Langhans W, Geary N (eds): Frontiers in Eating and Weight Regulation.
Forum Nutr. Basel, Karger, 2010, vol 63, pp 1–8
Introduction – Obesity and Food Intake:
Basic and Clinical Approaches
Annette D. De Kloeta ⭈ Stephen C. Woodsa,b
a
Program in Neuroscience and bDepartment of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USA
Background
This introduction considers the current status of research on obesity and therapeutic
strategies for it, including their relationships to the physiology of eating. Given the
immense research effort currently targeting overweight and obesity, this summary
is necessarily only a snapshot of a large and rapidly evolving area. It is nonetheless of
immense importance since there is no sign that the obesity epidemic is abating, and
because obesity per se carries so great a risk for numerous co-morbidities, such as
type-2 diabetes mellitus (T2DM), several cardiovascular disorders and certain cancers. The topic is at the heart of the theme of this volume, given that obesity cannot
exist unless energy intake (i.e. eating) chronically surpasses energy expenditure and
since tackling aspects of eating represents, at least at present, the more approachable
limb of the energy equation. As noted below, even the most successful therapeutic
method now available, gastric bypass surgery, ultimately owes its efficacy to reduced
energy intake.
Generally speaking, obesity refers to a state of excessive body fat and implies an
unhealthy or undesirable body condition. Depending on one’s perspective, obesity can
be considered a symptom that carries an increased risk for numerous serious medical
conditions or co-morbidities; a disease that warrants confrontation by governments,
national health agencies, private benevolent groups, and third-party (health insurance) providers; or merely a warning that one should consider changing his or her
lifestyle by consuming fewer calories each day [1]. Especially now that obesity has
become a major focus of many health-care organizations, much new information has
been forthcoming in the past few years and is beginning to influence the practice of
medicine. It is important to realize that obesity is not a novel human condition; rather,
evidence points to its existence in prehistoric times. What is novel is the persistent
creep upward in the incidence of overweight and obesity in most human populations,
a trend that is now widely considered an epidemic.
We now know much more about body fat than we did even a decade ago. Fat deposited in fat cells, or adipocytes, located in the abdominal region (i.e. the excess fat that
increases waist circumference, whether subcutaneous or intra-abdominal) carries a
greater risk for metabolic and cardiovascular disorders than fat located subcutaneously in the limbs or buttocks. As a general rule, females have a greater proportion of
fat distributed subcutaneously whereas males have proportionally more abdominal
fat. As fat mass increases, so does the complexity of the fat depot or individual fat
organ; further, as obesity develops, both the size and ultimately the number of individual adipocytes increases. The increased fat mass is also associated with increased
number and activity of macrophages and other immune cells that are attracted into
the organ. These along with the adipocytes themselves secrete increasing amounts of
hormones and other factors that predispose to metabolic and cardiovascular dysfunction, and they secrete less of some factors such as adiponectin that help prevent symptoms of diabetes. Several of these secretions are inflammatory factors, and obesity is
now recognized as a chronic inflammatory disorder. Finally, as energy intake continues to outpace energy expenditure and body fat continues to expand, fat is deposited
ectopically, i.e. outside the adipose tissue depots. Ectopic fat can occur in most tissues
as obesity worsens, including the liver, heart, pancreas and skeletal muscle, and in
each instance it compromises the normal functioning of those organs.
The increasing number of individuals with obesity, coupled with the growing
understanding of the health risks obesity carries, has increased the urgency of developing safe and efficacious treatment options. The current therapeutic approaches for
the treatment of obesity can be partitioned into lifestyle modifications, pharmacotherapy and bariatric surgery. The next sections briefly review each modality.
Lifestyle Modifications
Lifestyle modification is the first-order treatment for obesity recommended by the
World Health Organization and the National Institutes of Health of the USA (NIH)
[2, 3]. Their guidelines state that an individual should attempt lifestyle interventions
for at least 6 months before other approaches are considered, and then to supplement
the effort with additional approaches (e.g. pharmacotherapy) only with a physician’s
consent. Lifestyle interventions generally rely on increasing physical activity and/or
decreasing caloric intake, with the goals of reducing body weight as well as decreasing the risk of the co-morbidities associated with obesity [4–6]. While this formula
can be successful with frequent and intense educational and counseling programs, it
is difficult for many obese individuals to maintain it for prolonged intervals without
substantial support [5, 7]. Such relapse makes sense from a physiological perspective. That is, while significant weight can be lost in the short term (weeks or perhaps
months), this recruits negative-feedback controllers, such as the adiposity signals discussed below, that work to thwart those efforts, with a common outcome being that
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most lost weight is regained within a year or two [7]. It must be asked, therefore,
why gaining weight and becoming obese seems so much easier than being able to
lose it. While there are no obvious answers to this apparent paradox, it does seem to
be the case that the weight-regulatory system has an inherent bias favoring weight
gain whenever the environment permits it [8]. Many people believe that the current
epidemic of obesity is a natural consequence of an environment that favors taking in
more energy (i.e. in the form of calorie-dense, palatable foods, or significant amounts
of high-fructose corn syrup) while requiring less energy expenditure at many jobs, i.e.
that it is an unhealthy lifestyle that leads to obesity in the first place.
Dieting is the most common approach adopted by people trying to lose weight.
New popular diets appear regularly, most of which claim some unique advantage in
helping individuals be successful [7]. Many entail increasing or decreasing the intake
of one or another macronutrient (i.e. high or low proportion of fat, carbohydrate or
protein). However, meta-analyses comparing the efficacy of such diets indicate that
regardless of macronutrient composition, when matched for caloric content, the
weight-reducing effects of popular diets are equipotent, i.e. macronutrient content is
not important so long as caloric intake is less than caloric expenditure [7, 9].
Increased physical activity (i.e. more exercise) is considered an excellent alternative or complement to dieting, and it has the added benefit of improving other
parameters, such as insulin sensitivity and muscle tone, independent of weight loss.
Unfortunately, increasing exercise has proven to be even more difficult in the longterm than dieting for most obese or overweight individuals.
All in all, although lifestyle modifications are the initial and most common treatment options recommended for and used by overweight and obese individuals, their
modest efficacy coupled with their poor long-term success has focused research
efforts on other strategies, including pharmacotherapy and bariatric surgery.
Pharmacotherapy
Pharmacological targets for the treatment of excess weight include appetite
(sibutramine), fat absorption (orlistat), weight-regulatory brain circuits (cannabinoid
receptor-1 (CB1) antagonists), and metabolism (CB1 antagonists; drugs that stimulate uncoupling proteins). So-called ‘off-label’ applications of medications primarily
intended for other illnesses, such as the antidepressant fluoxetine, also may facilitate
weight loss. In addition, two types of medications targeting type-2 diabetes also have
weight-lowering properties, GLP-1 agonists and amylin agonists. Nevertheless, only
two compounds are currently approved for chronic weight loss in most countries:
orlistat (Xenical, Roche Laboratories, Inc.) and sibutramine (Meridia, Abbot Labs,
Inc.). Each results in an average weight loss of only 3–5 kg, and each has bothersome side effects, reducing long-term adherence. Given this situation, one readily
comprehends the massive efforts of pharmaceutical firms and universities to exploit
Introduction
3
our understanding of the physiology of eating, as detailed throughout this book, to
develop better medications for the treatment of obesity.
Sibutramine acts within the brain, reducing the reuptake of secreted serotonin and
nor-epinephrine, and to a lesser extent dopamine [10]; hence, sibutramine necessarily
impacts numerous circuits not directly relevant to energy homeostasis. Sibutramine
reduces eating and may also elicit a small increase of energy expenditure [11].
Numerous clinical studies have documented the ability of sibutramine to cause weight
loss and slow the rate of weight regain after dieting, as reviewed in recent meta-analyses [12, 13]. Chronic sibutramine treatment leads to modest weight loss, reduced body
fat and waist circumference, and improved glycemic and lipid profiles. The major side
effect is increased systolic and diastolic blood pressure and heart rate, symptoms that
can be problematic in some individuals [11]. Although the average weight loss due to
sibutramine is modest, an important point is that even small reductions of total fat
translate into proportionally larger reductions of visceral or abdominal fat, the fat that
poses the greatest risk for diabetes and cardiovascular problems [14].
Orlistat inhibits gastric and pancreatic lipase [15], resulting in about one third of
ingested fat not being absorbed and consequently excreted in the feces [16]. A recent
meta-analysis confirmed that orlistat reduces body weight, body fat, waist circumference and plasma glucose; results in slightly reduced systolic and diastolic blood
pressure, and decreases plasma low-density lipoprotein (LDL) triglyceride [13]. The
major side effect is oily fecal discharge, which greatly reduces long-term compliance.
Direct clinical comparisons of sibutramine and orlistat suggest that sibutramine has a
small, but significantly greater effect on weight loss and glycemic parameters.
Glucagon-like peptide-1 (GLP-1) is an intestinal incretin hormone secreted during
meals, and increasing evidence indicates it plays a role in satiation [17, 18]. Because
GLP-1 acts to augment prandial insulin secretion, small-molecule GLP-1 receptor agonists are prescribed as an adjunct treatment for T2DM. Patients receiving these compounds often experience modest weight loss in addition to improved glucose tolerance
[19–21]. However, it is not clear how the compounds act to reduce weight because
compounds that prevent the breakdown of endogenous GLP-1 share the antidiabetic
but not the weight-lowering properties of GLP-1 agonists [20], and because the mechanism may not involve reduced food intake [19, 22]. Two other gut intestinal hormones
that appear to have potential as antiobesity therapies are ghrelin and peptide YY [19].
Amylin is a peptide hormone co-secreted with insulin from pancreatic B cells,
whose role in eating is reviewed elsewhere in this book [23] and by other authors [18,
24]. Amylin analogs are used in the treatment of diabetes, and can result in modest
weight loss [23, 25].
CB1 receptor antagonists are another class of compounds with apparent promise for
reducing body weight and improving glucose and lipid profiles. In both animal models and human clinical trials, CB1 agonists cause a transient reduction of food intake
and maintained weight loss with associated reduction of plasma lipids and improved
glucose tolerance [26]. In spite of the metabolic improvements, CB1 antagonists have
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De Kloet · Woods
not been widely approved as weight-loss agents due to a tendency to exacerbate mood
disorders in some obese patients [27, 28]. An important goal of future research will be
to develop analogs of these compounds that lack the undesirable side effects.
Bariatric Surgery
At present, the most efficacious treatments for reducing excess body weight are one
or another type of bariatric surgery. These were initially developed with the intent to
manipulate the gastrointestinal tract so as to alter the intraluminal capacity for food
by reducing the volume of the GI tract, to reduce nutrient absorption, or both [29].
This led to procedures that place various kinds of restrictions to limit the available
volume of the stomach into which swallowed food can enter (i.e. gastric bands or
gastric sleeves) and/or rearranging the intestinal passageway so to reduce the transit
distance covered by ingested food (e.g. roux-en-Y gastric bypass (RYGB); ileal interposition). The number of humans undergoing such procedures, and the number of
variations of each procedure, has increased dramatically over the last few years, and
new data are forthcoming regularly, such that any conclusions are likely to be modified over the next few years. A few generalizations can nonetheless be made, and most
apply both to gastric banding and to RYGB, with RYGB having a greater effect in
reducing body weight. First of all, the degree of weight loss achieved by bariatric surgery is dramatically greater than can be achieved by any presently known lifestyle or
pharmacological means. Second, the weight loss is long-lasting in that many subjects
have been followed for more than 15 years with little weight regain [30]. In addition,
individuals with successful surgeries have reduced all-cause mortality over at least 15
years, pointing to a major health benefit [30]. Third, the major cause of weight loss
seems to be reduced appetite and avoidance of fatty (i.e. energy dense) foods, with
little evidence for malabsorption of nutrients. Fourth, and what has perhaps been
the most surprising from the medical standpoint, is the reduction in the severity of
symptoms of diabetes, with many bariatric surgery patients essentially undergoing
complete remission at the time they are discharged from the hospital postsurgery and
prior to significant weight loss [31, 32]. The mechanisms responsible for the decreased
appetite and remission of diabetes are unknown, but probably include some combination of enhanced nutrient stimulation of the distal intestine and consequent enhanced
release of incretin hormones (e.g. GLP-1), reduced stimulation of the proximal intestine, reduced secretion of gastric hormones such as ghrelin, or others [33].
Eating
This volume is rich with information on the myriad physiological influences on eating
[17]. As a generalization, most factors that influence eating can be considered either
Introduction
5
homeostatic or nonhomeostatic, with homeostatic factors relating to the regulation of
one or more key physiological parameters such as body fat, blood glucose, or energy
availability. Nonhomeostatic influences include hedonic and emotional factors, learning and experience, the social situation, stress, circadian rhythms, and so on.
My colleagues and I summarized the organization of homeostatic factors a decade
ago [34, 35], and the basic model still holds, albeit it with numerous refinements,
many described in this volume, having being added. Thus, as described in more detail
in another chapter of this volume [17], a few rudiments of the current view of the
physiology of eating are: (1) the initiation of meals is most often due to non-homeostatic factors such as habit or convenience; (2) meal termination is determined in part
by negative-feedback satiation signals such as cholecystokinin that are elicited during
the meal, usually stimulate the hindbrain and act to increase the feeling of fullness
and end the meal, and (3) hormones or other signals that are secreted in proportion
to body fat (adiposity signals, such as insulin and leptin) are integrated at the level of
the hypothalamus and alter the sensitivity of the brain to meal-generated satiation
signals. Thus, if one is dieting and loses weight, adiposity signals are reduced and the
brain becomes less sensitive to CCK and other satiation signals, and larger meals are
consumed until body weight is restored. Conversely, excess weight gain is accompanied by increases in adiposity signals and the brain is more sensitive to satiation
signals.
All aspects of this model are expertly covered in the various chapters of this volume. There are contributions on the generation and influence of satiation signals [19,
36], on adiposity signals and their entry into the brain [23, 37–39], on hypothalamic
circuits [40], their sensitivity to nutrients [41, 42], and their interactions with the
hindbrain [43, 44]. There are also contributions reviewing exciting new areas, including the articles by Cecil and Hetherington [45] and Neary and Batterham [46] on the
role of genetic factors, Kringelbach and Stein [47] on the emerging field of functional
brain imaging, and Stice and Dagher [48] on the integration of genetic and imaging
approaches.
Conclusion
Although human and animal studies indicate that lifestyle modifications can be effective obesity therapies; indeed, as described in a recent study [49], they are sometimes
more effective than pharmacological therapy, and the low level of adherence to these
lifestyle therapies has focussed contemporary translational research for treating overweight and obesity onto pharmacological and surgical approaches. Considerable further research is both needed and ongoing in this regard. This volume makes a valuable
contribution to providing the physiological foundation for that effort.
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Stephen C. Woods
Department of Psychiatry, University of Cincinnati
2170 East Galbraith Road
Cincinnati, OH 45237 (USA)
Tel. +1 513 558 6799, Fax +1 513 297 0966, E-Mail [email protected]
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