The objective of this research grant is to characterize the mechanisms for the differences between two strains of rats which differ in their susceptibility to obesity when eating a high fat diet. The Osborne- Mendel rat (OM) rapidly becomes obese when maintained on a high fat diet while the S5B/PI (S5B) rat remains lean when eating the same diet. We have recently demonstrated that the OM rat increases its intake of a high fat diet after administration of the 5-HT1A agonist, 8-hydroxy-2- (di-n-proplyamino)tetralin, which inhibits serotonin synthesis and release. S5B rats do not increase food intake after this treatment. In addition, fenfluramine treatment prevents high fat diet-induced obesity in the OM rat. This proposal focuses on the mechanisms underlying two aspects of this dietary-induced obesity.
Our first aim will be to elucidate the central nervous system neurotransmitter signals that mediate fat preference by examining the serotonin system in these two rat strains. We will test the hypothesis that the serotonergic system is more active in the S5B rat than the OM rat. The first three experiments in this aim will investigate the effects on food intake in OM and S5B rats by altering serotonin levels in the paraventricular nucleus. The next five experiments will determine the contribution of the dorsal raphe nucleus to the serotonin systems in OM and S5B rats. The last two experiments will examine the hypothesis that opioids in the hindbrain may modulate the serotonergic signals from the paraventricular nucleus. We will utilize the novel technique of central antisense oligonucleotide application in two critical experiments to test these systems.
The second aim will examine the difference in peripheral signaling systems that responds to nutrient infusion in these two rat strains. We will test the hypothesis that fatty acids in the GI tract activate vagal mechanisms more effectively int the S5B rat. We have already demonstrated that S5B rats are much more sensitive to the satiating effects of intraintestinal fat infusions. There are seven experiments proposed which will examine the involvement of the vagus nerve, cholecystokinin, glutamate, c-fos activated neurons and serotonin in the differential responsiveness to nutrient infusion in OM and S5B rats. Our laboratory has made significant advances toward understanding dietary-induced obesity. We now propose these well founded, important and exciting studies which will provide critical new insights into anatomical, physiological and molecular mechanisms by which high levels of dietary fat induce obesity.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Method to Extend Research in Time (MERIT) Award (R37)
Project #
Application #
Study Section
Special Emphasis Panel (NSS)
Program Officer
Yanovski, Susan Z
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Lsu Pennington Biomedical Research Center
Organized Research Units
Baton Rouge
United States
Zip Code
Primeaux, Stefany D; Braymer, H Douglas; Bray, George A (2013) CD36 mRNA in the gastrointestinal tract is differentially regulated by dietary fat intake in obesity-prone and obesity-resistant rats. Dig Dis Sci 58:363-70
Primeaux, Stefany D; Braymer, H Douglas; Bray, George A (2013) High fat diet differentially regulates the expression of olfactory receptors in the duodenum of obesity-prone and obesity-resistant rats. Dig Dis Sci 58:72-6
Primeaux, Stefany D (2011) QRFP in female rats: effects on high fat food intake and hypothalamic gene expression across the estrous cycle. Peptides 32:1270-5
King, Bruce M; Primeaux, Stefany D; Zadeh, Mohammad L et al. (2011) Olfactory bulbectomy impairs the feeding response to 2-deoxy-D-glucose in rats. Brain Res 1367:207-12
Primeaux, S D; Barnes, M J; Braymer, H D et al. (2010) Sensitivity to the satiating effects of exendin 4 is decreased in obesity-prone Osborne-Mendel rats compared to obesity-resistant S5B/Pl rats. Int J Obes (Lond) 34:1427-33
Barnes, Maria J; Argyropoulos, George; Bray, George A (2010) Preference for a high fat diet, but not hyperphagia following activation of mu opioid receptors is blocked in AgRP knockout mice. Brain Res 1317:100-7
Primeaux, Stefany D; Blackmon, Christine; Barnes, Maria J et al. (2008) Central administration of the RFamide peptides, QRFP-26 and QRFP-43, increases high fat food intake in rats. Peptides 29:1994-2000
Barnes, Maria J; Primeaux, Stefany D; Bray, George A (2008) Food deprivation increases the mRNA expression of micro-opioid receptors in the ventral medial hypothalamus and arcuate nucleus. Am J Physiol Regul Integr Comp Physiol 295:R1385-90
White, Christy L; Ishihara, Yuri; York, David A et al. (2007) Effect of meta-chlorophenylpiperazine and cholecystokinin on food intake of Osborne-Mendel and S5B/P1 rats. Obesity (Silver Spring) 15:624-31
Primeaux, Stefany D; Barnes, Maria J; Bray, George A (2007) Olfactory bulbectomy increases food intake and hypothalamic neuropeptide Y in obesity-prone but not obesity-resistant rats. Behav Brain Res 180:190-6

Showing the most recent 10 out of 42 publications