AgRP, agouti-related peptide; CCK, cholecystokinin; NPY, neuropeptide Y; POMC, pro-opiomelanocortin; PYY, peptide YY.

Insulin
Insulin is produced by the beta cells of the endocrine pancreas and regulates glucose
uptake, the storage of absorbed nutrients, and caloric or energy balance. Insulin can be
transported across the blood-brain barrier and binds to receptors present in areas of the
hypothalamus that control food intake. In patients with type 1 diabetes mellitus, the
absence of adequate insulin is associated with increased food intake. In rodents,
administration of insulin to the brain reduces food intake, whereas similar
administration of insulin antibodies increases feeding behavior and weight gain.
Additional evidence indicates that insulin potentiates satiety factors released from gut
endocrine cells.
Leptin
Until the 1990s, fat was believed to do li le but store calories and act as an insulator. In
1994 the discovery of leptin, an appetite-suppressing hormone secreted by fat cells,
started a new era of research involving fat and the control of food intake. Leptin
receptors have been identified on neurons present in both pathways in the arcuate
nucleus of the hypothalamus. The pathway producing the appetite-stimulating peptides
NPY and AgRP is inhibited by leptin, and the pathway producing POMC, which inhibits
food intake, is stimulated by leptin. Leptin is also secreted from endocrine cells in the
stomach in response to feeding and cholecystokinin (CCK). This is in contrast to the
leptin found in fat cells that is released constitutively. Leptin receptors are also present
on vagal afferent neurons. Disruption of leptin receptors in the hypothalamus produces
only modest obesity compared with that of total receptor knockout. This finding suggests
that the effects of leptin on vagal afferent receptors are more important. Leptin has been
demonstrated to increase the satiety response to CCK and may sensitize vagal afferent
neurons to this gut hormone.
Thus leptin appears to be part of a negative feedback system for the regulation of food
intake. As fat stores increase or during the response to a meal, more leptin is released,
food intake is inhibited, and energy expenditure is increased. The discovery of leptin
created great anticipation that it could be used to reduce food intake in obese persons,
until investigators showed that most obese persons have high circulating levels of the
hormone. Thus, although exogenous leptin reverses obesity in humans caused by its
absence, leptin deficiency is not the usual reason for overeating and obesity.
The Gastrointestinal System
Endocrine cells lining the GI tract are the source of several peptides known to regulate
feeding behavior. Some peptides act on vagal afferents, thereby relaying information to
the satiety center in the hindbrain. Others are transported through the blood-brain
barrier and act directly on the hypothalamus. The information reaching these two centers
is integrated into the overall satiety/hunger response.

Cholecystokinin
CCK was the first peptide shown to elicit satiety. In 1973 Smith, Young, and Gibbs
showed that CCK injection caused rats to stop eating and begin grooming. This response
occurred in animals with an open gastric fistula, which excluded gastric distention as a
stimulus. As discussed in Chapter 1, CCK is released from I cells in the duodenal mucosa
in response to fat and protein digestion products. CCK causes its inhibition of feeding by
acting on vagal afferents because its effects are reduced by vagotomy or by chemical
destruction of the vagal afferents with capsaicin. The effect of CCK also is inhibited by
lesions of the NTS. CCK1 receptors are present on intestinal vagal afferents, a finding
strongly supporting the idea that the short-term regulation of prandial satiety is largely
the result of the release of CCK. The CCK1 receptors on vagal afferents transmit signals
to the NTS, thus decreasing the expression of melanin RNA and inhibiting the release of
ghrelin and the expression of its receptor. One of the physiologic effects of CCK also is
the inhibition of gastric emptying. This results in increased gastric distention and
contributes to the satiety response. In humans, the infusion of CCK inhibits food intake
and decreases feeding time, and the infusion of a CCK1 receptor antagonist produces the
opposite effects. The arcuate nucleus of the hypothalamus and the NTS of the hindbrain
are connected by reciprocally projecting neurons. Thus the long-term effects of centrally
acting satiety hormones are potentiated by the short-term release of peripherally acting
CCK.

Peptide YY
Peptide YY (PYY) is another candidate for a short-term satiety factor released from the
gut. Like NPY, it is a member of the pancreatic polypeptide family and is produced as a
36–amino acid tyrosine containing peptide. PYY is released from enteroendocrine cells (L
cells) of the ileum and colon by fat digestion products and may act to inhibit gastric
emptying and secretion at the end of a meal. Circulating PYY reaches the hypothalamus
via semipermeable capillaries of the median eminence to bind Y2 receptors, thereby
inhibiting NPY neurons and releasing inhibition of POMC neurons. In humans,
intravenous infusion of PYY in amounts yielding blood levels similar to those following a
meal reduces food intake in both lean and obese persons. Obese persons have lower
endogenous serum levels of PYY than do those in control subjects of normal weight.
Unlike the case for leptin, persistent administration of PYY to obese subjects results in
weight loss. Thus there is interest in PYY as a possible appetite suppressor. However, the
overall significance of PYY both physiologically and clinically in the control of food
intake has not been established.

Ghrelin
Ghrelin is a 28–amino acid peptide secreted primarily by endocrine cells in the oxyntic
gland area of the stomach. Gastrectomy reduces plasma ghrelin levels by 65%, a finding
indicating significant contributions from extragastric sites. These include the
hypothalamus, small and large intestines, pancreas, and the kidney. Ghrelin binds to the
growth hormone secretagogue receptor, stimulates the release of growth hormone from
the pituitary, and increases the appetite, gastric motility, secretion of gastric acid,
adipogenesis, and insulin secretion. Plasma levels of ghrelin increase during fasting,
peak just before food intake begins or when the subject is expecting a meal, and fall
within an hour of the start of feeding. Neither protein intake nor gastric distention
associated with the intake of a meal inhibits ghrelin release. However, oral or
intravenous glucose and a high-fat meal reduced plasma levels of ghrelin. In the
hypothalamus, ghrelin stimulates neurons of the arcuate nucleus that express NPY. It
also exerts actions directly on vagal afferents and on the dorsal vagal complex.
Plasma ghrelin levels correlate with a patient’s nutritional status. Levels are high in
lean people, and intravenous ghrelin increases food intake in persons of normal weight.
Ghrelin plasma levels are low in obese persons and increase only a er weight loss, a
finding suggesting that increased circulating levels of the hormone are not responsible
for overeating. Following bypass surgery for obesity, plasma ghrelin decreases further
from already low levels, a response accompanied by decreased hunger. Patients with
anorexia nervosa have high plasma levels, which return to normal a er weight gain.
Additional evidence from animal experiments indicates that ghrelin inhibits the release
of leptin and that leptin has a negative influence on ghrelin release. A genetic deletion in
mice that causes a defect in the mechanisms leading to satiety results in hyperphagia and
abnormally high levels of plasma ghrelin. Taken together, these data indicate that
ghrelin initiates the feeding response.

Additional Peptides
Other peptides from the GI tract have been shown to inhibit food intake and may have
anorectic functions. Current research is in progress involving glucagon-like peptide 1
(GLP-1), oxyntomodulin (OXM), and pancreatic polypeptide (PP). In addition to
inhibiting food intake, GLP-1 stimulates insulin release and inhibits gastric emptying.
OXM, like GLP-1, is a product of the preproglucagon gene and has potent inhibitory
effects on food intake in rodents. Its effects, however, are exerted on the arcuate nucleus,
whereas those of GLP-1 are confined to the brainstem. PP reduces food intake in mice
when it is administered peripherally, but central administration produces the opposite
effect. In humans, PP inhibits the intake of food. Additional experiments are necessary to
elucidate whether any of these peptides has a significant physiologic role in the
regulation of caloric intake.
CLINICAL APPLICATIONS
Figure 13-2 presents the most likely approximation of current knowledge
regarding the regulation of food intake. The agents shown, in addition to
several others and/or their receptors, are candidates for the development of
drugs to treat obesity. Leptin is effective in treating the rare cases of leptin
deficiency, but resistance to the drug in the more common forms of obesity
limits its usefulness. Two drugs are currently licensed to cause loss of
weight. One of these inhibits pancreatic lipase and results in maldigestion
and malabsorption of fat. The resulting steatorrhea is an unpleasant side
effect, and the effectiveness of the drug is limited. The other acts centrally
to prevent the reuptake of serotonin and norepinephrine. It also may have
adverse side effects, although it does reduce appetite.

FIGURE 13-2 Summary of mechanisms involved in the regulation of food intake. CCK,
cholecystokinin; NPY, neuropeptide Y; NTS, nucleus tractus solitarius; POMC, pro-
opiomelanocortin; PYY, peptide YY.

With greater frequency, obese patients with related health problems are
turning to surgery as a means to lose weight. Weight reduction, or
bariatric, surgery has proved to be a successful and permanent solution for
many persons. The first procedures put into general practice were designed
to decrease the absorption of ingested food by bypassing most of the
absorptive surface of the small bowel. In the most popular of these
procedures, called jejunoileal bypass, the intestine was transected near the
duodenal-jejunal border, the jejunal end was closed, and the duodenal end
was anastomosed to the distal ileum. The problems caused by
malabsorption, however, made this procedure undesirable.
Currently, gastric bypass is the most commonly performed procedure. A
small gastric pouch is created to receive esophageal content. It in turn is
connected directly to the small intestine, so that the storage function of the
stomach is eliminated, thus reducing food intake. Weight loss of 65% to
80% of excess body mass is typical of most patients. Medically more
significant is a dramatic reduction in comorbidities. These include a
correction in hyperlipidemia, decreased hypertension, improvement in
obstructive sleep apnea, and a reduction in gastroesophageal reflux disease
in almost all patients. Of major interest is a currently unexplained reversal
of type 2 diabetes in up to 90% of patients that usually leads to normal
levels of blood glucose without medication, sometimes within days
following surgery. There was an 89% reduction in mortality over 5 years
following surgery in a large clinical trial when compared with a
nonoperated group of obese subjects.