The role of extracellular matrix remodelling in brown adipose tissue functions: New candidates

Brown adipose tissue (BAT) is specialised in energy expenditure, as it has the capacity to perform thermogenesis, which consists on dissipating energy by producing heat to maintain body temperature from the oxidation of lipids, primarily, upon norepinephrine stimulation. BAT can improve obesity-related metabolic complications by inducing BAT thermogenesis and increasing BAT mass through the recruitment and differentiation of precursors. Both events can be influenced by the status and functionality of the extracellular matrix (ECM). However, the main obstacle is that obese and diabetic patients have less active BAT mass. Understanding the mechanisms that regulate and impair BAT activity in obesity is essential for developing an efficient strategy to increase BAT mass and activation. Thus, our overall hypothesis are that 1) the ECM remodeling (ECMr) is required to sustain BAT functionality, and 2) impaired ECMr occurs in obesity, affecting BAT recruitment and activation. In this thesis, 1) I explored the role of ECMr in BAT adipogenesis, activation and dysfunction; 2) I characterised the impact of Pepd partial ablation (a prolidase involved in the last step of collagen degradation and turnover) in brown adipocytes functions in vitro; 3) I performed a data integration analysis to obtain a list of the most promising ECM-related candidates involved in BAT functions regulation; 4) I determined the role of Aplp2 and Cyr61, the two most relevant ECM-associated candidates involved in BAT functions regulation, in brown adipocytes functions in vitro using a siRNA- mediated knock-down model. In Chapter 3, we demonstrated that ECMr is required for brown adipogenesis and BAT activation, while hypoxia and inflammation impair ECMr, inducing BAT fibroinflammation and dysfunction. PEPD is a key ECMr regulator, and we showed in Chapter 4, that its partial ablation in vivo impairs ECMr, inducing fibroinflammation in BAT even upon activation conditions, while it induces a senescence-like phenotype in preadipocytes differentiated in vitro. In Chapter 6 and 7, we demonstrated that Cyr61 and Aplp2 play a significant role in ECM-mitochondrial crosstalk by different mechanisms, as the knock-down of either of them induces mitochondrial dysfunction and impairs brown adipocytes’ activation.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2024

Author dc:creator

• Figueroa-Juárez, Elizabeth

Advisor dc:contributor.advisor

• Vidal-Puig, Antonio

• Extracellular matrix
• Brown adipose tissue
• Fibrosis
• Obesity
• Aplp2
• Cyr61
• Pepd

Licence

• https://www.repository.cam.ac.uk/bitstreams/e8098a69-f77c-4a6d-a017-901b39c9dae0/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.110696

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/371541