Regulation of Metabolism 675but gain the characteristics of brown adipocytes upon cold expo-
sure, scientists have called these beige or brite adipocytes.
Diet is also an important regulator of adaptive thermogen-
esis, producing what is called the thermic effect of food. Starva-
tion decreases the metabolic rate by as much as 40%, and feeding
increases the metabolic rate by about 25% to 40% in average
adults, with corresponding increases in heat production. This
diet-induced thermogenesis is provoked most strongly by dietary
carbohydrates and fats (but not proteins) through the activation of
the sympathetic nervous system, which stimulates muscles and
b 3 -adrenergic receptors in brown adipose tissue.
The brain regulates adaptive thermogenesis, accomplished
largely by activation of the sympathoadrenal system. Sympathetic
innervation of skeletal muscles and brown fat, together with the
effects of circulating epinephrine, cause increased metabolism
in these tissues. Thyroxine secretion, controlled by the brain via
TRH (thyrotropin-releasing hormone, which stimulates TSH
secretion from the anterior pituitary—see chapter 11, fig. 11.16),
is also needed for adaptive thermogenesis. Although thyroxine
secretion is required for adaptive thermogenesis, the levels of thy-
roxine do not rise in response to cold or food, suggesting that the
role of thyroid hormones is mainly a permissive one. In starvation,
however, thyroxine levels do fall, suggesting that this decline may
contribute to the slowdown in the metabolic rate during starvation.
During starvation, adipose tissue decreases its secretion of
leptin and this fall is needed for the fall in TRH secretion that occurs
in starvation. Thus, the decline in leptin may be responsible for the
decline in thyroxine secretion. There is also evidence that decreas-
ing leptin during starvation may cause a decline in the sympathetic
nerve stimulation of brown fat. Through both mechanisms, the
decreased leptin levels that occur during starvation could cause a
slowdown in the metabolic rate. This effect would help to conserve
energy during starvation. Opposite responses when leptin levels
are high, conversely, would help to raise the metabolic rate and put
a brake on the growth of adipose tissue (see fig. 19.3 ).Hormonal Regulation of Metabolism
The absorption of energy carriers from the intestine is not con-
tinuous; it rises to high levels over a four-hour period following
each meal (the absorptive state ) and tapers toward zero between
meals, after each absorptive state has ended (the postabsorptive,
or fasting, state ). Despite this fluctuation, the plasma concentra-
tion of glucose and other energy substrates does not remain high
following periods of absorption, nor does it normally fall below
a certain level during periods of fasting. Following the absorp-
tion of digestion products from the intestine, energy substrates
are removed from the blood and deposited as energy reserves
from which withdrawals can be made during times of fasting
( fig. 19.6 ). This ensures an adequate plasma concentration of
energy substrates to sustain tissue metabolism at all times.
The rate of deposit and withdrawal of energy substrates into
and from the energy reserves and the conversion of one type of
energy substrate into another are regulated by hormones. The
balance between anabolism and catabolism is determined by
the antagonistic effects of insulin, glucagon, growth hormone,- Physical activity raises the metabolic rate and energy expen-
diture of skeletal muscles. This contribution to the total cal-
orie expenditure is highly variable, depending on the type
and intensity of the physical activity (see table 19.1 ).
In adaptive thermogenesis, a cold environment evokes cuta-
neous vasoconstriction and shivering, which increases the met-
abolic rate and heat production of skeletal muscles. Since the
skeletal muscles comprise about 40% of the total body weight,
their metabolism has a profound effect on body temperature.
Heat production in the absence of shivering is called
nonshivering thermogenesis. This is the major function of
brown adipose tissue (brown fat), although skeletal muscles and
other tissues also play a part. Brown adipocytes have many smaller
fat droplets (unlike the single large fat droplet in white adipocytes)
and have numerous mitochondria, which impart the brown color.
Brown fat is abundant in infants, who can lose heat rapidly due
to their high ratio of surface area to volume and have insufficient
skeletal muscle for thermogenesis from shivering. Although once
thought to be absent in adults, brown fat in adults—located pri-
marily in the supraclavicular region of the neck (a different loca-
tion than in infants)—was discovered by PET scans performed in
nuclear medicine. This is because brown fat, like tumors, can be
very metabolically active and take up radioactively labeled glu-
cose (^18 F-fluorodeoxyglucose).
Nonshivering thermogenesis in brown adipose tissue is due
to the presence of uncoupling protein 1 (UCP1) in their mito-
chondria. These proteins provide channels in the inner mitochon-
drial membrane that allows protons (H^1 ) to move down their
electrochemical gradient, from the intermembranous space to
the matrix of the mitochondrion. As a result, the ability of ATP
synthase to produce ATP in oxidative phosphorylation (chapter 5;
see fig. 5.11) is reduced. Because ATP has an inhibitory effect
on aerobic respiration (chapter 5), the reduced formation of ATP
increases the metabolism of the brown adipose tissue, generating
increased amounts of heat. There is some evidence that muscles
may also contribute to nonshivering thermogenesis.
Recent reports demonstrated that the activity of brown adi-
pose tissue is stimulated by exposure of the person to cold,
and by the sympathoadrenal system (through the stimulation
of b 3 -adrenergic receptors on the brown adipocytes). There is
more brown fat in women than in men, and more in lean people
than in those who are overweight or obese.
Furthermore, lean people who have a lower body mass
index (BMI) have more brown fat, and people with a higher BMI
have less brown fat (although some brown fat is still present in
most obese people). This suggests that the calories expended
by brown fat in nonshivering thermogenesis could significantly
affect body weight.
Scientists have also found that there are adipose cells within
white adipose tissue and skeletal muscle that can be induced by cold
exposure to become more like brown adipose cells. This involves
reduction in stored lipids, increased numbers of mitochondria, and
production of UCP1 to uncouple oxidative phosphorylation. As a
result of these changes, the cells have increased heat production
and calorie expenditure. Because these cells are white adipocytes,