Kapser-Fischer 2020 Thesis

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Kapser-Fischer IP (2020) Dietary interventions in C57BL/6 mice and their interplay with selected metabolic and genetic parameters. PhD Thesis 120.


Kapser-Fischer Ingrid Petra (2020) PhD Thesis

Abstract: Within the last three decades, the prevalence of obesity has doubled and the numbers of associated co-morbidities such as type 2 diabetes and non-alcoholic fatty liver disease have also risen. To study the etiology of obesity and novel pharmaceutical interventions for the cure of obesity, diet-induced obese mouse models are the preferred choice for many researchers worldwide. Yet, study protocols for the induction of diet-induced obesity (DIO) in mice vary with respect to numerous factors, which all affect the outcome of these studies themselves. Therefore, results of different DIO studies are often neither comparable, nor reproducible. For this thesis, it was examined how variations in the experimental design of DIO experiments, such as differences in strain and gender of the mice used as well as differences in feeding durations and dietary fat content of the (high fat) diets affect the phenotypical heterogeneity of C57BL/6 mice. In doing so, certain key parameters such as body weight and fat mass gain, as well as the development of hyperglycemia, glucose intolerance and hyperinsulinemia were compared. Undergoing a low-calorie diet is the most popular, non-invasive way to loose weight. Yet, the underlying molecular mechanisms following a diet-induced weight loss have not been fully understood. This thesis presents detailed transcriptional analyses of the molecular alterations in liver and adipose tissue of mice with a history of obesity. Briefly, male C57BL/6J mice with DIO underwent a switch from a high-fat diet to a low-fat diet ad libitum and displayed a “normalized” metabolic phenotype, comparable to age-matched never-obese mice, 7 weeks after the diet-switch. Yet, at this time point, signs of hepatosteatosis and fibrosis, together with increased proinflammatory gene expressions, were present in liver tissues of formerly obese mice. This was paralleled by depot-specific adipocyte hypertrophy and macrophage infiltration in the perigonadal adipose tissue of formerly obese mice. Microarray analyses of the perigonadal adipose tissue of formerly obese mice further revealed up-regulation of numerous, partly inflammatory genes and pathways. One of these up-regulated genes in perigonadal and brown adipose tissue (BAT) of obese and formerly obese mice was the Activating Transcription Factor 3 (ATF3). Thus, by creating an UCP1-specific conditional knockout of ATF3 in BAT of mice, the impact of BAT-derived ATF3 on the development of DIO was analyzed. Here, the conditional knockout of ATF3 in male and female mice displayed no significant impact on the susceptibility to DIO, regarding the onset of body weight and fat mass gain, glucose intolerance and hyperinsulinemia. Still, a hypertrophy of adipocytes in BAT and subcutaneous white adipose tissue from diet-induced obese Atf3fl/fl;Ucp1cre+ mice was identified, contributing first insights into the role of ATF3 in BAT. In summary, this thesis contributes to novel understandings on how different dietary interventions impact the pathogenesis and reversibility of DIO in mice and presents metabolic and genetic alterations due to a history of DIO. Moreover, the presented results indicate that the presence of ATF3 in brown adipocytes does not play a role for the development of DIO in mice.

Bioblast editor: Plangger M

Labels: MiParea: Respiration, Exercise physiology;nutrition;life style  Pathology: Obesity 

Organism: Mouse  Tissue;cell: Fat  Preparation: Homogenate 

Coupling state: LEAK, OXPHOS 

HRR: Oxygraph-2k