Browsing by Subject "Diet, High-Fat"
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Item Ghrelin: The Hunger Hormone that Isn't(2014-06-09) McFarlane, Matthew Ryan; Elmquist, Joel; Brown, Michael S.; Goldstein, Joseph L.; Olson, Eric N.; Horton, Jay D.Ghrelin is a 28-amino acid acylated peptide hormone secreted by endocrine cells in the stomach. It was first identified in 1999 and shortly thereafter shown to stimulate appetite when injected into rodents and humans. While ghrelin knockout mice have failed to show a decrease in appetite or bodyweight, the literature -- as well as the lay press -- continues to presume ghrelin levels are a mediator of appetite in vivo. For example, the suppression of ghrelin levels secondary to gastric bypass surgery is frequently invoked as a contributing factor in the resulting weight loss. In the literature, this incongruity has been rationalized as embryonic or neonatal compensation, a claim predicated on a study by Luquet et al. which showed that AgRP/NPY neurons (which express the ghrelin receptor and are thought to be the critical target for appetite stimulation) can be ablated without consequence in neonatal mice, while in adult mice ablation causes a rapid and profound loss of appetite. Widespread acceptance notwithstanding, the hypothesis that a reduction in ghrelin levels decreases appetite in adults has never been tested. We generated a mouse line expressing the simian diphtheria toxin receptor on ghrelin cells. With these mice we are able to rapidly ablate ghrelin cells in adulthood with the injection of diphtheria toxin. Despite an 80-95% loss of circulating ghrelin, our mice show no decrease in appetite or body weight in the short or long term and become obese and hyperinsulinemic in response to high fat feeding. To investigate why ghrelin seems to be sufficient but not necessary for hunger, we injected increasing doses of ghrelin and measured both food intake and the resulting plasma concentration. We found that the threshold dose for an appetite response raised blood concentrations more than 50-fold above physiologic levels -- well above the highest concentration we have observed even during extreme starvation. We show that at physiologic levels ghrelin is neither necessary nor sufficient for hunger and conclude that it is not a key regulator of appetite or weight gain in mice. Ghrelin's only essential role in mice appears to be the maintenance of plasma glucose during periods of starvation.Item The Maladaptive Response of Adipose Tissue to High Fat Diet Feeding(2018-04-05) Morley, Thomas S.; Gupta, Rana K.; Scherer, Philipp; Brekken, Rolf A.; Kittler, Ralf; Kim, JamesThe ability of organisms, from yeast to humans, to safely store energy as dense hydrophobic carbon chains secured away in lipid droplets represents an incredible evolutionary advantage. The further use of adipocytes as a professional lipid storage cells emphasizes the importance and benefit of safe long term energy storage. As lipids are capable of acting intracellularly as both signaling molecules and detergents, there proper storage and sequestration is of pivotal importance if they are to be used for the maintenance of energy homeostasis. With the safe storage of energy dense lipids and their later partitioning to other metabolically active tissues, the production of ATP can continue to occur in multiple organs during periods of food deprivation. With this in mind, many early investigators saw the importance of adipose tissue, though its true importance was not recognized till relatively recently.Item Role of Complement Factor H Polymorphism and Diet in Neuroinflammation(2014-02-04) Parnell, Samuel; Kasumu, Ade; Aredo, Bogale; Chen, Xiao; Ufret-Vincenty, RafaelBACKGROUND: Multiple lines of evidence point towards an important role for complement factor H (Cfh) in neuroinflammation. Evidence of activated microglia and activated astrocytes has been found in the brains of both Parkinson's disease and Alzheimer's disease patients.1 In addition, Cfh has been shown to be present in amyloid beta plaques in Alzheimer's disease.2 Our laboratory has developed a mouse model of early AMD based on expressing variant Cfh molecules in mice.3 The Cfh transgenic mice develop deposits under the retinal pigment epithelium, which resemble early changes seen on AMD. We believe these findings indicate that the variant Cfh molecules are less able to control chronic low grade inflammation at the tissue level. METHODS: Young (6m old) and aging (18m old) Cfh transgenic and control B6 mice were divided into groups and fed either a control diet or a high-fat diet for 5 months. Brains were collected after perfusion with 2% PFA/PBS and were post-fixed overnight in 4% PFA/PBS. Next, the brains were transferred to a 30% sucrose solution, weighed, and sectioned. Immunohistochemistry was then performed on 30 μm brain sections with antibodies specific for inflammatory, oxidative stress, and microglial markers. Stained images were visualized using a Leica fluorescence microscope with an objective lens of 10x. The microglia over the photographed field were counted and averaged in order to obtain a cells/field value for each mouse. Statistical analysis was then performed on the data. RESULTS: CfhTg brains weighed less than the corresponding B6 brains (0.447 vs. 0.482g; p=0.00024). Many of the tested antibodies, particularly those associated with oxidative stress, did not stain the sections, perhaps due to the fixation method. However, the anti-TREM2 and anti-Iba 1 antibodies stained well. There was no difference in the number of Iba-1+ microglia in the dentate gyrus of CfhTg vs. B6 mice (p=0.607). Younger mice seemed to have higher numbers of these cells compared to older mice (73.3 vs. 52.6 microglia/field; p=0.0352). In addition, the mice fed a high fat diet appeared to have less microglia per field compared to the mice fed a normal control diet (53.1 vs. 72.8 microglia/field; p=0.0469). TREM2 is considered to be a marker for microglial activation. Neither age (p=0.65), nor a high fat diet (p=0.435) appeared to affect the level of TREM2 expression. However, there was a trend towards higher numbers of TREM2+ cells in CfhTg mice compared to B6 mice (p=0.17), particularly in the old group of mice (p=0.12). CONCLUSIONS: Reduced brain mass in CfhTg mice suggests increased CNS oxidative stress and tissue injury. There was no difference in the number of Iba-1+ microglial cells in CfhTg vs B6 mice. However, there was a trend towards increased microglial activation in Tg mice. More brains will be analyzed with alternative methods of tissue collection and additional antibodies to corroborate these findings.Item [Southwestern News](2002-05-17) Carter, Wayne; Morrison, Susan