Dissertation

Exploring Mechanisms of Gene Expression Regulation in the Developing Murine Adipose Tissue

Hoang, Anh Cuong

2021

Overview

Background and objectives: Obesity is an epidemic, noncommunicable, metabolic disease which can develop early in life, leading to a rapid and dramatic increase in the global prevalence of obesity-associated diseases. To avoid obesity, we have to understand the developing adipose tissue at the level of its molecular mechanisms and genomics.Hypothesis and aims: Gene expression changes and immune-metabolic mechanisms of the obese adipose tissue in adulthood are well studied, however we know much less about these in the developing adipose tissue. In this thesis we aimed to identify unique and defining transcriptional landscape and morphology of the adipose tissue in the early postnatal life. Furthermore, since fat catabolism is greater in early life than in adulthood, we hypothesize that adipocytes in the developing fat household a high amount of mitochondria to fulfil the demand of fat metabolism. It is plausible to assume that the extensive mitochondrial network may require a suppression of the immune response elicited by mitochondrial contents. Therefore, we searched for immune regulators, signals and mechanisms which favour mitochondrial network expansion.Results: We found that during postnatal development, infant fat depots contained beige adipocytes. We show that these adipocytes perform thermogenesis and develop independently from the brown adipose tissue (BAT). Thermogenic adipocytes in the early postnatal life expand their mitochondrial network by suppressing the innate immune recognition of mitochondrial DNA and RNA (mtDNA and mtRNA). This was achieved through a suppressed interferon (IFN) regulatory factor 7 (IRF7) expression. A unique mtRNA-driven signal mechanism triggers the mitobiogenesis and beige adipogenesis. The role of mtRNA is restricted to infant adipocytes, since adult adipocytes respond with an IFN burst after mtRNA exposure. Obesity increased IRF7 expression, leading to IFN response towards mitochondria, eventually impairing the mitochondrial network. Vit-D3 allows IFN-free, mtRNA-mediated mitobiogenesis in diet-induced obese adult mice which ultimately reduce obesity development.Summary and impact: This thesis showed that (i) beige adipocytes could be identified in the developing fat, and that (ii) maintaining these adipocytes´ mitochondria is key for the lipid catabolism and beige adipogenesis. These finding have impact on the adipose tissue field because it may add a 3rd adipocyte type which is present during infancy and has to be reestablishing in adulthood to potentially reduce obesity.

• Publisher: ProQuest Dissertations & Theses
• Subject: Body mass index / Cellular biology / Genetics / Genomics / Insulin resistance / Lipids / Mitochondrial DNA / Obesity
• ISBN: 9798288845703