Molecular medicine-Introduction – Adipocytes and the Regulation of Metabolism

Although the physiology of adipose tissue
and the molecular and cellular biology of
the adipocyte have been subjects of research
interest for many years, new work
in this area has transformed our understanding
of the adipocyte and its role in
regulating human physiology. We now
recognize that in addition to its long appreciated
function as a lipid storage depot, the
adipocyte plays a much more active role
in regulating whole body fuel partitioning
and metabolism. The growing interest in
the physiology of adipose tissue and the
role that it plays in metabolic regulation is
fueled to a large degree by the realization
that we are in the midst of a growing
epidemic of the metabolic disorders of
diabetes and obesity. In most developed
countries, the incidence of both of these
diseases has increased dramatically in the
past few decades. Currently (as of 2003),
there are 16 million diabetics in the United
States, and the incidence of the disease has
increased by 49% from 1990 to 2000, with
projections indicating a 165% increase by
2050. There has also been a dramatic increase
in the incidence of obesity, with over
one-third of the population in the United
States now classified as obese. Although
the causal relationship between diabetes
and obesity is not fully understood, a likely
common link is the adipocyte.
In healthy individuals, excess fat is
stored in adipocytes while only low
amounts of triglyceride are maintained in
nonadipocytes. It is thought that in obese
individuals, the capacity for adipose tissue
to accommodate excess lipid is exceeded,
resulting in the abnormal accumulation
of lipid in other tissues. This elevation in
intracellular triglyceride content has been
associated with physiological dysfunction
(lipotoxicity) that contributes to the development
of obesity-related type 2 diabetes.
This pathological accumulation of lipid in
nonadipose tissue may be the result of a
physiological dysfunction of the adipocyte
that is induced by the obese state. In this
chapter, we will review the current state of
knowledge about fat cell lipid metabolism,
and how adipocytes function to balance
lipid storage and mobilization to meet
the energetic demands of the organism
without exposing nonadipose tissues to
deleterious fat accumulation.
In addition to its function as an energystorage
depot, we now understand that
adipose tissue is also a bona fide endocrine
organ, secreting hormones that
regulate fat metabolism in other tissues
throughout the body. The list of biologically
active peptides known to be secreted
by fat cells has grown significantly in recent
years, and although the physiological
function of most of these adipocyte-derived
hormones (adipokines) is not fully understood,
it is clear that they are important
components of the physiological system
4 Adipocytes
that controls lipid storage, distribution,
and utilization throughout the body. Our
current knowledge of the regulation of
adipokine production and their downstream
metabolic effects is reviewed below.
Our increased understanding of the active
role that adipocytes play in regulating
metabolism has stimulated a growing interest
in adipose tissue as a therapeutic
target for new agents to treat diabetes,
obesity, and other metabolic diseases.
The underlying assumption for this effort
is that drugs acting on adipocyte lipid
metabolism parameters or on hormone
production pathways could have beneficial
effects on metabolic abnormalities of
diabetes and obesity. In support of this
possibility are recent findings, which are
reviewed below, demonstrating that an important
family of antidiabetic drugs acts,
at least in part, by modulating adipocyte
physiology. A complete understanding of
the medical significance of the adipocyte
will require a comprehensive knowledge
of the development of adipocytes and
adipose tissue, of molecular biology and
physiology of mature adipocyte, as well
as the interaction of adipose tissue with
the broader regulatory systems that control
the whole body energy balance and
fuel partitioning.