Purpose: The present study investigates the potential anti-inflammatory effects of in vivo oxytocin (OT) infusion on adipose tissue inflammation in the Watanabe Heritable Hyperlipidimic Rabbits (WHHL). Methods: Twenty-eight 3-month-old WHHL were surgically implanted with osmotic minipumps containing OT (n = 14, infusion rate 250 ng/kg/hr) or vehicle (n = 14). Blood samples were taken at baseline, midpoint, and endpoint for lipids and C-reactive protein (CRP). After 16 weeks, animals were sacrificed and samples of adipose tissue (epididiymal, retroperitoneal, mesenteric, pericardial, and subcutanous) were collected and analyzed for pro-inflammatory cytokine (IL-6, TNF-α, and MCP-1) and anti- inflammatory adipokine (adiponectin and IL-10) expression levels by Real Time- Polymerase Chain Reaction. Adipose tissue was also immunohistologically analyzed for macrophage infiltration. Aortas were dissected, formalin-fixed, and stained with oil-red O for en face quantification of lesion area. Student’s t-tests were used to compare group means for all measures. Results: Endpoint OT levels were significantly different (p < .05) between the control ( M = 11.28 pg/ml, SEM = 2.5) and treatment group (M = 132.35 pg/ml, SEM = 8.5). Plasma lipids were not altered by OT infusion. OT-treatment significantly decreased plasma CRP, a marker of systemic inflammation, at midpoint and endpoint compared to controls (p = 0.05). OT-treated animals displayed significantly less atherosclerosis in the thoracic aorta (p < 0.05); a finding similar to our previously published study in a mouse model of atherosclerosis. In some fat depots, there was a trend suggesting adiponectin gene expression increased in the OT-treatment group. There were no significant differences or trends regarding macrophage infiltration in adipose tissue. Conclusions: Oxytocin infusion attenuated thoracic aortic atherosclerosis, plasma CRP, and may affect inflammatory cytokine expression in adipose tissue in the WHHL model.

Thesis (Ph. D. in Molecular Physiology and Biophysics)--Vanderbilt University, Dec. 2009. / Title from title screen. Includes bibliographical references.

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

Not available / text

Macrophage activation plays a crucial role in regulating adipose tissue inflammation and is a major contributor to the pathogenesis of obesity-associated cardiovascular diseases. On various types of stimuli, macrophages respond with either classic (M1) or alternative (M2) activation. M1- and M2-mediated signaling pathways and corresponding cytokine production profiles are not completely understood. The discovery of microRNAs provides a new opportunity to understand this complicated but crucial network for macrophage activation and adipose tissue function. We have examined the activity of microRNA-223 (miR-223) and its role in controlling macrophage functions in adipose tissue inflammation and systemic insulinresistance. miR-223-/- mice on a high-fat diet exhibited an increased severity of systemic insulin resistance compared with wild-type mice that was accompanied by a marked increase in adipose tissue inflammation. The specific regulatory effects of miR-223 in myeloid cell-mediated regulation of adipose tissue inflammation and insulin resistance were then confirmed by transplantation analysis. Moreover, using bone marrow-derived macrophages, we demonstrated that miR-223 is a novel regulator of macrophage polarization, which suppresses classic pro-inflammatory pathways and enhances the alternative anti-inflammatory responses. In addition, we identified Pknox1 as a genuine miR-223 target gene and an essential regulator for macrophage polarization. For the first time, this study demonstrates that miR-223 acts to inhibit Pknox 1,suppressing pro-inflammatory activation of macrophages; thus, it is a crucial regulator of macrophage polarization and protects against diet-induced adipose tissue inflammatory response and systemic insulin resistance.

Maintenance of body temperature is one of the first and most important physiological processes that must be initiated after birth. Failure to sustain homeothermy leads to hypothermia and death. Indeed, in sheep, 40% of non-predator lamb deaths are attributed to cold and cold-related causes. Brown adipose tissue (BAT) is an essential mediator of thermogenesis in many species and is responsible for 50% of the heat generated in the newborn lamb despite comprising only 2% of body weight. Previously, we found that maternal arginine supplementation increased fetal peri-renal BAT by 62%. This observation led us to test the hypothesis that increased the amount of fetal BAT will enhance neonatal thermogenesis at birth and thus combat the effects of cold stress. Thirty-one multiparous Suffolk ewes gestating singletons and twins were assigned to receive either intravenous injections of L-arginine (27 mg/kg bodyweight; n=17) or sterile saline (n=14) three times daily from Day 75 to Day 125 of gestation (term=147). Following parturition lambs were removed from their dams, placed in a thermoneutral environment, and fed artificial colostrum on a per body weight basis. At 4 hours of age, lambs were cold challenged at 0 degrees C for 2 hours. Rectal temperatures were recorded at 15 minute intervals. At 6 hours of age all singletons and one lamb of each twin pair was sacrificed. The remaining twin lamb was challenged again at 22 hours of age for an additional 2 hours prior to necropsy. Rectal temperature was greater for the duration of both cold challenges in lambs from arginine-treated ewes than lambs from saline-treated ewes (P<0.050). Interestingly, at time of necropsy, BAT weight did not differ (P>0.10) between treatments. UCP1 mRNA levels were not affected by treatment or age (P>0.10). However, TEK, PPARGC1A, NRF1, NRF2, PPARG, ADRB3, ARG2, RPS6KA1, EIF4EBP1, ODC1 were not affected by treatment (P>0.10) but were upregulated (P<0.05) by age; being greater at 24 hours of age versus 6 hours of age. Results indicate that maternal arginine treatment results in increased neonatal thermogenesis after birth. Although the underlying mechanisms remain to be elucidated, the data reported herein represent the first step in improving neonatal survival in response to cold.

Thesis (Ph.D.)--Tufts University, 2006. / Adviser: Andrew Greenberg. Submitted to the School of Nutrition Science and Policy. Includes bibliographical references. Access restricted to members of the Tufts University community. Also available via the World Wide Web;

Thesis (Ph. D.)--George Mason University, 2007. / Title from PDF t.p. (viewed Jan. 18, 2008). Thesis director: Ancha Baranova Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biosciences. Vita: p. 213 Includes bibliographical references (p. 188-212). Also available in print.

Thesis (Ph.D.)--Auburn University, 2007. / Abstract. Vita. Includes bibliographic references (ℓ. 104-133)

Thesis (M.Sc.(Hons.))--University of Wollongong, 2004. / Typescript. Includes bibliographical references: leaf 159-167.