Scientific Report 2008
Molecular and Integrative Neurosciences
Inflammation and Obesity
O. Osborn, S.E. Brownell, M. Sánchez-Alavez,
D. Salomon, H. Gram, T. Bartfai
is elevated in obese humans and rodents and is implicated in impaired insulin secretion,
decreased cell proliferation, and apoptosis of pancreatic beta cells. We have investigated
the therapeutic effects of an antibody to IL-1β
in hyperglycemic mice with diet-induced obesity. After 13 weeks of treatment, compared
with a group given a control antibody, the group given the antibody to IL-1β
had a significant improvement in glycemic control and in beta cell function, suggesting
this novel therapeutic approach may slow or prevent progression to type 2 diabetes.
is also a key mediator of impaired function and destruction of pancreatic beta cells
during the development of type 1 diabetes. Our findings suggest that an antibody
has therapeutic potential in the treatment of type 2 diabetes and may have beneficial
effects in other forms of diabetes in which tight glucose control is essential to
prevent induction of IL-1β
and thus limit beta cell destruction.
Galanin and Stress: Involvement of Galanin Receptor Subtypes
K. Mitsukawa, X. Lu, T. Bartfai
disorders are some of the most serious and prevalent medical conditions. Because
current clinical treatments for stress have limited efficacy and cause unwanted
effects in many patients, much effort has been put into understanding the molecular
basis of these devastating disorders. Recent studies indicate that the neuropeptide
galanin plays a role in mood disorders through its central G protein—coupled
receptors: galanin receptor subtypes 1—3 (GalR—GalR3). We evaluated the
effects of galanin on restraint stress in mice, a model of psychogenic stress.
Core body temperature and locomotor activity
were monitored by using radio telemetry devices. Intracerebroventricular injection
of galanin had a biphasic effect on stress-induced hyperthermia and the associated
increase in the levels of the stress hormones corticosterone and corticotropin;
low doses of galanin increased the stress response, whereas high doses had the opposite
effects. High doses of galanin activated neurons in specific brain regions implicated
in stress-related behaviors.
To further clarify which receptor subtype
is involved in the effects on stress-induced hyperthermia and associated changes
in hormone levels, we used mice that lack the gene for GalR1 or the genes for GalR1
and GalR2. Compared with a control group, these mice had no change in stress-induced
hyperthermia or hormone levels after treatment with high doses of galanin. These
results indicate that GalR1 plays a role in the galanin effects observed.
Transcriptional Profiling of Single Warm-Sensitive
I. Klein, I. Tabarean, O. Osborn, M.
Sánchez-Alavez, E. Gregorsson, B. Ross, B. Conti, T. Bartfai
core body temperature is one of the greatest sources of energy expenditure in mammals.
A small set of warm-sensitive GABAergic neurons in the preoptic area of the anterior
part of the hypothalamus are known to play a key role in thermoregulation. To facilitate
detailed molecular characterization of warm sensitivity at the level of single cells,
we used electrophysiologic methods to detect individual warm-sensitive neurons in
mouse embryonic hypothalamic cell cultures and in hypothalamic slices from adult
mice. The transcriptomes of warm-sensitive and warm-insensitive cells were amplified
by linear amplification and subsequently hybridized to microarrays. We found that
warm-sensitive neurons in slices from the anterior part of the hypothalamus have
functional receptors for several signal substances involved in the regulation of
metabolism, feeding, and inflammation as well as pyrogenic substances.
We are validating the microarray data
by using quantitative polymerase chain reaction and in situ hybridization. The functional
relevance of some of the expressed transcripts is being further investigated by
using available ligands. This approach accelerates pharmacologic characterization
of these neurons because receptors expressed in these cells can now be investigated
as putative drug targets for regulation of metabolic rates. The differential expression
of transcripts in warm-sensitive and warm-insensitive cells may also
provide the long-awaited tool for distinguishing and modifying temperature-sensitive
cells in vivo. Detailed molecular characterization of these neurons at a single-cell
level will provide new insights into the regulation of metabolic rate, body temperature,
and, indirectly, aging.
Effects of Core Body Temperature in Energy
M. Sánchez-Alavez, I. Tabarean,
B. Conti, T. Bartfai
Core body temperature
(CBT) in homeotherms is maintained at a constant level and is largely independent
of the temperature of the surroundings. Small but persistent changes in CBT are
associated with significant changes in energy demand and thus in metabolism. Some
temperature-sensitive GABAergic neurons in the preoptic area are involved in sensing
CBT and brain temperature and in response regulate metabolic rate to maintain CBT.
Microarray analysis followed by quantitative polymerase chain reaction indicated
that bombesin and prolactin receptors are expressed in warm-sensitive neurons in
the preoptic area. We are using available ligands to determine if CBT can be affected
by applying agonists of these receptors to the preoptic area.
Injection of bombesin into the preoptic
area induced profound hypothermia accompanied by a marked decrease in the respiratory
exchange ratio and heat production for 4 hours. Motor activity was increased during
the same period, but it could not prevent hypothermia. Injection of bombesin into
the pallidus raphe, which is one target of preoptic area projecting neurons, induced
slight hyperthermia for the next 3 hours, which coincided with a slight increase
in respiratory exchange ratio and heat production. Injection of prolactin into the
preoptic area or pallidus raphe induced a slight increase in CBT, respiratory exchange
ratio, and heat production, but the increases did not differ significantly from
those in controls. Our findings suggest that peptides can modulate activity in the
preoptic area; we are determining the mechanisms responsible for these effects in
Mitsukawa, K., Lu, X., Bartfai, T .
Galanin, galanin receptors and drug targets. Cell. Mol. Life Sci. 65:1796, 2008.