Role of Inflammation in Diet-Induced Obesity: A Dissertation

Obesity results from expansion of white adipose tissue. The inability of white adipose tissue to adequately store lipids leads to ectopic deposition of lipids in non-adipose tissue that can lead to systemic insulin resistance. It is well known that insulin resistance correlates with inflammation of adipose tissue in obese animals and humans. Decreasing inflammation in the adipose tissue has been proven as a therapeutic strategy for improvement of insulin sensitivity in vivo. Numerous factors secreted by immune cells, including macrophages, have been suggested as regulating adipose tissue insulin sensitivity. In the first part of my thesis, I describe the role of one such factor, CD40 in adipose tissue inflammation. The CD40-CD40L dyad acts as co-stimulation in the interaction of antigen-presenting cells, such as macrophages and dendritic cells, with effector cells, such as T cells, in adaptive immunity. We found that CD40 knockout mice were smaller but surprisingly more insulin resistant and glucose intolerant compared to wild-type mice when fed a high fat diet. Consistent with their metabolic phenotype, knockout mice displayed increased adipose tissue inflammation with infiltration of immune cells including macrophages and T cells. Consistent with increased inflammation, CD40 knockout adipose tissue displayed decreased lipid storage. Deficiency of CD40 also led to increased lipid deposition in liver, which may be due to increased lipid release into circulation from the adipose tissue as well as increased lipid synthesis in the liver. CD40 knockout mice had increased hepatic insulin resistance and increased gluconeogensis despite decreased hepatic inflammation. These findings suggest that CD40 is a novel regulator of adipose tissue inflammation in diet-induced obesity. In the second part of this thesis we examined perivascular adipose tissue and brown adipose tissue for the presence of inflammation. In contrast to visceral adipose tissue, macrophage infiltration was absent in perivascular and brown adipose tissue as defined by reduced F480+ cells by flow cytometry and immunohistochemistry. We also found that perivascular adipose tissue was similar to brown adipose tissue as shown by gross morphology and gene expression pattern. Inflammatory gene expression was not increased in brown or perivascular adipose tissue in obese mice as determined by microarray gene expression analysis. These findings suggest that perivascular adipose tissue is more similar to brown adipose tissue than white adipose tissue and that both perivascular and brown adipose tissue are resistant to inflammation. We conclude that, (1) CD40 protects against adipose tissue inflammation in diet-induced obesity, (2) the CD40 knockout mouse is an interesting model of hepatic steatosis with decreased inflammation and (3) perivascular adipose tissue is almost identical to brown adipose tissue in obese mice and that both are resistant to inflammation

Integrins in prostate cancer progression

Integrins, which are transmembrane receptors for extracellular matrix proteins, play a key role in cell survival, proliferation, migration, gene expression, and activation of growth factor receptors. Their functions and expression are deregulated in several types of cancer, including prostate cancer. In this article, we review the role of integrins in prostate cancer progression and their potential as therapeutic targets

Serotonin and Migraine

Migraine, experienced by more than 1 billion people, is the second leading cause of disability worldwide. It is a physiologically complex disorder with nervous, vascular, and inflammatory components, and is associated with genetic factors and environmental influences. Migraine triggers are poorly understood, and sufferers have little control in preventing migraines from occurring. The aim of this review is to bridge the physiological migraine processes with lifestyle behaviors that can be modified by individuals, focusing on serotonin. Migraines can be initiated when an external event triggers the release of vasodilators such as calcitonin gene-related peptide (CGRP), leading to cranial vasodilation, headache, and other migraine-associated symptoms. Under normal conditions, serotonin counters the effect of CGRP by inducing vasoconstriction; however, when it is absent or low, as seen in migraine patients, vasodilators can accumulate in the cranial vessels and vasodilation may persist, leading to migraine. Serotonin is a neurotransmitter, synthesized from the essential amino acid tryptophan obtained from the diet. Diets are variable, modifiable, and can be targeted toward increasing tryptophan intake, relative tryptophan availability, and serotonin synthesis. The majority of serotonin synthesis occurs in the gut by both enterocytes and bacteria of the microbiome, which can be increased by eating foods high in fiber, vitamin B6, and fermented products that favor a serotonin-friendly microbiome. Serum levels are also influenced by exercise, exposure to bright light, stress reduction, and positive mood induction. In summary, migraine sufferers can take control of their health through lifestyle modifications that increase serum serotonin and prevent migraine propagation

Connection Between Migraine Physiology and Modifiable Lifestyle Factors and Behaviors: A Literature Review

Migraine headache is a physiologically complex disorder that presents as an intense headache with other symptoms. Globally, more than one billion people suffer from migraine, and it is the second leading cause of disability worldwide. At present, migraines are targeted with many pharmaceutical interventions; however, there are no well-studied ways to combat migraines through lifestyle modifications alone. One of the molecules involved in migraine physiology is the calcitonin gene-related peptide (CGRP), which causes vasodilation and the sensation of pain. The focus of this thesis is to find connections between CGRP physiology and modifiable factors that individuals have the power and autonomy to change. This thesis explores the connections between migraine and the TRPA-1 receptor, serotonin, sleep patterns, melatonin, exercise, caffeine, and a variety of nutrients. Several modifiable lifestyle factors and behaviors are identified including changes to diet, physical activity, and sleep patterns to decrease the frequency and severity of migraine attacks

Abstract Rational Invariants of a Group Action. Construction and Rewriting.

Geometric constructions applied to a rational action of an algebraic group lead to a new algorithm for computing rational invariants. A finite generating set of invariants appears as the coefficients of a reduced Gröbner basis. The algorithm comes in two variants. In the first construction the ideal of the graph of the action is considered. In the second one the ideal of a cross-section is added to the ideal of the graph. Zero-dimensionality of the resulting ideal brings a computational advantage. In both cases, reduction with respect to the computed Gröbner basis allows to express any rational invariant in terms of the generators

Similarity of mouse perivascular and brown adipose tissues and their resistance to diet-induced inflammation

Thoracic perivascular adipose tissue (PVAT) is a unique adipose depot that likely influences vascular function and susceptibility to pathogenesis in obesity and the metabolic syndrome. Surprisingly, PVAT has been reported to share characteristics of both brown and white adipose, but a detailed direct comparison to interscapular brown adipose tissue (BAT) has not been performed. Here we show by full genome DNA microarray analysis that global gene expression profiles of PVAT are virtually identical to BAT, with equally high expression of Ucp-1, Cidea, and other genes known to be uniquely or very highly expressed in BAT. PVAT and BAT also displayed nearly identical phenotypes upon immunohistochemical analysis, and electron microscopy confirmed that PVAT contained multilocular lipid droplets and abundant mitochondria. Compared with white adipose tissue (WAT), PVAT and BAT from C57BL6/J mice fed a high-fat diet for 13 wk had markedly lower expression of immune cell-enriched mRNAs, suggesting resistance to obesity-induced inflammation. Indeed, staining of BAT and PVAT for macrophage markers (F4/80 and CD68) in obese mice showed virtually no macrophage infiltration, and FACS analysis of BAT confirmed the presence of very few CD11b(+)/CD11c(+) macrophages in BAT (1.0%) compared with WAT (31%). In summary, murine PVAT from the thoracic aorta is virtually identical to interscapular BAT, is resistant to diet-induced macrophage infiltration, and thus may play an important role in protecting the vascular bed from inflammatory stress