Abstract
Physiological Role of De-differentiating Dermal Adipose Tissue
Adipose tissue fibrosis is an integral component of dysfunctional fat tissue. This fibrosis exerts detrimental
effects on local metabolic responses within adipose tissue, in addition to initiating maladaptive systemic
responses. The exact cause(s) of fibrosis in adipose tissue are still a matter of debate and as such, are not
well defined. Here, we aim to focus on “dermal adipose tissue fibrosis”, primarily due to its 1) ease of
accessibility, 2) our new genetic mouse models that we generated to specifically examine dermal
adipose tissue dysfunction and, 3) our initial observation that identified extensive dermal adipocyte
differentiation and de-differentiation. We believe that the latter processes are a key aspect of the
pathological road to adipose tissue fibrosis. Dermal adipose tissue is skin-associated fat located directly
under the reticular dermis. Compared to other well-defined fat pads, dermal adipose tissue displays a high
degree of plasticity. Under a variety of physiological conditions, dermal adipose tissue has the capacity to
either rapidly and locally expand, or reduce its volume. Our in vivo preliminary studies showed that dermal
adipose tissue is negatively associated with collagen production in skin fibroblasts. Importantly, more
recent studies in our laboratory identified that the highly dynamic nature of dermal adipocytes allows them
to 1) undergo de-differentiation into pre-adipocytes or, 2) convert into alpha-SMA-positive myofibroblasts
(when examined in a bleomycin-induced fibrosis model). Here, we propose to examine the following
hypothesis: that the adipocyte itself is the major player in preventing adipose tissue fibrosis in
response to a metabolic challenge of high fat diet feeding, or bleomycin induction. We will address our
hypothesis in three Specific Aims: I) We will retain fat cells in a fully differentiated state, by either ectopically
exposing dermal adipocytes to PPARgamma agonists. In parallel, we aim to genetically overexpress PPARgamma then
assess the impact on the fibrotic response. In addition to this, we will examine the impact of a complete
elimination of adipocytes upon the local fibrotic response in the skin. II) Through lineage tracing, we aim to
genetically label and track mature adipocytes as they de-differentiate into pre-adipocytes. Some of these pre-
adipocytes can convert to myofibroblasts. We have developed a genetic approach to selectively eliminate
myofibroblasts that originate from mature adipocytes. This will allow us, for the first time, to examine the
functional relevance of these adipocyte-derived myofibroblasts towards the fibrotic response in adipose tissue.
III) With a newly developed “Split Cre” system, we take advantage of a dual promoter system that ensures
expression uniquely in the dermal adipocyte. We will manipulate leptin and adiponectin levels locally, then
address the impact of local adipokine action in the microenvironment of the dermal adipose tissue on the
fibrotic response. While we focus on dermal adipose tissue, results from the proposed studies will also
have a profound impact on the understanding of the fibrotic response in other fat depots.