Symposium: Ghrelin: Its Role in Energy Balance
Obesity and the Neuroendocrine Control of Energy Homeostasis:
The Role of Spontaneous Locomotor Activity1
Tamara R. Castañeda,* Hella Jürgens,† Petra Wiedmer,† Paul Pfluger,* Sabrina Diano,**
Tamas L. Horvath,** Mads Tang-Christensen,‡ and Matthias H. Tschöp*2
ABSTRACT Obesity represents one of the most urgent global health threats as well as one of the leading causes
of death throughout industrialized nations. Efficacious and safe therapies remain at large. Attempts to decrease fat
mass via pharmacological reduction of energy intake have had limited potency or intolerable side effects.
Increasingly widespread sedentary lifestyle is often cited as a major contributor to the increasing prevalence of
obesity. Moreover, low levels of spontaneous physical activity (SPA) are a major predictor of fat mass accumulation
during overfeeding in humans, pointing to a substantial role for SPA in the control of energy balance. Despite this,
very little is known about the molecular mechanisms by which SPA is regulated. The overview will attempt to
summarize available information on neuroendocrine factors regulating SPA. J. Nutr. 135: 1314 –1319, 2005.
KEY WORDS:
●
ghrelin
●
physical activity
●
energy expenditure
●
AGRP
●
NPY
●
CART
●
leptin
risk for cancer (8). As a result, the future of the health of the
U.S. population depends critically on identifying and providing the best treatment and prevention strategies for obesity in
the years ahead (9). To date, however, few treatments provide
safe and efficacious weight loss that can be sustained over long
periods of time (10).
Obesity: a serious nationwide health problem
The United States is the epicenter of an ongoing obesity
pandemic (1,2). Rates of obesity and its associated comorbidities are rising steadily in both adults and children in the
majority of the developed and developing world (3–5). This
makes obesity an escalating public health crisis that requires
scientific and public health attention (6). The obesity rates are
rising despite increased public awareness and increasing attention from governments highlighting the need for effective
therapeutic strategies. Currently, 61% of the U.S. population
is overweight or obese and therefore at increased risk for a
number of diseases that are associated with increased body fat
(1,7). Indeed, the obesity epidemic has already resulted in
dramatic increases in type-2 diabetes, particularly among
younger populations (5). Increased body fat also increases the
Low physical activity level as one cause for the increasing
prevalence of obesity
Body fat fluctuates with the difference between energy
intake and energy expenditure over time (11,12). Thus, understanding the regulation of energy balance can be partitioned into
understanding the factors that regulate both energy intake and
energy expenditure (13–15). Whereas the neuroendocrine control of energy intake has received intense scrutiny over the past
decade, much less attention has been paid to the control of
energy expenditure. Nevertheless, a compelling case can be made
that obesity is often associated with lowered rates of energy
expenditure (16). A large body of published evidence has documented, for example, a strong link between time spent watching
television or working at a computer with obesity in both children
and adults (17–21). Unfortunately, despite the apparent importance of energy expenditure for body weight regulation, our
understanding of the components that regulate energy expenditure is less developed (22) (Fig. 1).
1
Presented as part of the symposium “Ghrelin: Its Role in Energy Balance”
given at the 2004 Experimental Biology meeting on April 19, 2004, Washington,
DC. The symposium was sponsored by the American Society for Nutritional
Sciences and in part by Abbott Laboratories, Linco Research, Inc., and Merck
Research Laboratories. The proceedings are published as a supplement to The
Journal of Nutrition. This supplement is the responsibility of the Guest Editors to
whom the Editor of The Journal of Nutrition has delegated supervision of both
technical conformity to the published regulations of The Journal of Nutrition and
general oversight of the scientific merit of each article. The opinions expressed in
this publication are those of the authors and are not attributable to the sponsors
or the publisher, editor, or editorial board of The Journal of Nutrition. The views
expressed herein are those of the authors and do not necessarily reflect those of
Abbott Laboratories, Linco Research, Inc., and Merck Research Laboratories.
The Guest Editors for the symposium publication are Gary E. Truett, Department
of Nutrition, Knoxville, TN, and Elizabeth J. Parks, University of Minnesota, St.
Paul, MN.
2
To whom correspondence should be addressed.
E-mail: [email protected].
Spontaneous physical activity-induced energy expenditure
as an individual determinant of body fat mass
Humans show considerable interindividual variation in susceptibility to weight gain in response to overeating. The
0022-3166/05 $8.00 © 2005 American Society for Nutritional Sciences.
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*Obesity Research Center, Department of Psychiatry, University of Cincinnati, Cincinnati, OH; †Department
of Pharmacology, German Institute of Human Nutrition, Potsdam Rehbruecke, Germany; **Department of
Neurobiology and Department of Ob/Gyn, Yale Medical School, New Haven, CT; and ‡Rheoscience,
Copenhagen, Denmark
NEUROENDOCRINE CONTROL OF SPONTANEOUS LOCOMOTOR ACTIVITY
physiological basis of this variation was recently investigated
(23) by measuring changes in energy storage and expenditure
in nonobese volunteers who were fed in excess of weightmaintenance requirements. Not surprisingly, as energy intake
exceeds energy expenditure and body fat accumulates, the
system responds by increasing energy expenditure. That is, the
system compensates through changes of energy expenditure
when energy intake is no longer under voluntary control.
Importantly, two-thirds of the increase in total daily energy
expenditure in this situation was attributable to increased
spontaneous physical activity (SPA).3 In fact, changes in SPA
directly predicted resistance to fat gain with overfeeding on a
hypercaloric diet. These results point to SPA as a labile
component of total energy expenditure that is a key tool of the
homeostatic system that maintains relatively constant body fat
over time (23). Moreover, these results indicate that differences in the ability to recruit SPA in the face of positive
energy balance are not only predictive but also critical to the
large differences among individuals in their response to positive energy balance and the maintenance of body fat (24,25).
Particularly relevant to human obesity is the phenomenon
of nonconscious, nonexercise activity thermogenesis (NEAT),
a variable that relates to SPA in rodents. NEAT is defined as
the energy expended for everything we do that is not sleeping,
eating, or sports-like exercise (22). It ranges from the energy
expended walking to work, typing, performing yard work,
undertaking agricultural tasks, and fidgeting. Even trivial phys3
Abbreviations used: AGRP, agouti related protein; ARC, arcuate nucleus;
BMR, basal metabolic rate; CART, cocaine amphetamine regulated transcript;
GHS-R1a, growth hormone secretagogue receptor 1a; MCH, melanin concentrating hormone; NEAT, non-exercise activity thermogenesis; NPY, neuropeptide
Y; PVN, paraventricular nucleus of the hypothalamus; SPA, spontaneous physical
activity; TEF, thermic effect of food; VMH, ventromedial hypothalamus.
ical activities can increase metabolic rate substantially and it
is the cumulative impact of a multitude of such exothermic
actions that culminate in an individual’s daily NEAT (25). It
is, therefore, not surprising that NEAT is used to explain the
majority of an individual’s nonresting energy needs. Epidemiological studies highlight the importance of culture in promoting and/or quashing NEAT (26). Agricultural and manual
workers have high NEAT, whereas wealth and industrialization appear to decrease NEAT (27,28). Physiological studies
demonstrate that NEAT fluctuates with changes in energy
balance; specifically, NEAT increases with overfeeding and
decreases with underfeeding (29). Thus, NEAT could be a
critical component in how we maintain our body weight
and/or develop obesity or lose weight (24).
When humans overeat, activation of SPA can dissipate
excess energy and help preserve leanness, and failure to activate SPA may result in susceptibility to gain fat (22,24).
Although the lack of sufficient physical activity has clearly
been recognized as one of the major correlates for the rapidly
increasing prevalence of obesity, countermeasures are mostly
limited to educational recommendations. Although most
obese individuals are well informed about such recommendations, the combination of genetic predispositions with the
environmental challenges of abundant high-energy food,
tempting sedentary lifestyles, and increasingly stressful and
time-consuming professional occupation often conspire to
make a sufficient and chronic increase in physical activity
impossible (30 –32). Although physical activity is the most
variable and easily altered component of total energy expenditure, conscious efforts to increase physical activity must be
considered unsuccessful on an epidemic level, even given the
strong desire to lose weight and the accompanying and consequent high level of suffering in most obese individuals
(3,33). An efficient anti-obesity drug is needed, and a pharmacological increase of SPA may be one option that should be
investigated as one component of a future drug treatment
strategy for obesity.
The WHO, NIH, and the Surgeon General of the United
States have all stated that increasing physical activity is a
priority for obesity prevention and treatment. The WHO
specifically recommends strategies that augment nonexercise
activity and thereby increase energy expenditure by 834 kJ/d
(200 kcal/d). For the average obese subject, 834 kJ/d is the
equivalent to fidgeting-like activity of 2.5 h/d or a strollingequivalent activity (1.6 –3.2 km/h) of 1 h/d (34).
Mechanisms regulating SPA: lessons from rodent models
Gaining a better understanding of the biological determinants involved in the regulation of SPA is essential because, as
outlined above, reduced energy expenditure (NEAT) associated with decreased SPA is thought to be a major underlying
factor in the increasing prevalence of obesity. To facilitate
interpretation in humans, it is helpful to consider evidence
from interventional and less descriptive studies in animal
models. In rodent models, energy intake is frequently not the
major determinant of body fat mass. A better understanding of
the biological determinants involved in the regulation of SPA
from experiments in animal models will have important and
beneficial implications for the development of strategies for
the prevention of weight gain leading to obesity and subsequent morbidity and mortality in the human population. In
addition to its favorable effects on energy balance and fat mass,
increased SPA might also have a direct positive influence on
glucose metabolism (35,36).
To understand the molecular mechanisms regulating SPA,
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FIGURE 1 Energy expenditure can be partitioned into 3 basic
categories: BMR, the thermic effect of food, and SPA. These categories
can be assessed with the help of, i.e., an indirect calorimeter. Because
caged laboratory rodents do not exercise voluntarily in the way that
humans do, SPA in rodents is typically defined as all physical activity
occurring within a single-housed cage situation that is above BMR and
the TEF. Defined this way, SPA is independent of its specific character
(running, grooming, climbing, fidgeting, feeding, sniffing, rearing, drinking, etc.). A substantial change in ongoing SPA will therefore be reflected as a substantial change in energy expenditure as measured by
indirect calorimetry (22,37,40).
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SYMPOSIUM
Neuroendocrine regulation of energy balance
Energy balance is achieved when energy intake (ingestion
and absorption of calories) equals energy output (energy expenditure, thermogenesis). Based on more than half a century
of research on the regulation of food intake and energy expenditure in rodents and humans, but most importantly triggered by the discovery of leptin in 1994, the complex current
model for the neuroendocrine regulation of energy balance has
emerged. Based on this model, afferent signals continuously
inform central nervous circuits about acute and chronic
changes in energy homeostasis, which in turn integrate this
information and respond with efferent signals to immediately
initiate the respective adaptive changes and regain energy
balance (11,13–15,47–57) (Fig. 2).
Over the past 3 years, an important new aspect has been
added to this view by the discovery of the peptide hormone,
ghrelin, which is mainly derived from the stomach, but which
is also expressed in the pancreas, duodenum, and hypothalamus (58). Ghrelin administration stimulates food intake and
increases body fat mass (59). The only identified ghrelinresponsive receptor, the growth hormone secretagogue receptor (GHS-R1a) (60), is localized in specific neurons of the
hypothalamic arcuate nucleus, neurons which coexpress the
orexigenic neuropeptide Y (NPY) and agouti-related protein
(AGRP) (61,62). Circulating plasma concentrations, as well
as gastric mRNA levels of ghrelin, increase with energy restriction or fasting (59) and decrease immediately following
food intake in both rodents and humans (59,63,64). Based on
these findings, ghrelin has been proposed to represent the only
peripheral orexigenic agent and to finally prove the disputed
existence of a meal initiation factor (65). Although numerous
reports have focused on the orexigenic effects of ghrelin
(48,66 – 68), very few have investigated its effects on energy
expenditure (59,69,70), and we believe that the latter can
subtantially contribute to a ghrelin-induced increase in fat
mass.
Ghrelin and the neuroendocrine regulation of SPA
We recently reported preliminary data (71), which reveal
for the first time a suppressive effect of ghrelin on SPA. In
several independent rodent experiments, there was a substantial decrease of SPA following ghrelin administration into the
lateral-cerebral ventricle at the same dose that substantially
increased food intake in these rats. Although this finding
concurs with the conclusion that ghrelin is a hormone that
communicates to central nervous system centers at times that
energy should be saved (67), it may appear contradictory that
a factor that triggers food intake (which in and of itself
requires a certain amount of physical activity) also suppresses
SPA. However, whereas a single central administration of
ghrelin increases food intake in rats acutely, the decrease in
SPA occurs after a delay. We propose that in accordance with
the general aim to accrue and save energy in times of energy
restriction, ghrelin might first trigger appetite and food intake
and only later suppress nonessential energy expenditure such
as SPA to protect the newly ingested and/or the limited
remaining energy in store.
Intrigued by these findings, we have started to investigate
whether ghrelin-responsive neuropeptides, such as AGRP and
NPY, which are thought to mediate ghrelin’s orexigenic effects
(48,72), might have comparable effects on SPA. We therefore
have generated further unpublished data (73) indicating that
centrally administered AGRP suppresses SPA in a pattern and
to an extent comparable with that triggered by ghrelin,
whereas NPY, if anything, tends to increase SPA.
Expanding the neuroendocrine regulation of energy balance
to include SPA
Intrigued by our observations that some neuropeptides suppress SPA in rats in addition to their potent orexigenic activity, we carefully revisited the literature on neuroendocrine
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it is mandatory to explicitly define and consequently dissect its
physiological and behavioral components. As discussed above,
total energy expenditure is composed of basal metabolic rate
(BMR), the thermic effect of food (TEF), and physical activity
(Fig. 1) (37). One model provides a new environment for
rodents by placing them in an open field, thus eliciting increased exploratory activity (influenced by both motivational
and behavioral components) (38). Another model allows the
nonvolitional activity or SPA of an adapted rodent housed in
a single cage and includes ambulatory and climbing movements as well as rearing and fidgeting and food intake–and
drinking-associated activity (39).
Scientific understanding of the regulation of SPA is severely incomplete. Some authors argue that the predominant
direction of influence goes from body weight to compensatory
activity (40), whereas others argue that changes in activity are
responsible for changes in body weight (22). Several relatively
extensive and detailed reports have documented an influence
of diet, rodent strain, gender, age, or hypothalamic lesions on
the level of SPA in rodents (40). Diet has been suggested as
one determinant of SPA based on the observation of hyperactivity in food-deprived animals. However, no solid evidence
could be found to generalize this hypothesis, particularly because diet does not explain reduced activity in DIO rodents
(40). SPA does seem to be a function of the specific rodent
strain examined because there are considerable differences in
SPA among, for example, ob/ob mice, New Zealand obese
mice, and Zucker fatty (fa/fa) rats and between C57B mice
(average SPA) and BALB/c mice (rel. high SPA) or 129sv
mice (40,41). An age-related decrease in SPA has been reported (42), as well as a higher average SPA level in female
rats and mice relative to males (43). This difference varies
with the estrus cycle and has been suggested to be partially due
to changes in circulating concentrations of estrogen based on
studies in ovariectomized rats (44). Lesions of the ventromedial hypothalamus (VMH) increase food intake and body
weight, but also reduce SPA (45). Interestingly, rats with
lesions of the paraventricular nucleus of the hypothalamus
(PVN) develop an obese phenotype very similar to the one
observed in VMH-lesioned animals, but they do not exhibit
reduced SPA (46).
Although these findings are collectively suggestive with
respect to the lack of physical activity contributing to human
obesity, not all findings in rodents will be relevant for the
understanding of the causes, molecular mechanisms, and treatment modalities of human obesity (40). That said, SPA and its
contribution to energy expenditure are difficult to measure in
humans. Furthermore, the multiple environmental and voluntary influences on energy expenditure are difficult to control in
humans. For one thing, humans are conscious of the benefits of
physical activity, and this can bias the outcome of experiments. At another level, studies of hypothalamic neuropeptide
action or expression cannot easily be performed in humans.
Rodent models therefore provide several advantages for the
investigation of the molecular mechanisms controlling the
level of SPA.
NEUROENDOCRINE CONTROL OF SPONTANEOUS LOCOMOTOR ACTIVITY
1317
factors regulating food intake, focusing on possible reports of
effects on SPA.
Leptin and ghrelin are currently considered endogenous
opponents in the regulation of food intake and body weight
(48,67). Interestingly, whereas ghrelin decreases SPA, leptin
replacement therapy in ob/ob mice, which have a pathologically low level of locomotor activity, increases their SPA even
before a substantial decrease in body weight occurs (74).
Melanin concentrating hormone (MCH), a neuropeptide localized in the lateral hypothalamus that increases food intake
in rodents, decreases locomotor activity (75). As a matter of
fact, MCH may be a downstream mediator of leptin-induced
changes in SPA (76).
Cocaine amphetamine regulated transcript (CART) decreases food intake and body weight (77,78), but increases
locomotor activity in rats after central administration (79).
Genetic deletion of orexin A, a neuropeptide that is mainly
associated with arousal, but that also increases food intake,
causes narcolepsy (80). It therefore does not seem surprising
that intracerebroventricular orexin A administration causes an
increase of SPA in rats (22). Although AGRP, which is an
inverse agonist at the melanocortin 3 and 4 receptors, has not
been previously investigated with respect to the regulation of
SPA per se, it has been reported that AGRP counteracts
physical hyperactivity and self-starvation in rats presented
with running wheels (81). MTII (agonist) and SHU9119
(antagonist), powerful exogenous melanocortin 3 and 4 receptor ligands, have been reported to increase and decrease SPA
in rat, respectively (82,83). The novel neuropeptides W and B
appear to modify body weight by influencing both food intake
and locomotion activity via the recently characterized Gprotein coupled receptor GPR7 (84). Genetic ablation of
brain-derived neurotrophic factor, which has recently been
reported to influence food intake via the melanocortin receptor system, leads to increased SPA in mice (85). Neuromedin
U is a gut hormone and neuropeptide, which has been characterized as a satiety factor with additional stimulating effect
on SPA (86). Two neurotransmitters, ␥-amino-butyric acid
and dopamine, have been implicated in the regulation of
appetite and body weight (50) and are certainly both important for the central nervous control of motor activity (87).
The dopaminergic system has, for example, been suggested to
mediate orexin A–induced activity, and an involvement of the
ventral tegmental area dopaminergic system in orexin-induced
activity has already been demonstrated (88).
The important point is that there is a wealth of scattered
information indicating that the same neural signals that control food intake also may have a profound effect on physical
activity.
SUMMARY
During the preparation of this article, two other important
findings were reported. One of them provides strong evidence
for a causal role of posture allocation and specific patterns of
non-exercise activity for human obesity. Specifically, Levine
and colleagues (89) report that obese individuals are on average seated 2 h longer per d than lean individuals. This differ-
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FIGURE 2 Myriad peripheral signals (including many hormones) are
continuously providing central circuits
with information about ongoing energy
balance and metabolic homeostasis.
Specific areas of the brain that have
been identified as important for processing this afferent information as well
as for the continuous adjustment of an
appropriate efferent response are depicted in this figure and discussed in
this review article. These areas include
the nucleus of the solitary tract (NTS),
the lateral parabrachial nucleus (LPB),
and other areas in the brainstem region, as well as the arcuate nucleus
(ARC), the VMH, the dorsomedial hypothalamus (DMH), the PVN, and the lateral hypothalamus (LH). Communication among these neuronal circuits
relies on the generation and release of
specific neurotransmitters and neuropeptides. Although expression of the
potently orexigenic AGRP is strictly limited to the ARC, the similarly strong
appetite-promoting NPY is expressed
in numerous regions of the brain including areas involved in the regulation
of body weight. The exact anatomical
and functional blueprint of the projections among these other neuropeptides
and neurotransmitters regulating energy homeostasis [such as CART, MCH, thyrotropin releasing hormone (TRH), corticotropin releasing hormone (CRH), oxytocin (OXY), and
vasopressin (AVP)] is unknown. Even less known are the influences of visual, olfactory, and circadian inputs, which might in part be mediated through
specific neuronal circuits in brain areas such as the suprachiasmatic nucleus (SCN) or the supraventicular zone (SPZ). Based on our preliminary data
and scattered published evidence, we propose that specific parts of these neuroendocrine circuits are controlling SPA in addition to regulating food
intake. This schematic figure is based on data from Elmquist, Physiol. Behav. 74 (2001) 703–708; Barsh & Schwartz, Nat. Rev. Genet. 3 (2002)
589 – 600; Ahima & Osei, Trends Mol. Med. 7 (2001) 205–213; Berthoud, Neurosci. Biobehav. Rev. 26 (2002) 393– 428; Kalra et al., Endocr. Rev. 20
(1999) 68 –100; Saper et al., Neuron 36 (2002) 199 –211; Flier, Cell 116 (2004) 337–350.
SYMPOSIUM
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ACKNOWLEDGMENTS
The authors are grateful to Steve Woods and Randy Seeley for
very helpful discussions and comments on the manuscript.
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