The mechanisms underlying adipose depot morphogenesis are not well understood. This salient gap in our knowledge is important, because manipulation of adipose depot development represents an attractive strategy for obesity prevention. Our long-term goal is to define the developmental and environmental mechanisms regulating vertebrate energy balance. To help address this gap in our knowledge, we have recently established novel methods for studying adipogenesis in the zebrafish model system. The overall objective of this application is to exploit the unique advantages of the zebrafish model to define the cellular interactions, lineage contributions, and nutritional regulation underlying morphogenesis of adipose depots in living animals. The proposed research will address the central hypothesis that adipose depot morphogenesis is regulated by dynamic interactions between multiple adipocyte cell lineages, vascular endothelial cells, and the nutritional environment. The rationale that underlies the proposed research is that identification of the developmental and nutritional mechanisms governing adipose depot morphogenesis will provide novel strategies for preventing obesity and associated morbidities by controlling the formation of specific adipose depots. Guided by strong preliminary data, we plan to achieve the objective of this proposal through two specific aims: (1) Define the cellular mechanisms underlying visceral adipose depot morphogenesis in live animals, and (2) Identify the cell lineage contributions to the visceral adipose depot in vivo. Under the first aim, we will use vital fluorescent lipophilic dyes and longitudinal high-resolution imaging in live transgenic zebrafish to test the hypothesis that hyperplasia and hypertrophy of adipocytes within the nascent adipose depot are pre-patterned by the developing vasculature. In the second aim, we will use well-established techniques for cell lineage analysis in the zebrafish model to explore the hypothesis that the adipocytes which contribute to the nascent visceral adipose depot are derived from resident preadipocytes as well as non-resident preadipocytes via nutrientdependent mechanisms. The proposed research is innovative, in our opinion, because it constitutes the first high-resolution analysis of adipose depot morphogenesis in the intact physiologic context of a living animal. The contribution of the proposed research is expected to be the identification of the specific cellular interactions, cell lineage contributions, and nutritional regulatory mechanisms underlying in vivo morphogenesis of adipose depots. This contribution will be significant because it will provide a much-needed vertical advance in our understanding of adipose tissue development. This new understanding is expected to lead to new nutritional and pharmacologic strategies for preventing obesity by controlling adipose tissue development during early stages of life, and for treating obesity at older ages by reducing the size of specific adipose depots.
The proposed research is relevant to public health because the discovery of mechanisms regulating adipose tissue development is ultimately expected to lead to new strategies for preventing obesity by controlling the formation adipose tissues. The proposed research is therefore relevant to the part of NIH?s mission that pertains to developing fundamental new knowledge that will enhance health and reduce the burdens of illness.
