antagonism on Cerebrospinal Fluid Melanocortin Peptides and Cortisol Levels in Humans.

CONTEXT: Hypothalamic proopiomelanocortin (POMC) is processed to α-melanocyte-stimulating hormone, which interacts with the melanocortin antagonist agouti-related protein (AgRP), to regulate energy balance. The POMC-derived opioid peptide ß-endorphin (ß-EP) also affects feeding behavior via interactions with brain µ-opioid receptors (MORs), including autoinhibitory interactions with MOR expressed by POMC neurons. The opioid antagonist naltrexone (NTX) stimulates POMC neurons in rodents and decreases food intake. OBJECTIVE AND DESIGN: The effect of NTX on brain POMC in humans was assessed by measuring POMC peptide concentrations in lumbar cerebrospinal fluid (CSF). AgRP and cortisol levels were also measured because both are inhibited by opioids. In a double-blinded crossover study, 14 healthy subjects were given NTX (50 mg daily) or placebo for either 2 or 7 days. RESULTS: CSF ß-EP levels increased after 2 and 7 days of NTX treatment; CSF POMC levels did not change, but the ß-EP-to-POMC ratio increased. CSF AgRP levels did not change, but plasma AgRP levels tended to increase after NTX (P = 0.06). Cortisol increased in plasma and CSF after NTX treatment; these changes correlated positively with changes in AgRP levels. CONCLUSION: Opioid antagonism stimulates POMC peptide release into CSF in humans. The increase in the CSF ß-EP-to-POMC ratio could indicate selective release of processed peptides or an effect on POMC processing. Furthermore, AgRP and cortisol stimulation by NTX may mitigate POMC-induced decrease in food intake. It remains to be determined if biomarkers in CSF and plasma could be used to predict responses to pharmacotherapy targeting the melanocortin system.

Evaluation of CSF and plasma biomarkers of brain melanocortin activity in response to caloric restriction in humans.

The melanocortin neuronal system, which consists of hypothalamic proopiomelanocortin (POMC) and agouti-related protein (AgRP) neurons, is a leptin target that regulates energy balance and metabolism, but studies in humans are limited by a lack of reliable biomarkers to assess brain melanocortin activity. The objective of this study was to measure the POMC prohormone and its processed peptide, ß-endorphin (ß-EP), in cerebrospinal fluid (CSF) and AgRP in CSF and plasma after calorie restriction to validate their utility as biomarkers of brain melanocortin activity. CSF and plasma were obtained from 10 lean and obese subjects after fasting (40 h) and refeeding (24 h), and from 8 obese subjects before and after 6 wk of dieting (800 kcal/day) to assess changes in neuropeptide and hormone levels. After fasting, plasma leptin decreased to 35%, and AgRP increased to 153% of baseline. During refeeding, AgRP declined as leptin increased; CSF ß-EP increased, but POMC did not change. Relative changes in plasma and CSF leptin were blunted in obese subjects. After dieting, plasma and CSF leptin decreased to 46% and 70% of baseline, CSF POMC and ß-EP decreased, and plasma AgRP increased. At baseline, AgRP correlated negatively with insulin and homeostasis model assessment (HOMA-IR), and positively with the Matsuda index. Thus, following chronic calorie restriction, POMC and ß-EP declined in CSF, whereas acutely, only ß-EP changed. Plasma AgRP, however, increased after both acute and chronic calorie restriction. These results support the use of CSF POMC and plasma AgRP as biomarkers of hypothalamic melanocortin activity and provide evidence linking AgRP to insulin sensitivity.

Effects of prior cocaine versus morphine or heroin self-administration on extinction learning driven by overexpectation versus omission of reward.

BACKGROUND: Addiction is characterized by an inability to stop using drugs, despite adverse consequences. One contributing factor to this compulsive drug taking could be the impact of drug use on the ability to extinguish drug seeking after changes in expected outcomes. Here, we compared effects of cocaine, morphine, and heroin self-administration on two forms of extinction learning: standard extinction driven by reward omission and extinction driven by reward overexpectation. METHODS: In experiment 1, we trained rats to self-administer cocaine, morphine, or sucrose for 3 hours per day (limited access). In experiment 2, we trained rats to self-administer heroin or sucrose for 12 hours per day (extended access). Three weeks later, we trained the rats to associate several cues with palatable food reward, after which we assessed extinction of the learned Pavlovian response, first by pairing two cues together in the overexpectation procedure and later by omitting the food reward. RESULTS: Rats trained under limited access conditions to self-administer sucrose or morphine demonstrated normal extinction in response to both overexpectation and reward omission, whereas cocaine-experienced rats or rats trained to self-administer heroin under extended access conditions exhibited normal extinction in response to reward omission but failed to show extinction in response to overexpectation. CONCLUSIONS: Here we show that cocaine and heroin can induce long-lasting deficits in the ability to extinguish reward seeking. These deficits were not observed in a standard extinction procedure but instead only affected extinction learning driven by a more complex phenomenon of overexpectation.

Sexually dimorphic functional connectivity in response to high vs. low energy-dense food cues in obese humans: an fMRI study.

Sexually-dimorphic behavioral and biological aspects of human eating have been described. Using psychophysiological interaction (PPI) analysis, we investigated sex-based differences in functional connectivity with a key emotion-processing region (amygdala, AMG) and a key reward-processing area (ventral striatum, VS) in response to high vs. low energy-dense (ED) food images using blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) in obese persons in fasted and fed states. When fed, in response to high vs. low-ED food cues, obese men (vs. women) had greater functional connectivity with AMG in right subgenual anterior cingulate, whereas obese women had greater functional connectivity with AMG in left angular gyrus and right primary motor areas. In addition, when fed, AMG functional connectivity with pre/post-central gyrus was more associated with BMI in women (vs. men). When fasted, obese men (vs. women) had greater functional connectivity with AMG in bilateral supplementary frontal and primary motor areas, left precuneus, and right cuneus, whereas obese women had greater functional connectivity with AMG in left inferior frontal gyrus, right thalamus, and dorsomedial prefrontal cortex. When fed, greater functional connectivity with VS was observed in men in bilateral supplementary and primary motor areas, left postcentral gyrus, and left precuneus. These sex-based differences in functional connectivity in response to visual food cues may help partly explain differential eating behavior, pathology prevalence, and outcomes in men and women.

Anorexia of aging and gut hormones.

We are expected to live longer than if we had been born 100 years ago however, the additional years are not necessarily spent in good health or free from disability. Body composition changes dramatically over the course of life. There is a gradual increase in body weight throughout adult life until the age of about 60-65 years. In contrast, body weight appears to decrease with age after the age of 65-75 years, even in those demonstrating a previous healthy body weight. This age related decrease in body weight, often called unintentional weight loss or involuntary weight loss can be a significant problem for the elderly. This has been shown to be related to decline in appetite and food intake is common amongst the elderly and is often referred to the anorexia of aging. Underlying mechanisms regulate energy homeostasis and appetite may change as people age. In this review, peripheral factors regulating appetite have been summarized in regards to their age-dependent changes and role in the etiology of anorexia of aging. Understanding the alterations in the mechanisms regulating appetite and food intake in conjunction with aging may help inform strategies that promote healthy aging and promote health and wellbeing in the elderly years, with the end goal to add life to the years and not just years to our lives.

Comparison of body adiposity index (BAI) and BMI with estimations of % body fat in clinically severe obese women.

OBJECTIVE: Body adiposity index (BAI), a new surrogate measure of body fat (hip circumference/(height(1.5) - 18)), has been proposed as an alternative to body mass index (BMI). We compared BAI with BMI, and each of them with laboratory measures of body fat-derived from bioimpedance analysis (BIA), air displacement plethysmography (ADP), and dual-energy X-ray absorptiometry (DXA) in clinically severe obese (CSO) participants. DESIGN AND METHODS: Nineteen prebariatric surgery CSO, nondiabetic women were recruited (age = 32.6 ± 7.7 SD; BMI = 46.5 ± 9.0 kg/m(2) ). Anthropometrics and body fat percentage (% fat) were determined from BIA, ADP, and DXA. Scatter plots with lines of equality and Bland-Altman plots were used to compare BAI and BMI with % fat derived from BIA, ADP, and DXA. BAI and BMI correlated highly with each other (r = 0.90, P < 0.001). RESULTS: Both BAI and BMI correlated significantly with % fat from BIA and ADP. BAI, however, did not correlate significantly with % fat from DXA (r = 0.42, P = 0.08) whereas BMI did (r = 0.65, P = 0.003). BMI was also the single best predictor of % fat from both BIA (r(2) = 0.80, P < 0.001) and ADP (r(2) = 0.65, P < 0.001). The regression analysis showed that the standard error of the estimate (SEE), or residual error around the regression lines, was greater for BAI comparisons than for BMI comparisons with BIA, ADP, and DXA. Consistent with this, the Bland and Altman plots indicated wider 95% confidence intervals for BAI difference comparisons than for BMI difference comparisons for their respective means for BIA, ADP, and DXA. CONCLUSIONS: Thus, BAI does not appear to be an appropriate proxy for BMI in CSO women.

Sex-based fMRI differences in obese humans in response to high vs. low energy food cues.

Gender specific effects on human eating have been previously reported. Here we investigated sex-based differences in neural activation via whole-brain blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) in response to high energy-dense (high-ED) vs. low-ED visual and auditory food cues in obese men vs. women in both fed and fasted states. The results show that in response to high vs. low ED foods in the fed state, obese men (vs. women) had greater activation in brain areas associated with motor control regions (e.g. supplementary motor areas) whereas women showed greater activation in cognitive-related regions. In the fasted state, obese men had greater activation in a visual-attention region whereas obese women showed greater activation in affective and reward related processing regions (e.g. caudate). Overall the results support our a priori hypothesis that obese women (vs. men) have greater neural activation in regions associated with cognition and emotion-related brain regions. These findings may improve our understanding of sex specific differences among obese individuals in eating behavior.

Ghrelin and eating disorders.

There is growing evidence supporting a multifactorial etiology that includes genetic, neurochemical, and physiological components for eating disorders above and beyond the more conventional theories based on psychological and sociocultural factors. Ghrelin is one of the key gut signals associated with appetite, and the only known circulating hormone that triggers a positive energy balance by stimulating food intake. This review summarizes recent findings and several conflicting reports on ghrelin in eating disorders. Understanding these findings and inconsistencies may help in developing new methods to prevent and treat patients with these disorders.

Plasma cortisol levels in response to a cold pressor test did not predict appetite or ad libitum test meal intake in obese women.

Heightened cortisol response to stress due to hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis may stimulate appetite and food intake. In this study, we assessed cortisol responsivity to a cold pressor test (CPT) as well as appetite ratings and subsequent test meal intake (TMI) in obese women. Following an overnight fast on two counterbalanced days, 20 obese women immersed their non-dominant hand for 2min in ice water (CPT) or warm water (WW) as a control. Plasma cortisol (ng/ml), heart rate, and blood pressure, as well as ratings of stress, pain, and appetite, were serially acquired. An ad libitum liquid meal was offered at 45min and intake measured covertly. Fasting cortisol was higher at 15min (mean peak cortisol) following the CPT compared to WW. Higher stress was reported at 2 and 15min for the CPT compared to WW. Pain, an indirect marker of the acute stress, systolic and diastolic blood pressure increased following the CPT at 2min compared to WW. Hunger decreased after the CPT at 2 and 15min, and desire to eat ratings were lower following CPT compared to WW. Subjects did not have greater test meal intake (TMI) following CPT compared to WW. There was also no significant relationship between cortisol levels following stress and TMI, indicating that cortisol did not predict subsequent intake in obese women.

Neural responsivity to food cues in fasted and fed states pre and post gastric bypass surgery.

Reductions in mesolimbic responsivity have been noted following Roux-en-Y gastric bypass (RYGB; Ochner et al., 2011a). Given potential for postoperative increases in postprandial gut (satiety) peptides to affect mesolimbic neural responsivity, we hypothesized that: (1) post RYGB changes in mesolimbic responsivity would be greater in the fed relative to the fasted state and; (2) fasted vs. fed state differences in mesolimbic responsivity would be greater post-relative to pre-surgery. fMRI was used to asses neural responsivity to high- and low-calorie food cues in five women 1 mo pre- and 1 mo post-RYGB. Scans were repeated in fasted and fed states. Significant post RYGB decreases in the insula, ventromedial prefrontal cortex (vmPFC) and dorsolateral prefrontal cortex (dlPFC) responsivity were found in the fasted state. These changes were larger than neural changes in the fed state, which were non-significant. Preoperatively, fasted vs. fed differences in neural responsivity were greater in the precuneus, with large but nonsignificant clusters in the vmPFC and dlPFC. Postoperatively, however, no fasted vs. fed differences in neural responsivity were noted. Results were opposite to that predicted and appear inconsistent with the initial hypothesis that postoperative increases in postprandial gut peptides are the primary driver of postoperative changes in neural responsivity.

Effects of meal frequency and snacking on food demand in mice.

Ad libitum feeding patterns in mice show substantial differences between laboratories, in addition to large individual and time-of-day differences. In the present study, we examine how mice work for food when access to food is temporally restricted and so they are forced to take discrete meals. In a first experiment, separate groups of ICR:CD1 mice were given access to food for 4, 8 or 16 opportunities or meals per day, with the duration of access at each opportunity adjusted reciprocally so that the total time of availability was 160 min per day in all three conditions. During the periods of availability, mice were able to earn food pellets by nose poke responses, according to an incrementing series of fixed unit prices (FUP: 2, 5, 10, 25) with each schedule in force for 3-4 days. Total food intake was similar in all three groups, indicating that mice generally were able to adjust their intake to a range of temporal availabilities. In each group, food demand fell as FUP increased. In the 8 and 16 meal groups, no food was eaten in many of the opportunities. Within an opportunity, the rate of intake generally declined with time, indicative of satiation. At low FUPs, later opportunities in each day were associated with smaller meals than earlier opportunities; in contrast, at high FUPs the first opportunity was also a small meal. Collectively, these results show that mice eat less at higher costs but not because of time constraints of the schedule: instead, they exhibit an elective anorexia. In the second experiment, we examined whether snacking between imposed meals would affect subsequent meal(s). Mice were adapted to the foregoing 8 opportunity protocol. Then, half the mice received free snacks of sugar cubes after the 3rd, 4th and 5th meal opportunities and the intakes of sugar and pellets were examined at low and high unit costs for pellets (FUP2 and 25). At FUP2, mice decreased demand for pellets and compensated energetically for the sugar they consumed. At FUP25, mice also decreased demand, but by less than the energy obtained from sugar. These data show that choice for pellets over a free palatable snack, and subsequent compensation of energy intake, is modified by effort and demand.

Structure of motivation using food demand in mice.

Most animals have evolved to be foragers for food. We discriminate two types of foraging, the cost to locate or obtain access to the food, and the unit cost to consume the food once it is nearby. Using closed economy studies in normal weight and genetically obese mice, we have examined the effect of either access and/or unit cost on food demand and meal patterns. We also have included wheel running either as a voluntary activity or as an access cost. Our results showed that the demand functions differ between normal, exercising, and genetically obese mice, and that changes in intake normally occur via changes in the size of individual feeding bouts or meals. In contrast, changes in access cost have only a small effect on food demand but have large effects on the pattern of intake--on meal size and the number of meals taken. Thus, although food intake is sensitive to effort, the type of effort and the mode in which it is applied is critically important. These data are discussed in terms of potential economic strategies that could address the human obesity epidemic, for example by maximally targeting meal size and/or snacking behavior.

Comparison of voluntary and foraging running wheel activity on food demand in mice.

The effects of running wheel activity on food intake and meal patterns were measured under several cost conditions for food in CD1 mice. In a first experiment, voluntary wheel running activity increased daily food intake relative to a sedentary group, and runners consumed bigger but fewer meals. Although they ate more, runners had significantly lower body fat than sedentary mice. In a second experiment, running was used as an approach cost and food access was contingent on running wheel activity. Mice were able to emit more wheel revolution responses compared to a condition in which nose poking was the approach response. In both voluntary and foraging running protocols mice had inelastic demand functions compared to the non-running groups. When running was voluntary (experiment 1), the day-night cycle for activity was more pronounced compared to when running was a foraging or approach activity (experiment 2).

Food demand and meal size in mice with single or combined disruption of melanocortin type 3 and 4 receptors.

Mice with homozygous genetic disruption of the melanocortin-4 receptor gene (MC4R-/-) are known to be hyperphagic and become obese, while those with disruption of the melanocortin-3 receptor gene (MC3R-/-) do not become markedly obese. The contribution of MC3R signaling in energy homeostasis remains little studied. In the present work, we compare MC3R-/- mice with wild-type (WT), MC4R-/-, and mice bearing disruption of both genes (double knockout, DKO) on select feeding and neuroanatomical dimensions. DKO mice were significantly more obese than MC4R-/-, whereas MC3R-/- weighed the same as WT. In a food demand protocol, DKO and MC4R-/- were hyperphagic at low unit costs for food, due primarily to increased meal size. However, at higher costs, their intake dropped below that of WT and MC3R-/-, indicating increased elasticity of food demand. To determine whether this higher elasticity was due to either the genotype or to the obese phenotype, the same food demand protocol was conducted in dietary obese C57BL6 mice. They showed similar elasticity to lean mice, suggesting that the effect is of genotypic origin. To assess whether the increased meal size in MC4R-/- and DKO might be due to reduced CCK signaling, we examined the acute anorectic effect of peripherally administered CCK and subsequently the induction of c-Fos immunoreactivity in select brain regions. The anorectic effect of CCK was comparable in MC4R-/-, DKO, and WT, but it was unexpectedly absent in MC3R-/-. CCK-induced c-Fos was lower in the paraventricular nucleus in MC3R-/- than the other genotypes. These data are discussed in terms of demand functions for food intake, MC receptors involved in feeding, and their relation to actions of gut hormones, such as CCK, and to obesity.

Comparison of C57BL/6 and DBA/2 mice in food motivation and satiety.

Demand functions describe the relationship between the consumption of a commodity and its mean or unit price. In the first experiment, we analyzed food demand in two strains of mice (C57BL/6 and DBA/2) that differ on several behavioral dimensions, but have not been examined extensively for differences in feeding and meal patterns. Mice worked for food pellets in a continuous access closed economy in which total intake and meal patterns could be measured. A series of fixed (FUP), variable (VUP), and progressive (PUP) unit price schedules were imposed. Under all schedules, DBA/2 mice consumed significantly more food than C57BL/6, a difference that was not attributable to disparity in body weight or weight gain. The higher intake of DBA/2 mice was due predominantly to larger meal size compared with C57BL/6, with no strain difference in meal frequency. In a second experiment, strain differences in meal size were not found to correlate with anorectic sensitivity to cholecystokinin (CCK) administration, or with c-Fos expression induced by CCK in PVN, AP and NTS. Thus, DBA/2 mice were motivated to sustain a higher daily food intake and meal size than C57BL/6 under the range of demand costs employed in the present work, but this strain difference is unlikely to be due to CCK action or responsiveness.

Meal patterns of mice under systematically varying approach and unit costs for food in a closed economy.

Several field and experimental studies have investigated the behavioral economics of food intake. In the laboratory, operant behavior has been used to emulate cost and to generate demand functions that express the relationship between the price of food and amount consumed. There have been few such studies of motivated food seeking and intake in mice, and none has reported demand functions. Using albino (CD1) male mice, the present study compares food intake and meal patterns across a series of ratio cost schedules. The first experiment examined unit price. A closed economy was used in which the mice were in the test chambers for 23 h/day and earned all of their food via either a nose poke or lever press response under fixed (FUP5, FUP10, FUP25, FUP50), variable (VUP10, VUP20, VUP50), and progressive (PUP1.25, PUP1.5, PUP1.75) unit prices. Mice were run for 4 days at each cost. There were no consistent differences between the first and last day indicating that behavioral adjustments to schedule changes occurred rapidly. When averaged across all price schedules, mice in the nose poke group consumed more food than their lever press counterparts but the overall shapes of the demand curves did not differ between the two operant responses, with intake decreasing as price increased. The number of meals taken per day differed between two meal-defining criteria that we applied, and there were some differences between the types of unit price schedule. In the second experiment, approach cost in the form of nose poke responses was required to activate a response device (lever) on which a fixed unit price for food was in force. These approach and unit costs were varied systematically. Meal number decreased, and meal size increased, with increasing approach cost even though nose pokes accounted for only a small fraction of the total response activity. Thus, meal patterns in mice are sensitive to approach cost while total amount consumed is more sensitive to unit price. These data are discussed in terms of the concept of foraging cost as either a unitary or a multidimensional variable.