La lectura de la tesi es farà a la Sala de Graus de la Facultat de Medicina de la Universitat de Girona.

ABSTRACT

The prevalence of obesity has increased dramatically in recent years and has reached epidemic proportions. Obesity is a chronic multifactorial disease associated with an abnormal accumulation of dysfunctional adipose tissue and has been associated with multiple related disorders, including cognitive dysfunction. It is known that cognitive decline is a major health problem and is found to be exacerbated by metabolic comorbidities such as obesity. The aetiology of obesity is multifactorial, including environmental factors. Nowadays, environmental factors are changing due to global warming which is increasing the temperature of the Earth. It is known that the browning process is very important in the physiology of adipose tissue.

The aim of this thesis is to describe the bidirectional interaction between adipose tissue and cognitive performance in human subjects with morbid obesity, as well as in animal models, and to investigate how environmental temperature might affect adipose tissue physiology and metabolic traits in white adipose tissue. For this purpose, several cohorts of subjects, with and without obesity, were recruited and transcriptomic analysis were performed in the adipose tissue of these subjects. Brain function was assessed through neurocognitive tests. Temperature data was obtained from a cohort of more than 1,000 subjects from five different regions of Spain. Drosophila melanogaster and mice animal models were used to study the cognitive function by altering the expression of target genes in the fat body or adipose tissue.

Here, we identified 188 genes from RNA sequencing of adipose tissue in three cohorts that were associated with performance in different cognitive domains. These genes were mostly involved in synaptic function, phosphatidylinositol metabolism, the complement cascade, anti-inflammatory signalling, and vitamin metabolism. These findings were translated into the plasma metabolome. The circulating blood expression levels of most of these genes were also associated with several cognitive domains in a cohort of 816 participants. Targeted misexpression of candidate gene ortholog in the Drosophila fat body significantly altered memory and learning in flies. Among them, down-regulation of the neurotransmitter release cycle-associated gene SLC18A2 improved cognitive abilities in Drosophila and in mice. Up-regulation of RIMS1 in Drosophila fat body improved cognitive abilities.

The expression of genes associated with browning and ADIPOQ in adipose tissue were significantly and negatively associated with environmental temperatures. The latter temperatures were also negatively associated with the expression of genes involved in adipogenesis. Decreased expression of UCP1 and ADIPOQ messenger RNA and circulating adiponectin were observed with increasing temperatures in all individuals as a whole and in participants with obesity in univariate, multivariate and artificial intelligence analysis. The differences remained statistically significant in individuals without type 2 diabetes and in samples collected during winter.

Taken together, these findings suggest a bidirectional interaction between the adipose tissue transcriptome and brain function in humans, as well as in animal models. Furthermore, given the North-South gradient in obesity prevalence in the study regions, the present observations may have implications for the relationship between the obesity pandemic and global warming.