Medical strategies for weight loss in the overweight and obese patient.

In recent years, obesity has become a major public health problem in Western countries. The World Health Organization has defined obesity as a global epidemic of the third millennium. Treatment options for weight management include dietary intervention, physical activity, behavior modification, pharmacotherapy and surgery. However, the complexity of this chronic condition necessitates a coordinated multidisciplinary team-approach to the care of obese patients who fail weight control. The long-term duration of the treatment and the necessity of monitoring compliance and effectiveness should be considered. The objective of this article was to review the major controlled randomized clinical trials dealing with the different medical strategies for weight loss and its maintenance in overweight and obese patients.

Direction of weight change in recurrent depression. Consistency across episodes.

The direction and extent of weight change during two separate episodes of severe, unipolar depression were assessed in 53 (unmedicated) outpatients in the Pittsburgh (Pa) study of maintenance therapy of depression. There was a high concordance (45 of 53 patients) of direction of self-reported weight change during the two episodes. Twenty-three patients lost weight during both episodes, 17 gained weight, and 5 showed no change. The extent of weight change between the two episodes was highly correlated. Self-reported weight change corresponded closely to measured weight changes in a large sample of the study population. Changes in appetite paralleled those in body weight. Duration of the episode and body mass index were related to the weight change, but two features of depression with which weight loss in depression has been associated (the endogenous character of the depression and it severity) were not. Direction and extent of weight change in unipolar depression appear to be stable patient characteristics across episodes and are thus potential markers for subtypes of depression. This stability of weight change is in sharp contrast to the lack of stability of the endogenous subtype in consecutive episodes of major depression.

Short-term neuroendocrine effects of a large oral dose of monosodium glutamate in fasting male subjects.

Fasting male subjects received each of four treatments on different days: a large oral dose of monosodium L-glutamate (MSG; 12.7 g), the MSG vehicle, an iv injection of TRH, or a high protein meal. Blood samples were drawn via an indwelling venous line before and at 20-min intervals after each treatment for 4 h. Plasma glutamate levels rose 11-fold within 1 h of MSG ingestion, but did not change appreciably with any of the other treatments. Plasma PRL levels rose 10-fold after TRH infusion and 2-fold after the protein meal, but did not rise significantly after MSG ingestion. No effects resulted from any of the treatments on plasma LH, FSH, testosterone, GH, or cortisol concentrations. Plasma levels of TSH, T4, and T3 showed minimal changes after any of the treatments except TRH; TRH elevated plasma TSH and T3 levels. Self-rating instruments of mood and side-effects revealed no treatment-related effects on mood or physical state for up to 48 h after each treatment. Together, these results suggest that acute pharmacological elevations of plasma glutamate levels in adult men produce minimal, if any, effects on hypothalamic or pituitary function.

Appetite and food preference in depression: effects of imipramine treatment.

A nutritional survey, the Pittsburgh Appetite Test (PAT), was developed to study potential changes in appetite and food preference reported by patients during a depressive episode and during antidepressant treatment. We examined a group of 50 depressed outpatients who were drug-free for 2 weeks prior to treatment with imipramine and psychotherapy for 4 months. A significant increase in the desire for "sweets" (carbohydrate--fat-rich foods) was observed during a depressive episode, compared to periods when patients recalled feeling well (retrospective data). During imipramine treatment, no further changes were observed in preference for either "sweets" or carbohydrates when compared to the medication-free period. Alterations in patient self-reports of appetite and body weight change were noted during imipramine treatment.

Twenty-four-hour food intake in patients with anorexia nervosa and in healthy control subjects.

Ad libitum feeding over 24 hours was assessed in underweight restrictor anorectic (RAN) women (n = 8) and matched healthy control subjects (n = 9) in a relatively naturalistic laboratory setting. RAN consumed 828 +/- 210 kcal/day (20 +/- 6 kcal/kg/day); controls ingested 2274 +/- 564 kcal/day (41 +/- 13 kcal/kg/day). Expressed as macronutrient consumption, RAN, compared to healthy controls, ate less fat (13% vs 31%), more carbohydrate (73% vs 57%), and similar amounts of protein (14% vs 12%). RAN initiated fewer eating episodes than controls (4 vs 7). This study quantitatively confirms the growing body of evidence suggesting that RAN avoid fat-containing foods. Such persistent fat avoidance may significantly contribute to the difficulty RAN experience in gaining and maintaining body weight.

Effects of acute tryptophan depletion on mood in bulimia nervosa.

BACKGROUND: The present study investigated the role of serotonin in the pathophysiology of bulimia nervosa (BN) by studying the affective and appetitive responses of women ill with BN to an acute tryptophan depletion (ATD) paradigm. METHODS: Twenty-two women with BN and 16 healthy control women (CW) were studied on 2 separate days during the follicular stage of the menstrual cycle. Participants drank a control mix of essential amino acids (100 g + 4.6 g tryptophan) on one day and a tryptophan deficient (100 g - 4.6 g tryptophan) mixture (ATD) on the other in a double-blind fashion. Mood/appetite ratings and blood samples were taken at baseline and at intervals up to 420 minutes. Participants were then presented with an array of foods and were allowed to binge and vomit if they desired. RESULTS: CW and BN women had a similar and significant reduction in plasma tryptophan levels and the tryptophan: LNAA ratio after ATD. After ATD, the BN women had a significantly greater increase in peak (minus baseline) depression, mood lability, sadness and desire to binge compared to the CW. BN subjects and CW had similar peak changes in mood after the control amino acid mixture. BN subjects and CW consumed similar amounts of food after the two amino acid treatments. CONCLUSIONS: Women with BN seem more vulnerable to the mood lowering effects of ATD, suggesting they have altered modulation of central 5-HT neuronal systems.

Abnormal caloric requirements for weight maintenance in patients with anorexia and bulimia nervosa.

OBJECTIVE: This study tested previous findings that patients with eating disorders who attain normal weight have abnormal caloric requirements for maintaining weight. METHOD: Fifty-three female patients meeting the DSM-III-R criteria for anorexia nervosa and/or bulimia nervosa were divided into four subgroups, and their daily caloric intake was measured over a weight-stable period. Patients with anorexia nervosa (restricting and bulimic subtypes) were studied 4 weeks after refeeding and weight gain, when they had attained 95% of average body weight. Patients with normal-weight bulimia (previously anorexic or never previously anorexic) were studied 1-4 weeks after admission to an inpatient unit. RESULTS: After weight restoration, restricting anorexic patients required significantly more calories per day to maintain weight than did bulimic anorexic patients, as measured with corrections for weight, body surface area, and fat-free mass. Previously anorexic normal-weight bulimic patients required significantly more calories per day to maintain weight than never-anorexic normal-weight bulimic patients, as measured with correction for weight but not with the other factors used to correct caloric intake. CONCLUSIONS: To maintain stable weight after weight restoration, restricting anorexic patients require a significantly higher caloric intake than do bulimic anorexic patients. Differences in caloric needs between normal-weight bulimic patients with and without histories of anorexia may depend on the methods used to correct caloric requirements. Body surface area may be the most precise correction factor across different subgroups of eating disorder patients. Elevated caloric requirements, when coupled with reduced food intake, may particularly contribute to relapse in anorexic patients.

Acute tryptophan depletion and increased food intake and irritability in bulimia nervosa.

OBJECTIVE: Data suggest that serotonin activity is reduced in women at normal weight who have bulimia nervosa. The authors tested whether acute perturbations in serotonin activity could alter short-term eating behavior and mood. METHOD: They examined the effect of acute tryptophan depletion in 10 women with and 10 women without bulimia nervosa. RESULTS: Women with bulimia nervosa exhibited an increase in caloric intake and mood irritability after acute tryptophan depletion. CONCLUSIONS: These results indicate that women with bulimia nervosa have an exaggerated or pathological response to transient alterations in serotonin activity.

Brain tryptophan concentrations and serotonin synthesis remain responsive to food consumption after the ingestion of sequential meals.

The response of brain tryptophan concentration and serotonin synthesis to the ingestion of two sequential meals was examined in rats. Fasted rats ingested a carbohydrate meal followed 2 h later by a protein-containing meal and were examined 2 or 4 h after the first meal. Other rats ingested a protein meal first, followed by a carbohydrate meal. When the carbohydrate meal was fed first, brain tryptophan concentrations and serotonin synthesis increased at 2 h; these changes were reversed at 4 h if the second meal contained protein. When the protein meal was fed first, there were no changes in brain tryptophan or serotonin at 2 h, and a second carbohydrate meal at 2 h did not raise brain tryptophan or serotonin 2 h later. Carbohydrate ingestion 3 h after a protein meal, however, did raise brain tryptophan and serotonin 2 h later. Brain tryptophan concentrations and serotonin synthesis are thus responsive to the sequential ingestion of protein and carbohydrate meals if there is a sufficient interval between meals.

In vivo tyrosine hydroxylation in rat retina: effect of aspartame ingestion in rats pretreated with p-chlorophenylalanine.

Rats were pretreated with p-chlorophenylalanine (PCPA) to inhibit hepatic phenylalanine hydroxylase. Two days later, oral aspartame (APM; aspartylphenylalanine methylester) administration substantially increased serum phenylalanine (Phe) concentrations and the ratio, in serum, of Phe to the sum of its competitors for transport into brain and retina (the other large neutral amino acids). Smaller changes occurred in serum tyrosine (Tyr) concentrations and in the ratio, in serum, of Tyr to the sum of its competitors. P-chlorophenylalanine-pretreated rats showed normal increases in retinal Tyr hydroxylation rate after Tyr injection, indicating that the enzyme was functionally normal. APM (0, 500, 1000, 1500 mg/kg body wt) intubation of PCPA-pretreated rats produced a dose-related increment in retinal Phe concentrations (up to six times normal values), no changes in retinal Tyr concentration, and no changes in retinal Tyr hydroxylation rate. The results thus indicate that very large increments in retinal Phe concentrations produced by enormous doses of APM do not modify Tyr hydroxylation in vivo.

Effects of aspartame ingestion on the carbohydrate-induced rise in tryptophan hydroxylation rate in rat brain.

Effects of aspartame (aspartyl-phenylalanine-methylester) on increases in brain-tryptophan level and hydroxylation rate following a high-carbohydrate, protein-free meal were tested. After an overnight fast, rats consumed a protein-free meal containing one of several levels of aspartame. Blood and brain amino acid levels and the in vivo rate of tryptophan hydroxylation in brain were estimated at intervals thereafter. Ingestion of the meal alone increased brain-tryptophan level and hydroxylation rate. Aspartame did not modify these effects, except at doses of 530 mg/kg body weight or more. Results suggest a threshold dose of aspartame can be identified for the rat in single-meal studies above which suppression of carbohydrate-induced increases in brain-tryptophan level and serotonin synthesis occurs. This dose, however, is large and, when corrected for species differences in metabolic rate, is unlikely to be ingested by a human subject as a single load.

Resting metabolic rate in lean and obese children: relationship to child and parent weight and percent-overweight change.

Two studies were conducted to assess differences in metabolic rate as a function of child weight (study I); and the interaction of child and parent weight (study II). In both studies obese children had higher resting metabolic rates (RMRs) than lean children (p less than 0.05). Child weight accounted for 72 and 78% of the variance in RMR in studies 1 and 2, respectively. Including parental weight did not improve the prediction of RMR. After 6 mo of treatment, obese children decreased percent overweight, whereas lean children showed no change (p less than 0.01). RMR in both groups remained unchanged after 6 mo. These results indicate that the RMR is higher in obese than in lean children, that changes in percent overweight that result from increases in height and no change in weight do not decrease RMR over 6 mo, and parent weight does not improve the prediction of child RMR.

Metabolic effects of nicotine after consumption of a meal in smokers and nonsmokers.

The thermogenic effect of nicotine intake after calorie consumption was investigated to determine if nicotine influences metabolic response to a calorie challenge. Smokers and nonsmokers (10 males in each group), matched for body weight, age, and physical fitness, each participated in four sessions that involved consuming a liquid calorie load (4.77 kcal/kg body wt) or water, followed by nicotine (15 micrograms/kg body wt) or placebo via nasal spray every 20 min for 2 h. Energy expenditure was significantly increased above baseline resting metabolic rate (RMR) over the 2 h by nicotine alone (6.5% of RMR, p less than 0.01). However, the combined effect of nicotine after calorie load (20.1% of RMR, p less than 0.001) was not significantly greater than the effect of calorie load alone (18.4% of RMR, p less than 0.001). Smokers and nonsmokers did not differ in baseline RMR or in response to nicotine or calorie load. These results confirm the thermogenic effect of nicotine but suggest that the effect of nicotine after calorie consumption is less than additive.

Acute effects of nicotine on hunger and caloric intake in smokers and nonsmokers.

The inverse relationship between smoking and body weight may be due in part to nicotine's effects on reducing hunger and eating. Male smokers and nonsmokers (n = 10 each), abstinent overnight from smoking and food, participated in four sessions, involving consumption of a liquid caloric load or water followed by nicotine (15 micrograms/kg) or placebo via nasal spray every 20 min for 2 h. Hunger and satiety ("fullness") ratings were obtained prior to each dose presentation. At the end of the two sessions involving the caloric load (simulating breakfast), subjects were also presented with typical lunch/snack food items varying in sweet taste and fat content for ad lib consumption. Results indicated that, for both smokers and nonsmokers, the hunger-reducing effects of nicotine occurred only following caloric load consumption, and there was no effect of nicotine on hunger afer water consumption. Smokers unexpectedly reported greater satiation than nonsmokers following the caloric load regardless of nicotine or placebo condition. Nicotine also resulted in less caloric intake during the meal, and the decrease was not specific to consumption of sweet, high-fat foods. These results indicate that nicotine reduces appetite, possibly helping to explain the influence of smoking on body weight.

Monoamines and protein intake: are control mechanisms designed to monitor a threshold intake or a set point?

The concentration of TYR in brain changes directly with dietary protein content in the 0-10% PE range, but not higher. The effect is large: TYR concentrations rise as much as two- to threefold between 0% and 10% dietary protein content. This increase produces a clear stimulation of the rate of catecholamine synthesis, observed both for DA and NE, and notably in the hypothalamus, a brain area involved in appetite regulation. A similar relationship to chronic dietary protein intake may also exist for tryptophan and its neurotransmitter product, 5HT. Because the natural diet of rats, the animal model most commonly used in such studies, typically contains between 6% and 14% protein, and may contain less under unfavorable environmental circumstances, rats in the wild may frequently operate on the portion of the protein intake curve producing maximal changes in brain TYR (and perhaps TRP) concentrations. If so, then the production of catecholamines and 5HT may be similarly affected. By such a scenario, the brain might receive information regarding the animal's success in acquiring adequate amounts of protein in its diet. A similar argument can also be made for monkeys in the wild, based on their dietary habits, and thus possibly for humans. From this perspective, animals are hypothesized to monitor/regulate their intake of protein based on a threshold, rather than a set-point model. This notion is not new or unique to amino acids. For example, one current notion of leptin action is that it serves as a signal for energy intake important during periods of deficiency, but not excess. More generally, given the primacy in nature of the need to acquire adequate amounts of food in order to survive and reproduce, and the difficulty in achieving this nutritional goal, it may be that appetite control mechanisms have evolved in nature to center more on attaining and exceeding adequacy than on maintaining intake around a set-point well in excess of adequacy.

Serotonin and bulimia nervosa.

Serotonin (5HT) is one of several neuromodulators of feeding. Experimentally reducing 5HT activity in animals increases food intake, while increasing 5HT activity has the opposite effect. Studies suggest that women with bulimia nervosa show signs of reduced 5HT activity, which may be related to binge eating. Data supporting the theory that reduced central nervous system 5HT activity may play a role in the pathophysiology of bulimia nervosa is reviewed. Disturbances of 5HT activity and the relationship to other psychopathology in bulimia nervosa, such as depression, substance abuse, and impulsivity, are also reviewed.

Depression, antidepressants, and body weight change.

The excessive weight gain observed during treatment of depression with antidepressant medications is caused in part, at least in some persons, by reductions in resting metabolic rate. Such problematic weight gain appears unrelated to clinical recovery, weight change during the depressive episode, prior weight, or other related factors. Preliminary results suggest that increased energy efficiency (of about 16-24%) during treatment with tricyclic antidepressants could promote weight gain even in the absence of a change in caloric intake. This is not a property of all antidepressants, as demonstrated by the increase in metabolic rate and associated weight loss observed during treatment with the monocyclic antidepressant compound fluvoxamine. Should these serotonergic compounds continue to be effective antidepressants, they may be better accepted by patients, and their use help avoid medication noncompliance. In considering energy balance and weight change, our focus has been drawn to altered metabolic rate. Continuing studies do not suggest an effect of antidepressants on appetite, particularly the presence of "carbohydrate craving," either during treatment or during a depressive episode. Certainly, a notable preference for highly palatable foods (rich in fats and carbohydrates) occurs during the depressive episode, but not during treatment. These foods cannot be labeled carbohydrates.

Twenty-four-hour variations in rat blood and brain levels of the aromatic and branched-chain amino acids: chronic effects of dietary protein content.

Groups of young adult, male rats were given free access for 12 weeks to a single diet containing either 12%, 24%, or 40% protein (dry weight). At the end of this time, six rats from each diet group were killed every four hours throughout a single 24-hour period, and blood samples and brains were obtained for quantitation of several of the large neutral amino acids (LNAAs). The blood level of each LNAA varied significantly as a function of time of day (tending to be lower during the day than at night) and as a function of dietary protein content (typically rising as protein intake increased). Except for tyrosine and valine, the serum concentration ratio of each LNAA to the sum of the other LNAA (previously reported to be a good predictor of the competitive uptake of each LNAA into brain) and the brain level of each LNAA showed unremarkable variations with time of day and dietary protein content. In contrast, the serum ratios and brain levels of tyrosine and valine did show notable variations at night as a function of dietary protein intake. Together, the results show that within a chronic physiologic range of protein intakes, the serum ratios and brain levels of several large neutral amino acids, particularly tryptophan, bear no relationship to dietary protein level. Though good correlations between these parameters and protein intake were obtained for valine and tyrosine, their physiologic/metabolic significance, if any, is unknown. In general, the data do not support the broad, unvalidated use of serum LNAA ratios in chronic settings as predictors of brain LNAA levels.

Immunoreactive neurotensin levels in pancreas: elevation in diabetic rats and mice.

Neurotensin levels in pancreas, but not other tissues, were increased in diabetic animals. The concentration of pancreatic immunoreactiveneurotensin was 138% higher in streptozotocin-diabetic rats, and 68% higher in genetically diabetic (db/db) mice as compared to their respective control animals. Daily administration of insulin (10-15 IU/kg) to diabetic rats completely reversed this effect, and pancreatic neurotensin levels in these animals returned to control values. These findings suggest that elevated levels of pancreatic neurotensin may contribute to some of the metabolic and hormonal disturbances occurring in diabetes.

Effect of chronic protein ingestion on rat central nervous system tyrosine levels and in vivo tyrosine hydroxylation rate.

Groups of young adult male rats ingested ad libitum for two weeks diets containing 2%, 5%, 10% or 20% protein. They were then killed early in the daily dark period, 30 min after receiving m-hydroxybenzylhydrazine (100 mg/kg i.p., to allow measurement of in vivo tyrosine hydroxylation rate). Tyrosine levels in retina, hypothalamus and cerebral cortex were lowest in rats ingesting 2% protein, and rose progressively to a plateau in rats ingesting 10% protein. No consistent increase occurred between 10% and 20% protein. Tyrosine hydroxylation rate in retina and hypothalamus, but not prefrontal cortex rose in parallel with the increments in tyrosine level between 2% and 10% protein, showing no further increase between 10% and 20% protein. These changes were found to be related to the level of protein, not caloric intake. And, the low rates of hydroxylation observed in rats consuming low protein (2%) were found not to be attributable to low endogenous tyrosine hydroxylase activity. Together, the results indicate that the differences in tyrosine levels in some regions of the central nervous system (retina, hypothalamus) produced by chronic variations in protein intake may influence directly the rate of tyrosine hydroxylation, and thus perhaps the overall rate of catecholamine synthesis. This relationship might provide the hypothalamus (a region important in food intake control) with a signal for monitoring and ultimately modulating the chronic level of protein intake.