Transcriptomic analysis of white and brown adipose tissue during non-shivering thermogenesis
- Autores: Jordi Rodó i Morera
- Directores de la Tesis: Fàtima Bosch i Tubert (dir. tes.), Verónica Jiménez Cenzano (codir. tes.)
- Lectura: En la Universitat Autònoma de Barcelona ( España ) en 2019
- Idioma: español
- Tribunal Calificador de la Tesis: Malcolm Watford (presid.), Sergio Antonio Muñoz Forero (secret.), Dolors Serra Cucurull (voc.)
- Programa de doctorado: Programa de Doctorado en Bioquímica, Biología Molecular y Biomedicina por la Universidad Autónoma de Barcelona
- Materias:
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- Resumen
Obesity and type 2 diabetes (T2D) are two closely related diseases that represent a serious health, social and economic problem due to their high prevalence worldwide. Both diseases are also associated with other pathologies that present high mortality. The currently available therapies are not entirely effective. Thus, the development of new therapeutic strategies for obesity and T2D is crucial.
Adipose tissue has been defined as an organ that plays a central role in the control of energy balance. The proved endocrine and thermogenic functions of adipocytes has renewed interest in the study of this tissue. Non-shivering thermogenesis has been described as occurring in brown adipose tissue of mice, but under certain stimuli, such as prolonged cold exposure, brown fat-like cells (beige adipocytes), appear in some white adipose tissue depots of rodents and humans. The activation of non-shivering thermogenesis in humans through cold-exposure increases resting energy expenditure, whole-body glucose disposal, insulin sensitivity, and ameliorates glucose metabolism independently of BMI. However, more gene expression studies to gain insight into the molecular mechanisms underlying the cold-induced enhancement of non-shivering thermogenesis, as well as to determine differences between BAT activation and browning of WAT, are needed.
In this study, the transcriptomic response of epididymal and inguinal white adipose depots (eWAT and iWAT, respectively) as well as that of the interscapular brown adipose depot (iBAT) of mice either exposed to 22ºC or 4ºC for the period of 4 days were examined. Cold exposure increased the metabolic and thermogenic activity of iWAT. In this depot, genes related to glycolysis, tricarboxylic acid cycle, lipolysis, and the degradation of some amino acids presented a high upregulation to maintain the protonmotive power to generate heat. Moreover, the expression of thermogenic-related genes was also highly increased, demonstrating a cold-induced browning of iWAT. The eWAT depot has been reported to be resilient to browning. Thus, the observed metabolic activation of this depot was mild in comparison with that of iWAT, and no relevant enhancement of non-shivering thermogenesis was observed in this depot. Finally, iBAT already presented high expression levels of thermogenic genes because mice were not housed at thermoneutrality.
The observation that genes related to thermogenesis and metabolism presented a similar expression pattern among samples endorsed the utilization of pattern matching analysis tools to unravel Atp4b and 1700040L02Rik as novel genes potentially involved in thermogenesis. The overexpression of Atp4b and 1700040L02Rik in adipose tissue by means of AAV vectors produced a body weight gain reduction, decreased eWAT, and liver weight, amelioration of white adipocytes hypertrophy, and reduced hepatic steatosis potentially as a result of the detected enhanced thermogenesis in iWAT. Overall, these results indicate a new potential anti-obesogenic role for these genes.
The results from this thesis contributed to a better understanding of the induction of non-shivering thermogenesis in adipose tissue depots in mice. Among the different adipose depots, exploratory data analysis of the gene expression levels of mice exposed from 22ºC to 4ºC determined that iWAT was the depot that responded most significantly to cold exposure. Moreover, as observed in the pathway enrichment and gene ontology analysis, this response was highly coordinated, presenting a high number of genes related to metabolic pathways highly affected. The detailed study of the metabolic pathways led to the detection of a high induction of non-shivering thermogenesis, revealing that both energy production and energy consumption mechanisms were highly synchronized. This in detail study of the adipose tissue also allowed the identification of novel genes potentially involved in non-shivering thermogenesis.
