Lipid metabolism and mitochondrial respiration in adipose tissue and liver during obesity

Obesity is defined as the excessive accumulation of fat, which presents a risk to health, with 26% of adults in the UK classed as obese in 2024. Most fats are stored in white adipose tissue (WAT), which is greatly expanded during obesity, and shows impaired energetic function. In addition, the liver is a key site of ectopic fat deposition in obesity, resulting in changes in metabolic function. It has been proposed that changes in mitochondrial respiratory function are associated with WAT expansion and hepatic steatosis, but whether this is associated with alterations in the tissue lipid composition remains unclear. The impact of age and sex on lipid profile and mitochondrial respiration is also unresolved, and these factors are associated with differing risks, outcomes and disease phenotypes in the context of obesity. The effects of age and obesity were investigated in adipose tissues of obese mice. A lower mitochondrial function in obese mice correlated with lipid remodelling in membranes i.e. phosphatidylcholine/phosphatidylethanolamine (PC/PE) ratios in both brown and white adipose tissues. When the effects of sex and obesity were investigated in adipose tissue, a positive correlation was again detected between PC/PE ratio and mitochondrial respiratory function, with a more significant relationship in subcutaneous WAT from female than male mice. In liver, mitochondrial respiratory capacity was higher in female HFHS-fed mice compared with chow-fed females, but lower in male HFHS-fed mice than chow-fed males, and this was unrelated to mitochondrial content. Ceramide accumulation and increasing abundance of membrane lipids correlated negatively with mitochondrial respiratory function and density, and positively with fibrosis. In summary, obesity resulted in impaired mitochondrial function in most tissues, independent of changes in mitochondrial content, except in female liver where respiratory capacity increased. Changes in lipid pathways in obesity included alterations in membrane lipids and ceramide abundance, which showed a relationship with mitochondrial respiration in adipose tissue and liver. These associations were sex-specific and may therefore relate to differing clinical trajectories.

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

• Darwin, Paula

Advisors dc:contributor.advisor

• Murray, Andrew
• Griffin, Julian

• Age
• Lipid
• Lipidomics
• Metabolism
• Mitochondria
• Obesity
• Sex

Licence

• https://www.repository.cam.ac.uk/bitstreams/f3c04c95-683e-4507-85cc-95a510ff5d0b/download
• http://purl.org/NET/rdflicense/allrightsreserved

Language dc:language

eng

Author Identifier

0000-0002-8408-4680

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/392135