Browsing by Author "Chicco, Adam, advisor"
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- ItemOpen AccessFADS2 expression modulates effect of dietary polyunsaturated fatty acids on western diet-induced glucose intolerance(Colorado State University. Libraries, 2017) Linde, Peter, author; Chicco, Adam, advisor; Melby, Christopher, committee member; Bouma, Gerrit, committee memberFatty Acid Desaturase 2 (FADS2) haplotypes associated with hyperactivity of its gene product, delta-6-desaturase (D6D), are associated with obesity and type-2 diabetes in humans. D6D regulates long-chain polyunsaturated fatty acid (PUFA) biosynthesis and is upregulated in several rodent models of obesity/insulin resistance, but its direct influence on diabetes is unclear. D6D activity might favor pathogenic effects of omega-6 FA linoleic acid (LA) by enhancing production of its product arachidonic acid (AA). Conversely, D6D may promote protective effects of omega-3 FA α-linolenic acid (ALA) by enhancing production of ALA to long-chain PUFAs that displace AA in cell membranes. It is hypothesized that abundant LA found in the modern western diet will be converted to AA promoting an inflammatory phenotype. The present study is to determine the interaction of heterozygous knockout (HET) or transgenic overexpression (TG) of FADS2 in mice fed high fat diets (HFD), as well as the interaction of LA:ALA content in the HFD. Adult male mice with HET (low), wild type (WT; medium), and TG (high) expression of FADS2 were fed HFD (45% w/w) containing 8% PUFA supplied by a balanced mix of LA and ALA (1:1), LA-rich (41:1), or ALA-rich (1:4) for 16 weeks. Glucose intolerance developed in WT mice, with no difference between diets. In HET mice, glucose intolerance was attenuated but this protection was removed by ALA rich diet. TG mice developed more glucose intolerance than WT. TG mice fed high LA diets were more glucose tolerant than high ALA and mixed diets. In conclusion, FADS2 expression modulates metabolic responses to high fat feeding. HET provides some protection against glucose intolerance, except when given an ALA rich diet. Transgenic overexpression increases glucose intolerance while a high LA diet attenuates this effect. This is inconsistent with current hypotheses that AA production from LA increases metabolic risk.
- ItemOpen AccessFunctional responses of cardiac and skeletal muscle mitochondria to short-term obesity: are all obesities the same?(Colorado State University. Libraries, 2016) Lashbrook, Melanie, author; Chicco, Adam, advisor; Miller, Benjamin, committee member; Florant, Gregory, committee memberObesity is associated with metabolic alterations, specifically in the mitochondria, that may play a role in the development of insulin resistance and type 2 diabetes. In nature, there are circumstances where obesity is normal, even favored as seen in mammals that hibernate (hibernators). Understanding the consequences of obesity in ‘hibernators’ versus ‘disease’ models might yield novel insights on the effect of short-term obesity on mitochondrial function. The aim of this study is to compare mitochondrial function in a hibernator, the golden-mantled ground squirrel (Callospermophilus lateralis) and Ob/Ob mice following 4-6 weeks of hyperphagia versus their respective lean controls. Glucose tolerance tests were administered in lean, summer active squirrels (summer); hyperphagic obese, pre-hibernation period squirrels (prehib); and 5-week-old leptin-deficient (ob) and control (WT) C57-BL6J mice prior to sacrifice. High-resolution respirometry was used to examine mitochondrial function in permeabilized solei muscle fibers and isolated cardiac and skeletal muscle mitochondria obtained from all study groups. Body mass of obese animals was 30 and 50% greater than respective lean controls in squirrels and mice, respectively. Glucose intolerance developed with obesity in both species. Skeletal muscle mitochondria exhibited a greater capacity to oxidize pyruvate in the presence of lipids in squirrels, but not in mice. Cardiac oxidative phosphorylation (OXPHOS) capacity significantly increased only in squirrels, and exhibited a significantly greater capacity to oxidize pyruvate in the presence of lipids. No significant change was observed in mice cardiac mitochondria. Mitochondrial responses to obesity differed between models despite nearly identical effects of weight gain and glucose intolerance. Therefore, the observed differences between squirrel and mice likely reflect responses to different environmental cues or genetic background independent of ‘classic’ effects of obesity. The observed mitochondrial responses are not simply responses of obesity and glucose intolerance.
- ItemEmbargoGlucocorticoid receptor signaling is required for acclimation of skeletal muscle to hypobaric hypoxia(Colorado State University. Libraries, 2022) Whitcomb, Luke, author; Chicco, Adam, advisor; Maresh, Ryan, advisor; Melby, Christopher, committee memberHypobaric hypoxia (HH) encountered at high altitudes acutely impairs aerobic exercise capacity, which partially recovers following 1-2 weeks of acclimation to chronic HH. Persistent elevations in serum glucocorticoids occur during HH exposure, but their role in these acute and chronic physiological responses is unclear. We tested the hypothesis that glucocorticoid signaling is essential for the acclimation of aerobic exercise capacity to chronic HH, in part by mediating adaptive changes in skeletal muscle metabolism. Male F344 rats were administered the glucocorticoid receptor antagonist RU486 (RU; 60 mg/kg/d in chow) or no drug for 5 days prior to 15 days of continued normoxia (Fort Collins, CO; elevation 5,003 feet) or HH (simulated 17,200 feet in a hypobaric chamber) with or without continuous RU treatment (N=4-8/group). Graded treadmill exercise tests (GXT) were conducted on a motorized treadmill in normoxia, during acute HH exposure, and in HH after 15 days of HH acclimation. As expected, acute HH reduced GXT performance compared to normoxia in all rats, which improved following 15 days of acclimation to HH. RU pretreatment did not impact hypoxic GXT performance, but continuous treatment abolished improvements in GXT performance following chronic HH. RU attenuated HH-induced increases in hematocrit and muscle fatty acid oxidation efficiency assessed by high-resolution respirometry ex vivo, suggesting that glucocorticoid signaling may improve muscle oxygen utilization in response to chronic HH. RU also prevented HH-induced decreases in pyruvate dehydrogenase expression and increases in Krüppel-like factor 15, proteolysis and branched-chain amino acid aminotransferase in glycolytic muscle, implicating glucocorticoid signaling in a rewiring of glucose and protein catabolism to rid the cell of excess nitrogen in HH. In conclusion, these results demonstrate that glucocorticoid receptor signaling is essential for the acclimation of aerobic exercise capacity to HH, perhaps by mediating improvements in the bioenergetic efficiency of skeletal muscle metabolism.
- ItemEmbargoImpact of testosterone on trophoblast mitochondrial function(Colorado State University. Libraries, 2022) Parsons Aubone, Agata M., author; Chicco, Adam, advisor; Tesfaye, Dawit, committee member; Tjalkens, Ron, committee memberSeveral pregnancy disorders involve placental abnormalities, including gestational diabetes mellitus (GDM) (2-10% of pregnancies), preeclampsia (PE) (6-8% of pregnancies), and polycystic ovary syndrome affects (PCOS) (6 to 15% of women in reproductive age), which not only has a negative impact on maternal health but can also lead to birth defects and postnatal health complications. These disorders commonly also present high levels of androgens in maternal blood, accompanied by placental insufficiency. The placenta in these pathologies presents morphological and physiological alterations, including in the trophoblast mitochondria. The placenta is a multifunctional, transient organ that mediates the transport of nutrients and waste to and from the fetus, gas exchange, and endocrine signaling to maintain maternal and fetal homeostasis. To facilitate these diverse and important functions and enable proper fetal growth and development, the placenta is highly metabolically active and consumes ~40% of the total oxygen. Oxygen is used for the synthesis of ATP in mitochondria, which in turn is mainly used for cholesterol transport and steroidogenesis. The placenta is well recognized as a hormone-synthesizing and secreting organ; however, studies revealed it is a target of these hormones as well and contains receptors for various steroid hormones including androgens. Placental androgen receptor (AR) is relevant in pregnancy disorders with elevated androgens such as GDM, PE, and PCOS. These are accompanied by placental pathologies that include mitochondrial adaptations that vary according to the stage of the pathology, and in advanced stages when levels of reactive oxygen species (ROS) become too high they can have detrimental effects on the placenta and can even lead to pregnancy loss. Of particular interest here is the recent observation that AR has been identified as a regulator of mitochondrial function in other tissues such as the prostate and cancer. The production of ROS and/or the decrease in antioxidant defenses are the main mechanisms underlying placental insufficiency in pathologies with elevated androgens. A better understanding of the regulation of androgen signaling in placental mitochondria will lead to new insights and opportunities to understand and treat disorders of pregnancy that affect a significant number of pregnant women. Studying the human placenta in vivo presents several complications, so it is necessary to use in-vitro models. There are several human trophoblast cell lines available, but none are perfect replacements for the original organ, rather each one has qualities that allow investigators to choose one best suited for their study. The overall goal of our studies is to investigate the role of AR signaling in trophoblast cell mitochondrial respiration. Our hypothesis is that AR signaling regulates mitochondrial oxygen consumption and ROS production. The first chapter will provide an overview on the role of androgens in placental physiology and pregnancy, and the role of mitochondria in trophoblast cell function. In the second chapter, we present studies aimed at characterizing mitochondrial respiration in existing placental cell lines and elucidating a possible role for AR signaling in mitochondria. Specifically, we first demonstrated the presence of AR in placental mitochondria. Next mitochondrial oxygen consumption and ROS production are characterized and compared using an Oroboros O2K oxygen respirometer in three well-known human (ACH-3P, BeWo, and Swan-71) and one immortalized ovine trophoblast cell (iOTR) line. Finally, ACH-3P cells are selected to test mitochondrial responses to testosterone, mimicking placental pathologies seen in GDM, PE, and PCOS. Our results revealed that both human ACH-3P and Swan-71 cells, as well as the sheep iOTR cells, demonstrated normal oxygen consumption and ROS production following the addition of selected complex protein substrates. Chronic testosterone treatment led to significant increased ROS production in ACH-3P cells, which correlates with what has been observed in term placentas of women with placental hyperandrogenism. In conclusion, the ACH-3P cell line is a good in vitro model to study placental mitochondrial respiration. Ultimately, the presented data provide new information regarding the possible role of AR signaling in placental mitochondria and will pave the way for future studies aimed at uncovering the mechanism of AR regulation of mitochondrial function in normal and abnormal pregnancies (discussed in Chapter 3).