Mechanisms of Pathological Adipose Remodelling

Mechanisms of Pathological Adipose Remodelling

 

Premature diseases and deaths associated with obesity are largely accounted for not by obesity itself, but by obesity-associated conditions including type 2 diabetes, atherosclerosis, fatty liver disease, polycystic ovary syndrome, and some cancers.  The “metabolic” or “insulin resistance” syndrome (IRS), a clustering of abnormalities including insulin resistance (IR) and abnormal blood fat levels, is a critical link between obesity and these diseases.  Some develop IRS with minimally increased adipose tissue, while others develop extreme obesity with little metabolic upset.  Differences in “adipose expandability” have been invoked to explain this.  According to this concept adipose tissue has a finite ability to expand through cell division and enlargement to store excess energy safely, and when this is exceeded “adipose failure” occurs, leading to inflammation of adipose tissue, abnormal lipid deposition in distant tissues, and IR.  Adipose failure may be absolute, as in rare people who completely lack adipose tissue, but more commonly adipose tissue is present but unable to fulfil its metabolic role normally.  This often correlates with age-related redistribution of adipose tissue.  Understanding adipose remodelling, and how it goes awry in IRS, is critical to tackling “obesity-related” diseases.

Study of rare human disorders featuring severe abnormalities of adipose distribution and caused by a single gene defect has great value.  It can reveal hypomorphic (partial loss-of-function) mutations in genes that would be lethal if fully “knocked out” or neomorphic (“change-of-function”) mutations that perturb or change normal gene function.  These may unmask vulnerabilities in human adipose function. Two disorders that form the major focus of study at present in the lab in humans, animals and cell culture models are caused by mutations in either DNA polymerase delta (Weedon et al, Nature Genetics 2013; doi: 10.1038/ng.2670.) or mitofusin 2 (Rocha et al, Elife 2017; doi: 10.7554/eLife.23813.).  These are being used as windows into the role of DNA damage and repair and mitochondrial network dynamics respectively in maintaining adipose health.

Principal Investigator: Robert Semple

This project is supported by: