The metabolic syndrome in humans reflects a pre-diabetic state that is
characterized by visceral obesity, impaired glucose tolerance, and a dyslipidemia
which includes an increase in both the circulating triglyceride concentration
and the LDL:HDL. Recent discoveries have established a new paradigm for
the adipocyte as an active endocrine cell and participant in immune response
pathways. Dr. Spurlock's research program addresses this new paradigm,
as it relates to obesity and insulin resistance, with emphasis on leptin
and adiponectin. These two adipocyte-derived hormones regulate energy
metabolism and immunological pathways, locally, and in other cell types.
His laboratory has cloned the porcine adiponectin gene, and shown that
this adipocyte-derived hormone regulates the production of pro-inflammatory
cytokines in pig macrophages and a monocyte cell line, and that the anti-inflammatory
activity of adiponectin also encompasses an induction of the anti-inflammatory
cytokine, IL10 in the macrophage. In the adipocyte, Dr. Spurlock's laboratory
has shown that gram negative bacterial lipopolysaccharide does indeed
stimulate NFkB-mediated gene expression and cytokine production in isolated
adipocytes and that adiponectin is a negative regulator of this response
to lipopolysaccharide. Furthermore, his laboratory has identified an important
differential response in adipocytes vs. macrophages in that cAMP attenuates
NFkB signaling in macrophages and stimulates it in adipocytes. This finding
has broad potential implications for cell-specific means of regulating
IkBα, the cytosolic inhibitor of NFkB signaling. Leptin and adiponectin
establish strong integrated linkages among energy metabolism, adiposity,
and immune function, and are potentially very important to human health
because of their relationship to obesity and its co-morbidities.
Current projects in Dr. Spurlock’s laboratory target the mechanism by
which increased adipocyte size (as occurs with obesity) invokes an inflammatory
response and causes insulin resistance. He is also collaborating with
Dr. Sergei Zolotukhin at the University of Florida to develop a novel
gene therapy for obesity that is based on viral expression of adiponectin.
Whereas rodent models have been used widely to study the metabolic syndrome,
certain physiologic differences between rodents and humans, including
the presence of significant brown adipose tissue depots in young and adult
rodents, complicate the application of rodent data to humans. The Ossabaw
breed of swine is genetically predisposed to the metabolic syndrome, and
thus has much potential as a model for the human disease.
Dr. Spurlock is working with members in the Comparative Medicine Program
at Purdue University, and with Dr. Michael Sturek, Indiana University
School of Medicine, to develop the Ossabaw pig as a model for the metabolic
syndrome in humans.
Diet Formulations