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Scientific Report 2008


Molecular and Integrative Neurosciences




Inflammation and Obesity


O. Osborn, S.E. Brownell, M. Sánchez-Alavez, D. Salomon, H. Gram, T. Bartfai

The proinflammatory cytokine IL-1β 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. IL-1β 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 to IL-1β 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

Stress-related 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 Hypothalamic Neurons


I. Klein, I. Tabarean, O. Osborn, M. Sánchez-Alavez, E. Gregorsson, B. Ross, B. Conti, T. Bartfai

Maintenance of 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 Homeostasis


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 the brain.

Publications

Mitsukawa, K., Lu, X., Bartfai, T . Galanin, galanin receptors and drug targets. Cell. Mol. Life Sci. 65:1796, 2008.

 

Tamas Bartfai, Ph.D.
Professor and Chairman


Galanin and Stress: Involvement of Galanin Receptor Subtypes

Transcriptional Profiling of Single Warm-Sensitive Hypothalamic Neurons

Effects of Core Body Temperature in Energy Homeostasis

Publications



Molecular & Integrative Neurosciences Reports

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