The role of NR1D1 in obesity-related fibrosis, inflammation and insulin resistance

Background. Obesity- and age-related metabolic dysfunction are major public health concerns in the UK and globally. In
health, white adipose tissue (WAT) is an essential metabolic buffer, safely storing and supplying energy according to intake
and metabolic demand. As obesity develops, expansion of the WAT beds accommodates excess lipid storage. However,
profound adipocyte hypertrophy and WAT expansion ultimately drive tissue hypoxia, adipocyte dysfunction, immune cell
infiltration, and tissue fibrosis. This is especially evident in visceral WAT depots, and the degree of visceral adiposity is
associated with poor metabolic outcomes (e.g. insulin resistance) in humans and animal models. Despite many decades of
research, the events which trigger a transition from safe and efficient fat storage to tissue dysfunction remain a subject of
debate. It is well recognised that aberrant WAT function during obesity is a prominent feature of compromised metabolic
health. Here, attenuated metabolic activity, endocrine function and adipogenic capacity of WAT reduces healthy metabolic
profile, and progression to WAT inflammation and fibrosis elevates risk for pathologies such as diabetes and cancer. We have
identified the nuclear hormone receptor, NR1D1, as a major regulator of adipose tissue, whereby selective deletion of this
factor in adipocytes prevents development of WAT inflammation and fibrosis even amid profound obesity1
. In work leading
up to this PhD proposal, components extracellular matrix (ECM) have emerged as clear regulatory target of NR1D1 activity in
adipocytes, and we propose that altered collagen dynamics underlie the 'healthy' obese phenotype driven by Nr1d1 deletion.
Adipocytes are embedded in an ECM that must allow tissue expansion and regression, but also provide structural support for
relatively fragile lipid laden adipocytes. Critical here is the tissue and metabolic-state specific expression ECM proteins such
as collagens and their modifiers. The impact...