This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Chronic excess of free fatty acids (FFAs) leads to their accumulation in peripheral tissues, and this induces resistance to the effects of leptin and insulin. In the brain, short-term administration of fatty acids may act as a nutrient signaling for satiety. We hypothesized that chronic excess of FFAs in the brain could induce central nervous system (CNS) leptin resistance and cause hyperphagia and weight gain. To test this hypothesis, chow-fed, 8 week old, male Sprague Dawley rats received 5 months of intracerebroventricular (ICV) infusion of either control artificial cerebrospinal fluid (aCSF) or oleic acid (0.2 mmol) solution via osmotic pumps. ICV oleate-treated rats weighed more than the controls (p<0.05) in part due to increased food intake (p<0.001). To assess whether CNS oleic acid infusion resulted in a change in the fatty acid composition of phospholipids in the brain, we measured the fatty acid composition of brain tissue from both groups with ESI/MS. Three different forms of sphingomyelin were identified by ESI-MS in both groups. The ICV oleate-treated rats had significantly higher levels of C16 (p<0.005) and C18 (p<0.05) sphingomyelin compared to the control group. C24 sphingomyelin was not significantly different. Five different forms of ceramide were identified by ESI-MS in the brain tissue samples. The oleate-treated rats had significantly higher levels of C16 ceramide (p<0.005) and C18:0, C18:1, C20:0 and C24:1 ceramide (p<0.05 respectively) compared to the control group. Five different forms of phosphatidylcholine (PC) were identified. PC 16:0/16:0, 16:0/18:1, 16:0/20:4 and 18:0/18:1 were significantly higher in the ICV oleate-treated group compared to controls (p<0.05).Oleate-treated rats also had a higher oxygen consumption, lower respiratory exchange ratio (RER) and higher heat production. Oleate-treated rats had higher blood insulin (p=0.01) levels and tended to have higher leptin levels, but no difference in their blood FFA or glucose levels were observed compared to controls. The hypophagic response to ICV leptin [10 mcg/day] was abrogated in oleate-treated rats, which reflects leptin resistance. In response to intraperitoneal leptin administration [1 mg/kg], impaired phosphorylation of STAT3 in the hypothalamus was observed in oleate-treated rats. Brain samples from the ICV oleate-treated animals showed a 2-fold increase in accumulation of ceramide and sphingomyelin compared to the control group (p< 0.05 respectively). We conclude that chronic free fatty acid excess in the brain leads to lipid accumulation, induces leptin resistance, stimulates food intake and results in modest but significant weight gain.
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