Browsing by Subject "adipose tissue"

Now showing 1 - 3 of 3
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    Mechanisms of the pro-lipolytic and anti-obesity effects of the VGF-derived peptide TLQP-21
    (2015-10) Cero, Cheryl
    Obesity is a major public health problem; in the U.S. nearly one third of the population is obese. The adipose tissue is innervated by the sympathetic nervous system (SNS), which regulates fat mass by playing a key role in initiating lipolysis and regulating lipid mobilization. TLQP-21, a 21 amino acid peptide encoded by the pre-pro-peptide VGF (non acronymic) expressed in the brain and sympathetic neurons innervating the adipose organ. Complement 3a receptor 1, C3aR1, is the target receptor for TLQP-21. Based on previous finding where peripheral TLQP-21 decreases adipocyte diameter and enhance β-adrenergic receptors (β-ARs) lipolysis in adipocytes the hypothesis tested in my thesis is that C3aR1 and β-ARs are required for TLQP-21 anti-obesity effects and the pro-lipolytic effects are mediated by increased mobilization of [Ca2+]i. Departing from the first experimental structural analysis of TLQP-21 in solution and receptor-bound state, we tested our hypothesis using a combined in vitro and in vivo approach. Using 3T3L1 cells and pre-adipocytes as our in vitro model, we determined that TLQP-21 enhances lipolysis via increased intracellular Ca2+ concentration [Ca2+]i, and activation of the MAPK/ERK pathway. The physiological effects of TLQP-21 were investigated in vivo using wild type, β-less (β1, β2, β3-AR KO) and C3aR1 KO mice. Chronic TLQP-21 treatment in obese wild type mice significantly decreased body weight and fat mass promoting an overall healthier metabolic phenotype. Conversely β-less and C3aR1 KO resulted fully resistant to the anti-obesity effects. Herein we identified the mechanism of TLQP-21 pro-lipolytic and anti-obesity effect and could thus be regarded as a novel target for pharmacotherapies of obesity.
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    Protein carbonylation in the adipocyte nucleus
    (2017-11) Hauck, Amy
    As the incidence of obesity rises globally, it has become increasingly imperative to identify the mechanisms that cause obesity-related metabolic disease. In particular, oxidative stress in the adipose tissue is known to cause metabolic dysfunction, but the mechanisms that contribute to this process remain unclear. Protein carbonylation refers to the post-translational modification of lysine, cysteine, and histidine residues by diffusible electrophilic lipids. Specifically, 4- hydroxy-2-nonenal (4-HNE) and 4-hydroxy-2-hexenal (4-HHE) are produced at high levels in obese adipose tissue as a direct result of increased oxidative stress. The studies herein focus on the hypothesis that protein carbonylation is a mechanistic link between elevated oxidative stress and metabolic dysfunction in obese adipose tissue. We found that protein carbonylation is elevated specifically in the nucleus of adipocytes as a consequence of obesity and of aging. Proteomic evaluation of these modifications revealed that the core histones and zinc finger proteins are major targets of carbonylation. Since these proteins are critical regulators of transcriptional mechanisms, these data describe a potential link between oxidative stress and altered expression of metabolic pathways in adipose tissue.
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    Understanding The Role Of Pentraxin 3 In Adipose Tissue Inflammation And Aging
    (2022-01) Lin, Te-Yueh
    Obesity and aging are often accompanied by chronic low-grade inflammation in adipose tissue. Metabolic endotoxemia (elevated circulating lipopolysaccharide [LPS] level) is the inducer of systemic and adipose tissue inflammation and dysfunction, which is developed during obesity and aging. As a soluble pattern recognition receptor, Pentraxin 3 (PTX3) plays a vital role in innate immunity and can be induced by inflammatory stimuli in adipose tissue and adipocyte. Altered PTX3 levels have been observed in adipose tissue and blood during obesity and aging, while the role of PTX3 in adipose tissue during inflammation and aging is not fully understood. My Ph.D. research attempts to understand the role of PTX3 in adipose tissue inflammation and aging. In the first project, we investigated how PTX3 regulates inflammation in adipose tissue, and we found that PTX3 plays an anti-inflammatory role partially by regulating miR-21 expression and secretion in brown adipocytes. In the second project, we explored PTX3 secretion from adipose tissue and adipocyte and found that PTX3 is secreted mainly through conventional protein secretion, while a small percentage of PTX3 is released in exosomes from LPS-stimulated adipocytes. In the third project, we examined the physiological role of PTX3 in adipose tissue during aging, and we showed that PTX3 deficiency induced senescence and inflammation in adipose tissue and promoted lipid transport and oxidation in white adipose tissue of old female mice. In summary, my doctoral research reveals that adipose-derived PTX3 plays an essential role in regulating LPS-stimulated inflammation and cellular senescence during aging, and adipocyte-derived PTX3 is secreted via conventional protein secretion and exosomes.