Date of Award
Bachelor of Science
obesity, depression, patients, population, cortisol, assay, diagnosis
The shared circuitries of depression and the stress response, regulated by the Hypothalamic-Pituitary-Adrenal (HPA) axis, implies that major depression may reflect dysregulations of the HPA axis. Previous studies find that that melancholic depression is accompanied by hyperactive HPA activity, anxiety, insomnia etc. Adversely, patients with atypical depression present CRH deficiency accompanied by lethargy and fatigue. According to the corticosteroid receptor hypothesis, HPA axis dysregulation that causes these variable phenotypic depressive moods may be attributed to defective GR expression or function. Multiple GR polymorphisms that could impact its expression or function have been identified. Due to limitations, it was not feasible to study a depressed patient population at this time. Fortunately, the strong correlation between depression and obesity both being induced HPA dysregulation means that a similar study can be done by examining metabolic disorders. A diagnosis of Metabolic Syndrome (MS) requires patients to present three or more of the following symptoms: elevated fasting blood glucose levels, elevated serum triglyceride levels, low serum HDL levels, elevated blood pressure, and truncal obesity. This pathology overlaps with Cushing’s Syndrome (CS) except a diagnosis of CS requires hypercortisolemia. This similarity has led our lab and others to hypothesize that MS may be a Cushingoid-like state caused by hypersensitivity of the glucocorticoid receptor (GR), a nuclear hormone receptor that is activated upon the binding of cortisol. Using an allele specific polymerase chain reaction (PCR) protocol, previous research in our lab found significant correlations between the BclI and N363S polymorphisms of the GR and altered patient metabolic profiles in a population of patients seeking bariatric surgery. This suggests that each contributes to obesity related diseases. Recent work in our lab has expanded our study to include the cortisol resistance polymorphism TthIII1 (rs10052957) to test the hypothesis that there would be a decreased prevalence of this polymorphism in our subject population. The TthIII1 allele is present at a lower frequency in our research population compared to reported frequencies, consistent with our hypothesis. In addition to investigating the glucocorticoid receptor, we have also developed an allele specific PCR assay for previously identified single nucleotide polymorphisms (rs12086634 and rs846910) in the cortisol reductase enzyme known as 11beta-hydroxysteroid dehydrogenase (11b-HSD) type 1. The 11B-HSD1 enzyme converts inactive cortisone to cortisol, working primarily in adipose tissue. The polymorphisms listed above are associated with over activity of the enzyme and may cause the Cushingoid-state observed in MS patients. In our patient population, the frequency of heterozygosity for the rs12086634 SNP was nearly 50% higher than the reported frequency in the general population, suggesting that this polymorphism may contribute to increased obesity and the MS metabolic profile, by increasing the localized cortisol in adipose tissue. Greater understanding of the interplay between these SNPs can help physicians and patients make more informed decisions about treatment options for obesity and metabolic syndrome.
Salm, Justin Robert, "Development of Novel Allele Specific PCR Based Assays to Investigate the Contribution of Cortisol to Metabolic Syndrome and it's Potential Implications in Depression Treatment" (2017). Honors Theses and Student Projects. 251.
Available for download on Friday, June 15, 2018