Models for Environmentally Induced Eating Disorders: Dietary Hyperphagia and Anorexia Nervosa

Mary Ann Pelleymounter1, R.H. Kant2, Paul Aravich3

1 Neurocrine Biosciences, San Diego, California, 2 Accu Scan/Omnitech Instruments, Columbus, Ohio, 3 Eastern Virginia Medical School and Veterans Affairs Medical Center, Norfolk and Hampton, Virginia
Publication Name:  Current Protocols in Pharmacology
Unit Number:  Unit 5.19
DOI:  10.1002/0471141755.ph0519s05
Online Posting Date:  May, 2001
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Abstract

The two protocols in this unit provide suggestions for constructing models of eating disorders that are at the opposite ends of the spectrum: dietary hyperphagia and anorexia nervosa. The greatest degree of dietary hyperphagia is induced by giving rats or mice access to a daily choice of highly palatable foods (e.g., chocolate or bread) in addition to their regular chow. Like humans, rats overeat and actually develop physiological requirements for these foods. This model can be used to test the effects of putative anorectic agents on both acute and chronic administration regimens. The second protocol describes a model of compulsive behavior that results in profound weight loss, which is produced by moderate food deprivation along with continuous access to exercise wheels.

     
 
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Table of Contents

  • Strategic Planning
  • Basic Protocol 1: Induction of Dietary Hyperphagia
  • Basic Protocol 2: Induction of Anorexia Nervosa
  • Commentary
  • Figures
  • Tables
     
 
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Materials

Basic Protocol 1: Induction of Dietary Hyperphagia

  Materials
  • Rats (12 to 15/group, see Critical Parameters), individually housed
  • Diet: quartered chocolate chips, shredded white bread, powdered chow (Purina 5001, ground version); also see Table 5.19.1
  • Automated food and weight monitors, one per animal (AccuScan/Omnitech; Columbus or glass jar alternative; see Strategic Planning)
  • Test compound(s) (see Table 5.19.2)
  • Vehicle
  • Additional reagents and equipment for behavioral tests (Crawley et al., )
NOTE: If energy values for the diet components are required, they can be easily calculated. Fat has 9 calories/gram, and protein and carbohydrates have 4 calories/gram. Energy values for common supermarket foods as listed above are provided by the manufacturer.
Table 5.9.1   MaterialsEffect of Diet Manipulations on Average Energy Intake, Percent of Control Diet Consumed, and Days to Achieve HyperphagiaEffects of Anorectic Agents on Food Intake in Rats Obesified with a Cafeteria Diet

Type of diet Nutrient composition Formulation Average energy intake (kcal/day) % Over control diet Time to reach asymptotic energy intake (days) Reference
High sucrose/starch diets Control diet with 25% sucrose Pellets/no option 97.2 11.8 23 Naim et al. ( )
Chow plus sucrose powder Pure powder/ sucrose option 80.5 14 40 Sclafani ( )
Chow plus sucrose solution Pure powder/32% sucrose option 88.1 25 40 Sclafini ( )
High fat diets Chow with corn oil option Pure oil 68 8 48 Lucas et al. ( )
Chow with corn oil emulsion option 35% corn oil emulsion 75 21 48 Lucas et al. ( )
31% fat, 41% starch, 20% casein Pellets/only option 105 9.3 23 Naim et al. ( )
Combined high sucrose/high fat diets 32.6% fat, 52% starch, 15% protein Pellets/only option 17.61 (SJL.J mice) 25 49 West et al. ( )
31% fat, 25% sucrose, 41% starch, 20% protein Pellets/only option 96.9 1 23 Naim et al. ( )
Formulated cafeteria diet 31% fat, 25% sucrose, 41% starch, 20% protein Options of pellets with several different flavors 111 16 23 Naim et al. ( )
Traditional cafeteria diet White bread, regular chow, chocolate All powdered, but in separate feeders 108 60 20 Rogers and Blundell ( )
Potato chips, chocolate chip cookies, cheese crackers, regular chow Crumbled, scattered together in cage 96 33 14 Rolls et al. ( )
Regular diet plus cafeteria items Pellets, crumbled food scattered together in cage 99.8 50 15 Rothwell et al. ( )
Regular chow, chocolate chip cookies, sweetened condensed milk, Crisco Powdered if possible presented as constant selection 60 kcal/6‐hr interval 40 21 Sclafani et al. ( )
Test agent Time of administration Stage of obesity at time of measurement Reduction in energy intake derived from cafeteria diet (% control diet) a Reference
Dexfenfluramine (1.8‐4.5 mg/kg in drinking water) dose normalized to energy intake Simultaneous with development of obesity First 36 days of 116‐day regimen 40% more suppression on cafeteria diet, but NS b Blundell and Hill ( )
Last 76 days of 116‐day regimen 75% more suppression on cafeteria diet, but NS Blundell and Hill ( )
After 80 days on cafeteria diet dietary obesity well developed Last 36 days of 116‐day regimen 247% more suppression on cafeteria diet than on control diet Blundell and Hill ( )
D‐Amphetamine (0.3‐10 mg/kg) After 3 weeks on cafeteria diet or regular chow all rats fasted for 18 hr prior to study Food intake measured for a 6 hr period after injection At 1 hr, IC 50 for chow was 0.8 mg/kg, cafeteria diet was 3.7 mg/kg both diets suppressed at 6 hr Bowden et al. ( )
(−)‐Hydroxycitrate (30‐100 mg/kg) See amphetamine See amphetamine No suppression with cafeteria diet 40% to 70% suppression with regular chow, both time points Bowden et al. ( )
Fenfluramine (0.3‐10 mg/kg) See amphetamine See amphetamine 30% to 80% suppression on both diets, all time points Bowden et al. ( )
Naloxone (1‐30 mg/kg) See amphetamine See amphetamine 40% to 70% suppression on both diets at 1 hr effect almost gone for both diets at 6 hr Bowden et al. ( )

Table 5.9.2   MaterialsEffect of Diet Manipulations on Average Energy Intake, Percent of Control Diet Consumed, and Days to Achieve HyperphagiaEffects of Anorectic Agents on Food Intake in Rats Obesified with a Cafeteria Diet

Type of diet Nutrient composition Formulation Average energy intake (kcal/day) % Over control diet Time to reach asymptotic energy intake (days) Reference
High sucrose/starch diets Control diet with 25% sucrose Pellets/no option 97.2 11.8 23 Naim et al. ( )
Chow plus sucrose powder Pure powder/ sucrose option 80.5 14 40 Sclafani ( )
Chow plus sucrose solution Pure powder/32% sucrose option 88.1 25 40 Sclafini ( )
High fat diets Chow with corn oil option Pure oil 68 8 48 Lucas et al. ( )
Chow with corn oil emulsion option 35% corn oil emulsion 75 21 48 Lucas et al. ( )
31% fat, 41% starch, 20% casein Pellets/only option 105 9.3 23 Naim et al. ( )
Combined high sucrose/high fat diets 32.6% fat, 52% starch, 15% protein Pellets/only option 17.61 (SJL.J mice) 25 49 West et al. ( )
31% fat, 25% sucrose, 41% starch, 20% protein Pellets/only option 96.9 1 23 Naim et al. ( )
Formulated cafeteria diet 31% fat, 25% sucrose, 41% starch, 20% protein Options of pellets with several different flavors 111 16 23 Naim et al. ( )
Traditional cafeteria diet White bread, regular chow, chocolate All powdered, but in separate feeders 108 60 20 Rogers and Blundell ( )
Potato chips, chocolate chip cookies, cheese crackers, regular chow Crumbled, scattered together in cage 96 33 14 Rolls et al. ( )
Regular diet plus cafeteria items Pellets, crumbled food scattered together in cage 99.8 50 15 Rothwell et al. ( )
Regular chow, chocolate chip cookies, sweetened condensed milk, Crisco Powdered if possible presented as constant selection 60 kcal/6‐hr interval 40 21 Sclafani et al. ( )
Test agent Time of administration Stage of obesity at time of measurement Reduction in energy intake derived from cafeteria diet (% control diet) a Reference
Dexfenfluramine (1.8‐4.5 mg/kg in drinking water) dose normalized to energy intake Simultaneous with development of obesity First 36 days of 116‐day regimen 40% more suppression on cafeteria diet, but NS b Blundell and Hill ( )
Last 76 days of 116‐day regimen 75% more suppression on cafeteria diet, but NS Blundell and Hill ( )
After 80 days on cafeteria diet dietary obesity well developed Last 36 days of 116‐day regimen 247% more suppression on cafeteria diet than on control diet Blundell and Hill ( )
D‐Amphetamine (0.3‐10 mg/kg) After 3 weeks on cafeteria diet or regular chow all rats fasted for 18 hr prior to study Food intake measured for a 6 hr period after injection At 1 hr, IC 50 for chow was 0.8 mg/kg, cafeteria diet was 3.7 mg/kg both diets suppressed at 6 hr Bowden et al. ( )
(−)‐Hydroxycitrate (30‐100 mg/kg) See amphetamine See amphetamine No suppression with cafeteria diet 40% to 70% suppression with regular chow, both time points Bowden et al. ( )
Fenfluramine (0.3‐10 mg/kg) See amphetamine See amphetamine 30% to 80% suppression on both diets, all time points Bowden et al. ( )
Naloxone (1‐30 mg/kg) See amphetamine See amphetamine 40% to 70% suppression on both diets at 1 hr effect almost gone for both diets at 6 hr Bowden et al. ( )

 aResults represent an average for the range of doses tested.
 bNS not statistically significant.

Basic Protocol 2: Induction of Anorexia Nervosa

  Materials
  • Light machine oil
  • Animals (rats, hamsters, gerbils, guinea pigs, chipmunks, or mice)
  • Diet: powdered or pellet, natural or synthetic
  • Test compound
  • Vehicle
  • Activity running wheels of appropriate size for experimental animal (see )
  • Torque meter
  • Water bottles with stainless steel sipper tubes (Unifab or Allentown Caging)
  • Water bottle springs to attach food containers to side cages (Unifab or Allentown Caging)
  • Small (e.g., 118‐ml) glass jars or commercially available metal feeding cups for powdered diets (Unifab or Allentown Caging)
  • Disposable plastic cups for preweighed food (e.g., 500‐ml urine collecting cups)
  • Scale (0‐ to 1000‐g range; 0.1‐g accuracy)
  • Tables/racks to position wheels in vivarium
  • Portable timer/watch with audible indicator to sound the end of daily restricted feeding period
NOTE: Provide water freely throughout the entire experiment as water deprivation will suppress caloric intake and energize running. In fact, restricted water access produces an exercise‐stress syndrome similar to that produced by restricted food access (Aravich, ).
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Figures

Videos

Literature Cited

Literature Cited
   American Psychiatric Association. 1994. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM‐IV). American Psychiatric Press, Washington, D.C.
   Aravich, P.F. 1996. Adverse effects of exercise stress and restricted feeding in the rat: Theoretical and neurobiological considerations. In Activity Anorexia: Theory, Research, and Treatment (W.F. Epling and W.D. Pierce, eds.) pp. 81‐97. Lawrence Erlbaum, Mahwah, N.J.
   Blundell, J. 1987. Nutritional manipulations for altering food intake: Towards a causal model of experimental obesity. Ann. N.Y.Acad. Sci. 499:144‐155.
   Blundell, J. and Hill, A. 1985. Effect of dextrofenfluramine on feeding and body weight: Relationship with food composition and palatability. In Metabolic Complications of Human Obesities. (J. Vague, B. Guy‐Grand, and P. Bjorntorp, eds.) pp. 199‐206. Elsevier/North‐Holland, Amsterdam.
   Bowden, C., White, K., and Tutweiler, G. 1985. Energy intake of cafeteria‐diet and chow‐fed rats in response to amphetamine, fenfluramine and (‐)‐hydroxycitrate, and naloxone. J. Obes. Weight Regu. 1:5‐13.
   Crawley, J.N., Gerfen, C.R., McKay, R., Rogawski, M.A., Sibley, D.R., and Skolnick, P. (eds.) 1999. Current Protocol in Neuroscience. John Wiley & Sons, New York.
   Doerries, L.E. 1996. Gender differences in activity anorexia: Predictable, paradoxical, or enigmatic. In Activity Anorexia: Theory, Research, and Treatment (W.F. Epling and W.D. Pierce, eds.) pp. 69‐77. Lawrence Erlbaum, Mahwah, N.J.
   Jakubzak, L.F. 1967. Age differences in the effect of terminal food deprivation (starvation) on activity, weight loss, and survival of rats. Gerontology 22:421‐426.
   Lucas, F., Ackroff, K., and Sclafani, A. 1989. Dietary fat‐induced hyperphagia in rats as a function of fat type and physical form. Physiol. Behav. 45:937‐946.
   Naim, M., Brand, J., Kare, M., and Carpenter, R. 1985. Energy intake, weight gain and fat deposition in rats fed flavored, nutritionally controlled diets in a multichoice (“cafeteria”) design. J.Nutr. 115:1447‐1458.
   Pierce, W.D. and Epling, W.F. 1996. Theoretical developments in activity anorexia. In Activity Anorexia: Theory, Research, and Treatment, pp. 23‐ 41. Lawrence Erlbaum, Mahwah, N.J.
   Pierce, R.C., and Kalivas, P. 1999. Locomotor behavior. In Current Protocols in Neuroscience (J.N. Crawley, C.R. Gerfen, R. McKay, M.A. Rogawski, D.R. Sibley, and P. Skolnick, eds.) pp. 8.1.1‐8.1.8. John Wiley & Sons, New York.
   Ramirez, I. 1989. Resistance to dietary hyperphagia in juvenile rats. J. Nutr. 119:1333‐1339.
   Ramirez, I. 1991. Strain differences in dietary hyperphagia: Interactions with age and experience. Physiol. Behav. 49:89‐92.
   Rogers, P. and Blundell, J. 1984. Meal patterns and food selection during the development of obesity in rats fed a cafeteria diet. Neurosci. Biobehav. Rev. 8:441‐453.
   Rolls, B., Rowe, E., Rolls, E., Kingston, B., Megson, A., and Gunary, R. 1981. Variety in a meal enhances food intake in man. Physiol. Behav. 26:215‐221.
   Rolls, B., Rowe, E., and Turner, R. 1980. Persistent obesity in rats following a period of consumption of a mixed, high energy diet. J. Physiol. 298:415‐427.
   Rothwell, N., Stock, M., and Warwick, B. 1985. Energy balance and brown fat activity in rats fed cafeteria diets or high‐fat, semisynthetic diets at several levels of intake. Metabolism 34:474‐480.
   Sclafani, A. 1980. Dietary obesity. In Obesity (A.J. Stunkard, ed.) pp. 166‐181. W.B. Saunders, Philadelphia.
   Sclafani, A. 1987. Carbohydrate‐induced hyperphagia and obesity in the rat: effects of saccharide type, form, and taste. Neurosci. Biobehav. Rev. 11:155‐162.
   Sclafani, A. 1989. Dietary‐induced overeating. Ann. N.Y. Acad. Sci. 575:281‐289.
   Sclafani, A., Aravich, P.F., and Landman, M. 1981. Vagotomy blocks hypothalamic hyperphagia in rats on a Purina Laboratory Chow diet and sucrose solution, but not on a palatable mixed diet. J. Comp. Physiol. Psych. 95:720‐734. [Correction in Behav. Neurosci. 1983, 97:269.]
   West, D., Boozer, C., Moody, D., and Atkinson, R. 1992. Dietary obesity in nine inbred mouse strains. Amr. J. Physiol. 31:R1025‐R1032.
Key References
   Epling, W.F. and Pierce, W.D. (eds.). 1996. Activity Anorexia: Theory, Research, and Treatment. Lawrence Erlbaum, Mahwah, N.J.
  An edited volume with articles by numerous investigators who have used the exercise‐stress syndrome.
   Rogers and Blundell, 1984. See above.
  This review not only gives details about the diet recommended in , but also describes the behavioral aspects observations associated with the development of dietary hyperphagia.
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