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Lady Davis Institute, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec, Canada H3T 1E2
REGULATION OF BODY
WEIGHT is a complex and dynamic process. Many aspects of this
regulation have been addressed by recent publications in the
American Journal of Physiology-Regulatory, Integrative and
Comparative Physiology. Among them are delineation of pathways
signaling satiation; interactions with other physiological control
systems, notably cardiovascular and reproductive systems; exploration
of factors that determine susceptibility to diet-induced obesity; and
temporal aspects of body weight regulation. The last includes rhythmic
events of various cycle lengths, from infradian to circa-annual
periods, and also developmental and age-related events.
Today, leptin, neuropeptide Y (NPY), orexins, cocaine- and
amphetamine-regulated transcript (CART), amylin, and
proopiomelanocortin (POMC) are studied largely in relation to their
putative or demonstrated roles in the regulation of food intake and of
body weight. Recent studies published in the journal illustrate that
most, if not all, of these peptides are also involved in regulation of
other behavioral or biochemical processes. Thus orexins A and B given intrathecally are shown to activate sympathetic preganglionic neurons
and raise both blood pressure and heart rate (3). Similar effects are seen after central orexin injections that target sites in
the medulla known to be involved in cardiovascular control (7). The effect of intracerebroventricular CART to reduce
food intake occurs primarily at a hindbrain site and is associated with
specific alterations of motor behavior that appear unrelated to
ingestion (1). Amylin, infused into the nucleus accumbens, reduces not only feeding and drinking but also ambulation
(4). Administration of NPY intracerebroventricularly
stimulates feeding and also inhibits sexual behavior in male rats
(2) and in female hamsters (10). The latter
report shows that the feeding and sexual behavior responses are
mediated by different receptor subtypes. Injection of leptin
intracerebroventricularly reduces food intake and, as expected,
this effect is attenuated by SHU9119, an antagonist of melanocortin
receptors. The same leptin injection also elevates circulating
gonadotropin levels and increases the weight of seminal vesicle; these
effects were not affected by SHU9119, suggesting that leptin
affects the two systems via separable circuits (22).
Other interactions between the reproductive system and regulation of
body weight are also addressed. In female rats, estradiol reduces meal
size, food intake, and body weight largely by increasing the potency of
satiation signals such as glucagon (18). In the nucleus of
the solitary tract and downstream sites involved in negative feedback
control of meal size, estradiol enhances the induction of
c-Fos by feeding (16). Typically such studies
are performed using ovariectomized animals with or without estradiol replacement. Davidge et al. (14) showed that to assure
biological lack of estrogens, it is necessary to either reduce caloric
intake to match control body weight or to include an aromatase
inhibitor. A similar caution is raised by the report that lack of
estrogens induces salt-sensitive hypertension in female spontaneously
hypertensive rats and that the phytoestrogens found in regular rat chow
are sufficient to prevent the problem (17).
Laboratory rats can be separated either a posteriori (8,
25) or by breeding (27) into groups that differ in
their susceptibility to obesity when placed on a high-fat diet. These
studies demonstrate the importance of increased caloric intake to gain
of body weight and fat content (8). Palatability of the
food employed also affects intake over both short and long terms
(24, 26), whereas fat content of the diet per se alters
responses to satiety signals (11, 12, 28). Different
strains of mice show distinct dietary preferences that appear to depend
on palatability in some cases and on postingestive signals in others
(38, 39). Interestingly, rats that are susceptible to
diet-induced obesity show much smaller responses to stressors (plasma
corticosterone, norepinephrine excretion, expression of
corticotropin-releasing hormone) than do the diet-resistant rats
(27).
Given the importance of overeating to weight gain in rodents as in
humans, it is not surprising that pathways involved in signaling
satiety are under intensive study. CCK is perhaps the archetypal
satiety signal, being secreted from the intestine in response to the
presence of fatty acids in the lumen. In humans, the satiating effect
of CCK is mediated by the CCK-A receptor (5, 20). Under
some conditions, responses to CCK can be strong enough to prevent
weight gain in rats over extended periods (13). Adaptation
to a high-fat diet (12) or chronic CCK infusion
(11) blunts the ability of CCK to reduce food intake.
There is evidence for a synergistic interaction between CCK and leptin
to reduce body weight to a greater extent than can be explained by the
reduction of caloric intake (31), although others have
failed to detect significant interaction between CCK and leptin
(42). Similarly, leptin delivered subcutaneously over 75 days caused substantially more weight loss in ob/ob mice
than occurred in pair-fed mice (34). Vagal afferents play
an important role in signaling gastric distension (19),
and some part of the actions of CCK is mediated by activation of vagal
afferents (35). Studies employing destruction of visceral
afferents by capsaicin indicate redundant signaling (23,
28). Another satiety signal, amylin, is cosecreted with insulin and acts both peripherally and centrally (4) with
similar potency as CCK to inhibit gastric emptying and food intake
(36). Lutz and colleagues showed obligate dopaminergic
involvement in amylin signaling (30) and also provided
evidence for involvement of histamine H1 receptors (33).
Dopaminergic signaling in hypothalamic nuclei has also been implicated
in the anorexia seen in tumor-bearing rats (37).
Time-dependent events contribute significantly to the regulation of
body weight; these include cyclic (e.g., circannual) events as well as
developmental or age-related changes. These studies provide insight
into long-term regulation of body weight. Thus short "winterlike"
day length induces lipolysis in white adipose tissue that is mediated
by direct sympathetic innervation of the fat pads and by epinephrine
released from the adrenal medulla (15). Retrograde tracing
of sympathetic fibers from these fat pads caused labeling of neurons in
the suprachiasmatic nucleus that express melatonin receptors
(40). Superimposition of acute food restriction on a
long-term short-photoperiod regimen exposed differential regulation of
the orexigenic agouti-related protein and NPY mRNA in the arcuate
nucleus of the hypothalamus (32). Among other rodents,
woodchucks maintained at constant ambient temperature, with variation
only of photoperiod, display pronounced circannual variation of
circulating leptin, body weight, and food intake (9). Body
weight and particularly food intake appear to lead leptin levels,
although interpretation is perhaps complicated by obligate torpor in
this species. Rats also display photoperiod-dependent rates of weight
gain and sexual maturation, and differences among strains suggest
genetic heterogeneity (21). Lesioning experiments in sheep
indicate the arcuate nucleus plays an obligate role in the generation
of photoperiod-induced rhythms of food intake and body weight in that
species (29).
It is well known that appetite is reduced in the elderly, although the
mechanism(s) involved are not clear. A study by Blanton et al.
(6) differentiates between aged and senescent rats in their response to intracerebroventricular NPY. In healthy aged rats
(i.e., still gaining weight), NPY induced feeding that was not
different from that seen in younger animals. In contrast, the senescent
rats (i.e., during the terminal weight losing phase of life) had a
markedly blunted eating response to NPY. At the other end of life,
Truett et al. (41) studied weight gain by baby Zucker rats
that were weaned naturally by their mothers. Up to 21 days of age,
homozygous fatty rats (fa/fa) had very similar rates of
weight gain as their lean (+/±) littermates. Hyperphagia and increased weight gain emerged only at 22-23 days of age,
suggesting a developmental switch that enables the program that
responds to leptin in older animals.
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Address for reprint requests and other correspondence: W. A. Cupples, Lady Davis Institute, SMBD-Jewish General Hospital, 3755 Cote-Ste-Catherine, Montreal, Qc, Canada H3T 1E2 (E-mail: wcupples{at}ldi.jgh.mcgill.ca).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/ajpregu.00728.2001
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REFERENCES
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