REGULATION OF FOOD INTAKE

It is the balance between food intake and energy expenditure that determines overall body weight. Food
intake is primarily under the control of the hypothalamus, although higher CNS centers and other areas also
play roles. Hypothalamic centers respond to two major kinds of afferent input: short-term factors that reflect
daily meal activity and long-term factors that reflect whole-body energy stores.
Hypothalamic Centers Control the Sensations of Satiety and Hunger
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Table 57-7. HYPOTHALAMIC FACTORS THAT CONTROL APPETITE
ANOREXIGENIC (INHIBIT FEEDING)
OREXIGENIC (STIMULATE
FEEDING)
Corticotropin-releasing hormone (CRH) Neuropeptide Y (NPY)
Glucagon-like peptide I (GLP-I) Norepinephrine (NE)
-Melanocyte-stimulating hormone (-MSH) Gamma-aminobutyric acid (GABA)
Cocaine- and amphetamine-regulated transcript
(CART)
Galanin (GAL)
Ghrelin
Endogenous opioid peptides (EOP)
Orexin-A, -B
Modified from Kalra SP, Dube MG, Pu S, et al: Interacting appetite-regulating pathways in the hypothalamic regulation of body
weight. Endocr Rev 20:68-100, 1999.
Classic studies-in which investigators made lesions in, or electrically stimulated, specific brain
regions-identified two areas in the hypothalamus that are important for controlling eating. The "satiety
center" is located in the ventromedial nucleus (VMN; see Fig. 46-3). Electrical stimulation of the satiety
center elicits sensations of satiety, even when an animal is in the presence of food. Conversely, a lesion of
the satiety center causes continuous food intake (hyperphagia) even in the absence of need. The "hunger
(or feeding) center" is located in the lateral hypothalamic area (LHA) (see Fig. 46-3). Electrical stimulation
of the LHA elicits a voracious appetite, even after the animal has ingested adequate amounts of food. A
lesion of the hunger center causes a complete and lasting cessation of food intake (aphagia).
A vast array of neurotransmitters within the hypothalamus appear to modulate food intake. These
neurotransmitters fall into two major groups (Table 57-7). Injecting orexigenic (Greek orexis, "appetite")
substances stimulates feeding, whereas injecting anorexigenic substances into the brain inhibits feeding.
Investigators have identified areas within the hypothalamus that synthesize these neurotransmitters or store
them in relatively high concentrations. Other studies have identified and localized receptors for these
neurotransmitters. However, these molecular-localization studies have not yet led to a wiring diagram for
the hypothalamic neurons that regulate appetite. In general, orexigenic factors are associated with the LHA
(hunger center), whereas anorexigenic factors are associated with the VMN (satiety center).
Among the orexigenic factors (Fig. 57-10), neuropeptide Y (NPY) appears to play a central role.
NPY-containing neurons in the arcuate nucleus project to the paraventricular nucleus, which makes
corticotropin-releasing hormone (CRH). Exciting new orexigenic factors are the peptides orexin A and
orexin B, which are present in neurons in the LHA. The orexin receptor is G-protein linked and signals the
cell by opening Ca
2+
channels and raising [Ca
2+
]
i
. Consistent with their roles as orexigenic factors, both
NPY and preproorexin mRNA levels increase with fasting. Among the anorexigenic factors, one of the
most important seems to be CRH (p. 1054), which is made in the paraventricular nucleus of the
hypothalamus. A recent addition to the list of anorexigenic factors is a peptide called "cocaine-and
amphetamine-regulated transcript" (CART). Food deprivation decreases mRNA levels of CART in the
arcuate nucleus.
Short-Term Factors That Regulate Feeding Include Plasma "Nutrient" Levels and Gastrointestinal
Hormones Such as Cholecystokinin
Investigators have proposed various theories to explain the short-term regulation of food intake, including
models focusing on the regulation of levels of blood glucose (glucostatic), amino acids (aminostatic), or lipid
(lipostatic). For example, hypoglycemia produces hunger and also increases the firing rate of
glucose-sensitive neurons in the hunger center, but decreases the firing rate of glucose-sensitive neurons
in the satiety center. Hypoglycemia also activates orexin-containing neurons in the LHA.
Feedback from the GI tract also controls the short-term desire for food (Fig. 57-10). GI distention triggers
vagal afferents that suppress the hunger center. Peripherally administering any of several "GI peptides"
normally released in response to a meal-gastrin-releasing peptide (GRP), glucagon, somatostatin, and
cholecystokinin (CCK)-reduces meal size. The most important is CCK, which is more effective when
injected directly into the peritoneal cavity; this effect requires an intact vagus nerve. Therefore, CCK may
act by stimulating vagal afferents, which then transmit the signal to the hypothalamus. Additionally, an
oropharyngeal reflex responds to chewing and swallowing; it may meter food intake, inhibiting further eating
after a threshold.
A Long-Term Factor That Suppresses Appetite Is Leptin, a Protein Secreted by Adipocytes That Binds to
Hypothalamic Receptors
In addition to the short-term regulatory pathways, the body has long-term mechanisms for controlling
hunger. One such long-term regulator is leptin, the plasma levels of which seem to reflect whole-body fat
stores. Research on a strain of obese mice led to the discovery of the mutant ob gene that accounts for
their obesity. The normal gene encodes a 167-amino-acid polypeptide hormone called leptin (Greek leptos,
"thin"), which adipocytes produce. Mice that are homozygous (ob/ob) for a missense leptin mutation are
severely obese, hyperphagic, and hypoactive. Administering leptin to ob/ob mice reverses the symptoms.
Because leptin is particularly effective when injected directly into the brain, leptin secreted into the blood by
adipocytes may feed back on the brain to produce satiety (see Fig. 57-10). In the brain, leptin binds to
tyrosinekinase-associated receptors (p. 111) and inhibits expression of NPY (orexigenic), but stimulates
expression of CART (anorexigenic). Mice that are homozygous for a mutation that deletes a portion of the
leptin receptor also become obese and are resistant to treatment with exogenous leptin.
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Figure 57-10 Control of appetite. Table 57-7 defines the abbreviations of the anorexigenic and orexigenic factors.
Plasma leptin levels reflect total-body fat stores (i.e., a long-term signal). Over a wide range of body-fat
mass, more fat is associated with higher plasma leptin levels. In addition, leptin levels reflect the fed/fasting
state (i.e., short-term signal). Thus, even in obese animals, which have high baseline leptin levels, fasting
decreases plasma leptin levels.
Obesity Reflects a Chronic Excess of Energy Intake Over Expenditure
The regulation of food intake does not work effectively in everyone. Obesity is a condition in which energy
intake exceeds energy output over time, and body fat becomes greater than 30% of ideal body weight. The
development of obesity requires months and years to occur because the storage of one kg of fat represents
an excess energy intake (over output) of 9,400 kcal. Because the average caloric expenditure of a
sedentary person is approximately 2100 kcal/day, a sedentary person ingesting an excess of 1000 kcal/day
(i.e., a diet of 3100 kcal/day) would require 9 to 10 days to store 1 kg of fat.
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Fat stores are not limited in the same manner as carbohydrate and protein stores. Adipocytes can increase
in number (hyperplasia) or in size (hypertrophy) during the evolution of obesity. Hyperplastic obesity
usually develops during the first few years of life and is maintained thereafter. The rate of formation of new
adipocytes is greatest during these first years of life, and the absolute number of adipocytes becomes fixed
during this period. Individuals who became obese in early childhood may not respond well to weight
reduction regimes as adults, because the number of fat cells contributes in some Way to the hypothalamic
feedback control of fat storage. Hypertrophic obesity, in contrast, first occurs in adulthood and is most
often associated with diabetes and other age-related metabolic alterations. Adult-onset obesity may be
caused by a reduction in the hormone-sensitive lipase in adipose tissue, making it more difficult to mobilize
the fat deposited there. Hormone-sensitive lipase activity depends on physical activity as well as factors
associated with aging, so adult-onset obesity can be reversed by caloric restriction and increased activity.
In contrast to the ob mice, most obese humans produce large quantities of leptin but are insensitive to its
effects. Thus, obese people may have defective leptin receptors, reduced numbers of leptin receptors,
defective post-receptor signal transduction, or another factor that overrides the leptin satiety signal.
Obesity is probably a multifactorial condition, involving both genetic and environmental factors. For
example, a significant proportion of obese patients scores high on tests for measuring mental depression.
In addition, obese patients consistently underestimate the number of calories they consume each day.
Because obesity is a major risk factor for major chronic diseases (e.g., cardiovascular disease, adult-onset
diabetes, cancer), investigators have invested much effort searching for ways to minimize fat storage,
especially in older people who are at greater risk.
Integration link: Obesity - treatment
Taken from Clinical Medicine 5E
Starvation Depletes Body Carbohydrate Stores Immediately, Fat Stores Thereafter, and Protein Stores Last
The average 70-kg adult uses approximately 2100 kcal/day to support resting metabolic needs. During
starvation, all of this energy must come from body stores. The total energy stored as glycogen in liver and
skeletal muscle is at most approximately 3000 kcal. The body uses this glycogen preferentially during
starvation, depleting it within 1.5 days. The average 70-kg adult also has fat stores of approximately
131,000 kcal. Mobilization and subsequent oxidation of this entire fat depot could theoretically sustain the
body's resting metabolic requirement for approximately 2 months. In addition, the body can mobilize about
half of its protein store, representing another approximately 20,000 kcal, sufficient for an additional 10 days.
In reality, people seldom survive for 2 months without nutrition (even assuming unlimited water availability),
because vitamin deficiencies and their associated effects begin to appear after a week or two and
compromise body function.
During starvation, fat becomes the fuel of choice once carbohydrate stores are expended. Fatty-acid
oxidation continues at a constant rate throughout starvation. Ketone bodies form as a byproduct of
fatty-acid oxidation during starvation and in diabetes mellitus (when lack of insulin inhibits glucose
utilization; see the box on diabetes mellitus on p. 1084). The liver releases the major keto-acids
(acetoacetic and -hydroxybutyric acid) into the circulation, thus lowering blood pH and creating a condition
known as ketoacidosis. Acetone, another ketone produced by the liver, is eliminated in the expired air,
accompanied by the fruity smell characteristic of ketosis. Ketone bodies can cross the blood-brain barrier
and serve as the primary fuel for the CNS when glycogen stores are depleted and the only means for
generating glucose is by transamination of amino acids (gluconeogenesis) in the liver.
Protein oxidation is rapid during the initial stage of starvation due to its use as a precursor for glucose in
transamination reactions in the liver. Once easily mobilized protein has been consumed, the rate of
gluconeogenesis falls markedly, and the body's protein stores are relatively conserved during starvation.
Finally, during the latter stage of starvation, when the body has used most of its fat stores, protein becomes
the only source of energy left, forcing the body to draw on these stores as a last gasp for survival.
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