Nature Genetics
25, 6 - 7 (2000)
doi:10.1038/75610
Triglycerides and toggling the tummyC Ronald KahnJoslin Diabetes Center, Harvard Medical School,
Boston, Massachusetts 02215, USA.
c.ronald.kahn@joslin.harvard.edu Multiple mechanisms regulate adipose mass and body weight. In addition
to factors controlling appetite and energy expenditure, mechanisms controlling
adipocyte number, triglyceride synthesis and triglyceride breakdown have important
functions. But recent studies challenge our concepts concerning each of these.
It was only a few years ago that physiologists and physicians believed
that the control of body weight was as simple as "you are what you eat".
In short, weight gain in the form of increased body fat, leading to obesity,
would occur when energy intake exceeded energy expenditure, whereas weight
loss would occur when the converse was true. Energy intake, of course, represents
eating, and was thought to be largely under control of the individual, with
minor influence from external cues, such as the time of day and the availability
and taste of food (Fig. 1). Energy expenditure was also
believed to be largely under the control of the individual through exercise
and work, in addition to a small component referred to as the "basal
metabolic rate", thought to be controlled mainly by the level of thyroid
hormone in the blood.
 | | |
Whereas the fundamental principle of energy balance represented by the
first law of thermodynamics is still true, it has become clear that the mechanisms
involved in the control of fat mass are extraordinarily complex (
Fig. 1). Appetite and energy expenditure are, in fact, highly regulated
at many levels and by different regulatory mechanisms and feedback loops.
It is now also clear that energy storage within the adipocyte can be regulated
by the number and size of the adipocytes, the activity of the transcription
factors that control adipocyte differentiation, and the lipases that are available
to break down the stored triglyceride, the major form of energy stored in
fat. On page 87, Steven Smith
and colleagues1 add more complexity to the regulation of fat
mass by demonstrating that the acyl CoA:diacylglycerol transferase (DGAT),
believed—until now—to uniquely control the one common step of
synthesis of triglycerides in all tissues, is not the only protein to fulfil
this function; mice deficient of the enzyme have a normal fat mass.
The most important control of adipose tissue mass in normal animals and
humans is related to the balance between energy intact and energy expenditure.
The need to have several mechanisms to regulate energy balance becomes evident
on considering that the average human consumes between 800,000 and 1,000,000
calories per year. If there were a consistent error as small as 1% in intake
versus expenditure, one would store an extra 10,000 calories—about 3
pounds of fat—over the course of a year. Whereas regulation of appetite
is dependent to some extent upon external cues, it must be highly regulated
over the course of days, weeks and months; hence the need for the kind of
robust 'super' system that is comprised by interconnected, highly
regulated sub-systems. A brief review of the known molecular players provides
a glimpse of the complexity inherent in weight control.
Coming to terms with complexity
Regulation of appetite is accomplished through a large number of peptides
produced in both the brain and peripheral tissues. These appetite-regulating
hormones can be divided into the orexigenic peptides that stimulate eating
and the anorexigenic or anorectic peptides that inhibit eating2,
3,
4.
The former include neuropeptide Y, melanin-concentrating hormone, agouti-related
peptide, galanin, and the orexins A and B. Appetite suppressants include leptin
(a peptide expressed primarily in white fat tissue),  -melanocyte−stimulating
hormone, corticotropin-releasing hormone, cholecystokinin, glucagon-like peptide-1,
neurotensin, and the cocaine- and amphetamine-regulated transcript (CART).
The roles of many of these factors have been dramatically elucidated through
the occurrence of natural mutations in both rodents and humans, as well as
the creation of transgenic mice in which these hormones and their receptors
have been either overexpressed or eliminated, respectively. For example, extreme
obesity occurs in mice and humans with mutations in the genes encoding leptin5,
6, the leptin receptor7 and the melanocortin-4 receptor8. On the other hand, mice that lack melanin-concentrating hormone
tend to be thin and resist gaining weight9.
Total energy expenditure is comprised of the energy used in exercise (unfortunately,
only 10−20% in most of us), with the remainder represented by the basal
metabolic rate and thermogenesis. In mammals, at least 20% of this is due
to an 'energy leak' that occurs through movement of protons across
the mitochondrial inner membrane of cells. This leak is largely regulated
by a subgroup of the mitochondrial anion transporter superfamily comprising
the uncoupling proteins10 (UCPs).
There are three mammalian uncoupling proteins: UCP1, UCP2 and UCP3. Each
is the product of a separate gene and has a unique tissue distribution. For
many years the only known member of this family was UCP1, a protein that is
expressed almost exclusively in mitochondria of brown fat tissue (the small
pool of adipose tissue that is involved primarily in energy expenditure, rather
than energy storage) and is highly regulated in its expression by thyroid
hormone and adrenergic agents. Transgenic mice in which brown fat is eliminated
by expression of a toxigene become obese11, but mice with targeted
inactivation of UCP1 are neither obese nor hyperphagic, suggesting that other
UCPs may compensate its deficiency12. UCP3 is expressed in heart,
brown and white adipose tissue and skeletal muscle, and is regulated in both
lean and obese individuals undergoing fasting. Several polymorphisms in this
protein have been identified, and some are associated with severe obesity
and type 2 diabetes13. UCP2 is ubiquitously expressed, but the
phenotype of the mutant mouse indicates that it may not have a significant
influence in resting metabolic rate (B. Lowell, pers. comm.).
About the adipocyte
The final site of regulation of adipose tissue mass is the adipocyte itself.
It has long been known that obesity may occur as a result of an increase in
the number of adipocytes (hyperplasia), an increase in the amount of triglyceride
stored in the adipocyte (that is, adipocyte hypertrophy), or a combination
of the two. Although adipocyte number has been traditionally viewed as being
stable throughout most of life, it is probably a balance between the size
of the precusor pool, the rate and extent of differentiation, and the rate
of cell loss through apoptosis. The rate and extent of differentiation is
controlled by a number of transcription factors, including SREBP-1 (also known
as ADD1), C/EBP and PPAR (ref. 14).
Several models of defects in adipocyte generation (for example, that represented
by lipodystrophy) have been created in mice through the introduction of normal
or dominant mutant variants of SREBP-1 or C/EBP, and two different variants
of PPAR have been identified in humans and associated with obesity17,
18.
With regard to the synthesis and breakdown of fat itself, the situation
also used to be quite simple. Triglycerides are the major storage form of
energy in adipocytes. Whereas diacylglycerol can be synthesized from either
2-monoacylglycerol (in intestinal mucosa) or glycerol 3-phosphate (in most
other tissues), triglyceride synthesis depends on DGAT, a membrane-associated
protein that catalyses the final unique step in the pathway using diacylglycerol
and fatty acyl CoA as substrates (Fig. 2). As such,
DGAT was thought to have a fundamental role in the metabolism of cellular
diacylglycerol and physiologic processes involving triacylglycerol synthesis,
such as the formation of adipose tissue, intestinal fat absorption, lipoprotein
assembly and lactation. The Dgat-/-
mice obtained by Smith et al.1, however, can still synthesize
triglycerides and maintain a normal fat mass while on a regular chow diet.
Curiously, they are resistant to dietary-induced obesity, but this is due
to increased energy expenditure rather than a change in the rate of lipid
synthesis. Although the site of increased energy expenditure has not been
identified, this finding suggests that there may be another unrecognized link
between triglyceride synthesis and regulation of the UCPs, perhaps at an intracellular
level.
| | |
And so, as with other systems regulating body weight and fat mass, there
must be at least two mechanisms to synthesize triglycerides in the mouse.
This is paralleled by recent observations indicating redundant mechanisms
for lipid breakdown19. The genetic discoveries made over the
past decade indicate that the regulation of adipose tissue mass is not as
simple as we used to think—and that staying thin is even harder than
it used to be.
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