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.

The new role of pharmacotherapy for weight reduction in obesity.

Obesity is associated with an increased risk for a wide variety of chronic health conditions. Despite this fact, less than half of obese patients are advised by healthcare professionals to lose weight. Creating a viable plan for losing weight and maintaining weight loss is difficult. Lifestyle change is always the cornerstone of treatment, but two new therapeutic agents approved for long-term use, sibutramine and orlistat, can help maximise success. Increased weight loss can lead to reductions in the risk of obesity-related co-morbidities. Sibutramine and orlistat offer new weight reduction opportunities for obese patients.

Diet, monoamine neurotransmitters and appetite control.

This article has attempted to point out some of the relationships between 5-HT and catecholamine (NE, DA) neurons in brain and the control of appetite and food intake. At least two bodies of evidence support this connection. The first is pharmacologic, and demonstrates that drugs that stimulate transmission across 5-HT and/or catecholamine synapses suppress hunger and food intake. The second is physiologic and metabolic, and reveals that the ingestion of foods, on either an acute (single meal) or chronic basis, can reliably modify the uptake of TRP and TYR into brain (and hypothalamus), and directly alter the synthesis of their transmitters (5-HT and the catecholamines, respectively). The synthesis of these two bodies of information has led to models by which (1) changes in dietary carbohydrate ingestion, by modifying brain TRP uptake and 5-HT production, may cause like changes in 5-HT release, and in the stimulation of 5-HT receptors in brain circuits that control carbohydrate appetite, and (2) dietary protein intake, by altering brain TYR uptake, directly influences DA and NE synthesis (notably in hypothalamus), perhaps providing a signal to brain circuits monitoring dietary protein adequacy regarding protein intake. In this case, one might imagine that stimulating DA and/or NE receptors in such circuits might suppress protein intake, a possibility we are now examining in rats. As indicated in the Introduction, the broader issue being touched upon in this article concerns the body's need to acquire and maintain an optimal (or adequate) nutritional balance (for growth and ultimately, reproductive success). Rats and humans evolved in an environment that does not provide continuous access to all essential nutrients, and one that presents nutrients in a complex matrix (other animals, plants) that can also include toxic compounds. Together with the fact that animals and humans do not carry a guidebook to healthy eating, we must presume that the brain mechanisms that have evolved to optimize the acquisition of essential nutrients are 'automatic' (i.e., not conscious) and quite complex. In this context, the relationships described here must be viewed as rudimentary, touching only a small portion of this complex regulatory mechanism. The hope is, as further insights develop, that we will gain a better understanding of the workings of these mechanisms, and also be able to apply this knowledge to the development of better pharmacologic (and other) aids for controlling appetite and obesity in our modern, man-made environment.

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.

Treating obesity in the family practice setting.

The health risks of obesity include the development of comorbid conditions and increased overall mortality. Obesity increases health-related costs for both patients and the healthcare system and significantly affects workforce productivity through increased absenteeism and higher health and insurance payments for employers. Discrimination against obese individuals exists in the workplace and in various social contexts. Obesity is a chronic condition with complex, multiple causes involving physiologic, genetic, and behavioral components, all of which must be addressed for successful treatment. Traditional treatment options include diet, exercise, and behavior modification, but recently, pharmacotherapy has been incorporated as an effective and safe adjunct for long-term treatment of obesity. Additionally, bariatric surgery is an option for selected morbidly obese individuals. Weight losses of only 5% to 10% of initial body weight confer proven clinical benefits. Such modest weight losses can be achieved and maintained within a supportive environment provided in a primary care practice.

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.

Diet-induced changes in serum cholesterol concentrations do not alter tryptophan hydroxylation rate or serotonin concentrations in gerbil brain.

The relationship between serum cholesterol concentrations and serotonin synthesis rate in brain was examined in Mongolian gerbils chronically fed diets containing 20% fat (safflower oil, beef tallow or butterfat) with or without added cholesterol (0.5%, dry weight). After 22 days on these diets, circulating cholesterol concentrations ranged between approximately 1.5 and approximately 20 mumol/ml. Despite this enormous range, in vivo tryptophan hydroxylation rate, and serotonin and 5-hydroxyindoleacetic acid concentrations in cerebral cortex, hypothalamus and brainstem did not differ significantly among the diet groups. Tryptophan concentrations in serum and brain were also unaffected. These results do not support the hypothesis that the link between depression, suicide and violent deaths and below-normal or reduced serum cholesterol concentrations in humans involves an alteration in serotonin synthesis and/or release by brain neurons.

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.

Drugs that cause weight gain.

Among drugs which cause weight gain, the tricyclic antidepressant medications are a drug class producing persistent and problematic body weight gain in many treated patients. Major depressive illness is often associated with reductions in appetite and body weight, and treatment with antidepressants effectively restores mood, appetite and weight. However, a frequent complaint of patients treated with tricyclic drugs is of excessive and unwanted weight gain, often times resulting in medication noncompliance. The incidence of weight gain during acute and chronic treatment with different, frequently prescribed antidepressant drugs will be reviewed, as will the possible mechanisms by which such drugs alter caloric intake and expenditure, contributing to drug-induced weight gain.

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.

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.

Acute tyrosine depletion reduces tyrosine hydroxylation rate in rat central nervous system.

An amino acid cocktail was devised that would rapidly reduce central nervous system (CNS) tyrosine levels in rats following gastric intubation. The effect of this treatment on in vivo tyrosine hydroxylation rate was examined. Serum tyrosine (TYR) levels, the serum ratio of TYR to the sum of its transport competitors, and CNS TYR concentrations fell substantially within 60 minutes of intubation and remained low for at least 3 hr. In vivo tyrosine hydroxylation rate, evaluated in hypothalamus and retina 2 hr after amino acid intubation, also declined significantly. The results suggest that an amino acid mixture can be devised that will cause an acute reduction in TYR levels and hydroxylation rate in rat CNS. This procedure may ultimately prove applicable to humans to examine functional consequences in particular CNS regions of reducing neuronal catecholamine synthesis.

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.

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.

Large changes in serum free tryptophan levels do not alter brain tryptophan levels: studies in streptozotocin-diabetic rats.

The effect of meal-induced changes in serum free tryptophan (TRP) levels on brain TRP levels was examined in streptozotocin-diabetic rats. Diabetic rats, fasted overnight, were given free access to a non-protein food containing either no fat or large amounts of fat (45% by weight), and were killed 1, 2 or 3 hr thereafter. Ingestion of the high-fat meal produced large increases in both serum non-esterified fatty acid (NEFA; 2-fold) and free TRP levels (2.5-fold), but no increments in cerebral cortical or hypothalamic TRP levels or in the rate of serotonin synthesis in these brain regions. Because the rats were diabetic, serum levels of the other large neutral amino acids (which compete with TRP for transport into brain) did not vary from fasting values in any of the treatment groups. There thus was no uncontrolled variation in the competitive transport of TRP into brain that might have obscured potential effects due to the alterations in serum free TRP levels. The results add further evidence to the notion that TRP transport into the central nervous system is not influenced by the size of the free TRP pool in blood.

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.

Weight change in depression: influence of "disinhibition" is mediated by body mass and other variables.

The direction of weight change (gain or loss) in depression has recently been found to be a stable characteristic of patients across depressive episodes. A search for determinants of the direction of weight change revealed two candidates: the body mass index (BMI) (weight in kilograms/height in meters squared) and a psychological variable, "disinhibition" of dietary restraint. The present study, of 68 patients with a history of recurrent depression, found a significant correlation between BMI and weight change; in other words, heavier persons were more likely to gain weight if depressed. There was also a correlation between "disinhibition" and weight change. "Disinhibition" correlated with BMI and, when controlled for BMI, age and sex, the correlation between "disinhibition" and weight change fell to insignificance. We conclude that BMI along with age and sex mediated the correlation between "disinhibition" and weight change.