Human Physiology, 14th edition (2016)

Regulation of Metabolism 673

Ghrelin, Cholecystokinin, and PYY

Signals from the stomach and small intestine regulate hunger and

satiety (a feeling of “fullness, and thus a reduction of appetite) on

a meal-to-meal basis. This signaling is performed by the secre-

tion of several polypeptide hormones, which were earlier known

to regulate digestive function by targeting different parts of the

gastrointestinal tract. Later, they were shown to also regulate

appetite by targeting the arcuate nucleus of the hypothalamus.

Included among these are the polypeptides ghrelin, cholecystoki-

nin, polypeptide YY (PYY), and several others.

Ghrelin is an important hunger signal secreted by the stom-

ach. Ghrelin secretion rises between meals, when the stomach

is empty, and stimulates hunger. This ghrelin effect results from

stimulation in the arcuate nucleus of the neurons that release neu-

ropeptide Y and AgRP. As the stomach fills during a meal, the

secretion of ghrelin rapidly falls and hunger is thereby reduced.

However, one study demonstrated raised levels of ghrelin in diet-

ers who lost weight. If this raised ghrelin level enhances appetite,

it may partially explain why it is so difficult for most dieters to

maintain their weight loss.

Another hormone that regulates eating is the intestinal

hormone cholecystokinin (CCK). Secretion of CCK rises

during and immediately after a meal and suppresses hunger

(promotes satiety). CCK thus acts antagonistically to ghrelin,

helping to reduce appetite immediately after a meal.

Ghrelin and CCK are involved in the regulation of hun-

ger on a short-term, meal-to-meal basis. Another intestinal

hormone, polypeptide YY (PYY) , may reduce appetite on

a more intermediate-time basis. The intestinal satiety hor-

mones—including CCK, PYY, and glucagon-like peptide-1

(GLP-1)— suppress hunger by acting in the arcuate nucleus of

the hypothalamus to stimulate neurons that release MSH and

inhibit neurons that release neuropeptide Y.

Leptin and Insulin

The areas of the hypothalamus that regulate hunger are also

influenced by a circulating satiety factor (appetite suppressant)

secreted by the adipose tissue. This satiety factor, a 167-amino-

acid polypeptide, is the hormone leptin. Leptin is involved in

more long-term hunger regulation than the hormones of the diges-

tive tract. Leptin secretion increases as the amount of stored fat

increases, suppressing appetite and thus reducing further calorie

intake. Rather than regulating meal-to-meal food consumption

like the hormones of the digestive tract, however, leptin helps

maintain the body’s usual level of adiposity (fat storage). In addi-

tion to suppressing appetite (promoting satiety), leptin increases

the metabolic rate and calorie expenditure of the body (discussed

in the next section).

Leptin secretion increases in proportion to the amount of

stored fat and acts on the arcuate nucleus of the hypothalamus

to suppress appetite. It does this by indirectly inhibiting the

orexigenic (hunger-promoting) neurons that release neuropep-

tide Y and AgRP, while also indirectly stimulating the anorexi-

genic (hunger-suppressing) melanocortin neurons that release

MSH (see fig.  19.3 ). This is believed to enhance the brain’s

energy substrates ( fig.  19.2 ), the release of MSH produces
a suppression of appetite and increased metabolic energy
expenditure. At the same time, the neurons that release neu-
ropeptide Y and AgRP (which would increase appetite) are
inhibited. Conversely, when there is a reduction in circulat-
ing energy substrates, the neurons that release MSH are sup-
pressed, while those that release neuropeptide Y and AgRP
are activated to increase appetite ( fig. 19.3 ).
The activation of these hypothalamic neurons and the release
of their neurotransmitters must be regulated by signals from other
brain areas (because psychological factors, and the smell and
taste of food, influence hunger), and by signals from the body.
In particular, hunger and appetite are responsive to signals from
the digestive tract and from the adipose tissue. As illustrated in
figure  19.4 , hunger is stimulated by the hormone ghrelin and
inhibited by the hormones PYY, CCK, insulin, and leptin.

Figure 19.3 The action of leptin. Leptin crosses the
blood-brain barrier to affect neurotransmitters released by neurons
in the arcuate nucleus of the hypothalamus. This influences other
hypothalamic nuclei, which in turn reduce appetite and increase
metabolic rate. The figure also shows that insulin stimulates
adipose cells to secrete leptin and is able to cross the blood-brain
barrier and to act in a manner similar to leptin.

Appetite Metabolic rate

Neuropeptide Y

Leptin

Insulin

Melanocortin peptides

(primarily MSH)

Secondary Hypothalamic Nuclei

Endocrine changes;

increased sympathetic

nerve activity

Arcuate Nucleus

Blood vessel

Hypothalamus

Adipose Mass

Through blood-brain barrier

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