Regulation of Metabolism 671The hypothalamus—a target of leptin action regulating
appetite—is also involved in regulation of the reproductive sys-
tem (chapter 20, section 20.2). There is evidence that leptin may
be involved in regulating the onset of puberty and the menstrual
cycle ( menarche ). Adolescent girls who are excessively thin enter
puberty later than the average age, and very thin women can
experience amenorrhea (cessation of menstrual cycles). Adequate
amounts of adipose tissue are thus required for proper functioning
of the immune and reproductive systems.Obesity
Obesity is a risk factor for cardiovascular diseases, diabetes, gall-
bladder disease, obstructive sleep apnea, and a number of malig-
nancies that include colorectal, endometrial, and breast cancers.
In this regard, the distribution of fat in the body is important.
White adipose tissue is divided into visceral fat (the fat in the
mesenteries and greater omentum) and subcutaneous fat. There
is a greater risk of cardiovascular disease when a high amount
of visceral fat produces a high waist-to-hip ratio, or an “apple
shape,” as compared to a “pear shape.” The larger adipocytes of
visceral fat, producing the apple shape, are less sensitive to insu-
lin than the smaller adipocytes of subcutaneous fat, and so pose a
greater risk of diabetes mellitus.
The number of adipocytes increases through childhood and
adolescence, but a recent study suggests that the number gener-
ally remains constant through adulthood (although there is about
a 10% turnover, where new adipocytes are formed to replace
those lost). Obesity in childhood results from an increase in the
number of adipocytes as well as their size, whereas obesity in
most adults is produced mostly by an increase in the size of exist-
ing adipocytes. When weight is lost, the adipocytes get smaller
but their number remains constant.
It is thus important to prevent further increases in weight
in all overweight people, but particularly in children. Weight
loss can be achieved by a calorie-restricted diet higher in
proteins and lower in carbohydrates and saturated fat com-
bined with a regular exercise program. Prolonged exercise
of low to moderate intensity promotes weight loss because
the skeletal muscles use fatty acids as their primary source
of energy under those conditions (chapter 12; see fig. 12.22).
However, once weight is lost it is often regained because
of increased hunger and decreased energy expenditure by
the body.
Obesity is often diagnosed using a measurement called
the body mass index (BMI). This measurement is calculated
using the following formula:
BMI 5
w
__
h^2
where
w 5 weight in kilograms (pounds divided by 2.2)
h 5 height in meters (inches divided by 39.4)
Obesity has been defined by health agencies in different
ways. The World Health Organization classifies people with
a BMI of 30 or over as being at high risk for the diseases ofThree other adipokines that are known to be increased in
obesity are leptin, resistin, and retinol-binding protein 4.
There is evidence that these hormones also may contribute to the
reduced sensitivity of skeletal muscles and other tissues to insu-
lin in obesity and type 2 diabetes mellitus. By contrast, there is
another adipocyte hormone— adiponectin —that is decreased in
obesity and type 2 diabetes mellitus. Adiponectin stimulates glu-
cose utilization and fatty acid oxidation in muscle cells. Through
these actions, adiponectin has an insulin-sensitizing, antidiabetic
effect. Also, in contrast to other adipokines that promote inflam-
mation and thereby aggravate cardiovascular disease, adiponec-
tin exerts a protective effect.
The adipocyte hormone leptin, secreted in proportion to
the amount of stored fat, has another important function. It acts
on the hypothalamus to help regulate hunger and food intake.
In other words, it acts as a signal from the adipose tissue to the
brain, helping the body maintain a certain level of fat storage.
This function is described in more detail shortly.
Low Adiposity: Starvation
Starvation and malnutrition are the leading causes of dimin-
ished immune capacity worldwide. People suffering from
these conditions are thus more susceptible to infections. It is
interesting in this regard that leptin receptors have been identi-
fied on the surface of helper T lymphocytes, which aid both
humoral and cell-mediated immune responses (chapter 15; see
figs. 15.17 and 15.18).
During starvation, there is lipolysis of the triglycerides stored
in adipose tissue. This is caused by a fall in insulin secretion
coupled with increased growth hormone secretion and increased
sympathetic nerve stimulation of adipose tissue. The reduced
adiposity of starving people is accompanied by decreased leptin
secretion. This can contribute to a decline in the ability of helper
T lymphocytes to promote the immune response, and thus can—
at least in part—account for the decline in immune competence
in people who are starving.
CLINICAL APPLICATION
Anorexia nervosa and bulimia nervosa are eating disor-
ders that affect mostly young women who are obsessively
concerned about their weight and body shape. Anorexia is
a potentially fatal condition caused by a compulsive pur-
suit of excessive thinness. There can be seriously low heart
rate and blood pressure, decreased estrogen secretion and
amenorrhea, and depression. Anorexics have neuroendo-
crine changes consistent with starvation. For example, there
is osteopenia and osteoporosis (discussed in section 19.6),
dry skin, anemia, hypothermia, intolerance to cold, and other
symptoms. In bulimia, the person engages in large, uncon-
trolled eating binges followed by methods to avoid weight
gain, including induced vomiting, use of laxatives, and exces-
sive exercise.