Developmental origins of dermal adipose tissue

University Of Pennsylvania, Philadelphia PA

Investigators

Abstract

Obesity is one of the most pressing public health challenges of the 21st century. Weight gain occurs in the setting of nutrient excess, which stimulates adipose tissue expansion via both healthy hyperplastic and pathologic hypertrophic processes. The metabolic consequences of obesity, including diabetes and fatty liver disease, are believed to stem from a relative deficiency in hyperplastic expansion of adipocyte progenitor cells specifically within the subcutaneous adipose depot. Subcutaneous adipose is generally considered metabolically beneficial in humans, however our understanding of the developmental origin, and cellular composition of this depot remain relatively limited. Recent studies have revealed the presence of distinct anatomic layers including dermal adipocytes. Dermal adipose is more metabolically dynamic than deeper layers of subcutaneous or visceral adipose, demonstrating massive expansion in obesity and involution with caloric restriction. Given its widespread distribution in humans, dermal adipose is thought to comprise a significant portion of the subcutaneous depot and thus play a significant role in whole body metabolism. Dermal adipose represents a critically important metabolic organ, yet its distinct developmental origins remain unknown. To address this knowledge gap, we have performed preliminary single cell studies during murine embryonic dermal development, which revealed the presence of a novel population of mesenchymal cells marked by Bcl11b expression. We discovered that dermal adipogenesis is dependent upon BCL11b transcriptional signaling and that this effect is highly specific to the dermal adipose. Our central hypothesis is that embryonic dWAT formation is dependent upon niche-forming Bcl11b+ cells, which utilize the transcription factor BCL11b to modulate the local Wnt signaling environment and enable adipogenic differentiation in the dermal compartment. The Aims of this grant are to: (1) Determine the mechanism by which BCL11b promotes adipogenesis within the dermal niche (2) Characterize murine and human dermal adipose progenitor cell dynamics in obesity. To attain these objectives, we will utilize novel mouse models, advanced transcriptomic techniques, metabolic phenotyping and analysis of human subcutaneous adipose tissue samples to investigate the mechanisms driving dermal adipose development. This work will address long-standing questions in the field regarding the developmental regulation of dermal adipose tissue, define the molecular mechanisms underlying its establishment, and generate insight into the relationship between mouse and human dermal adipose, thus highlighting the importance of this understudied adipose depot to human metabolic disease. MODIFIED SPECIFIC AIMS: Obesity is one of the most profound public health challenges of the 21st century. The metabolic consequences of obesity are hypothesized to stem from a relative deficiency in hyperplastic adipose expansion specifically within the subcutaneous depot, leading to compensatory visceral fat hypertrophy, lipid spillover into the liver and muscle, and subsequent insulin resistance. Adipose metabolic activity is strongly influenced by its anatomic location, which is established during embryogenesis. Thus, the distinct developmental environment in which adipose originates is a principle determinate of its expansion capacity, however our understanding of subcutaneous adipose organogenesis is incomplete. This proposal aims to define the molecular pathways directing the development of dermal adipose tissue (dWAT), and relate these discoveries to human subcutaneous adipose pathophysiology. Subcutaneous adipose serves as a central hub for metabolic homeostasis through its capacity for hyperplastic expansion, however this generalization does not capture the complex anatomy of this organ, which can be further divided into discrete anatomic layers including dermal/superficial vs deep subcutaneous. Dermal adipose is more metabolically dynamic compared with deeper layers, capable of massive expansion in obesity and involution with caloric restriction. Furthermore, due to its distinct anatomic location, dWAT engages in many unique physiological processes, including: thermoregulation, wound repair, innate immune defense, support of hair follicle growth, and skin fibrosis/aging. Thus, dWAT represents a critically important yet poorly understood metabolic organ, the developmental regulation of which is unknown. Preliminary single cell studies from my lab identified a novel population of embryonic dermal mesenchymal cells marked by Bcl11b expression. We discovered that dermal adipogenesis is contingent upon Bcl11b regulation of Wnt signaling within the dermal microenvironmental niche, and that this influence is highly specific to the dWAT. Based upon these preliminary data, our central hypothesis is that embryonic dWAT formation is regulated by niche-forming Bcl11b+ cells, which utilize the transcription factor BCL11b to modulate the local Wnt signaling environment and enable adipogenic differentiation within the dermal compartment. Our research team has an established track record of translating single cell discoveries into rigorous and high impact publications. As a physician scientist and Director of the UPenn Human Metabolic Tissue Bank, I am well-positioned to expand these findings into relevant human pathophysiology. In the following specific aims, we will utilize novel mouse models, human adipose tissues, advanced transcriptomics, and metabolic phenotyping to investigate the mechanisms driving dWAT development. Aim 1: Determine the mechanism by which BCL11b promotes adipogenesis within the dermal niche. Dermal adipocytes arise within the Wnt-rich microenvironment of the reticular dermis, however the cell types and mechanisms that facilitate differentiation within this relatively anti-adipogenic niche are unknown. We discovered a novel population of Bcl11b-expressing mesenchymal cells that are essential for embryonic dWAT development. The downstream mechanism by which BCL11b promotes dermal adipogenesis will be determined through in vitro interrogation of BCL11b-regulated genes including: Sost, Adamts18, Nes and Sod3. Aim 2: Characterize human dermal adipose progenitor cell dynamics in obesity and weight loss. The distinct developmental ancestry of adipose depots imprints clinically relevant physiological properties, however the regulation of human dWAT development has not been rigorously studied. To determine the functional changes occurring in dermal adipose with obesity and/or weight loss we will utilize our pipeline to human adipose from lean, obese and weight loss patients to quantify relative adipogenic potential. We will investigate the mechanistic contribution of BCL11b target genes SOST, ADAMTS18, NES and SOD3 in regulating adipogenesis within human superficial and deep subcutaneous layers