Plastic Surgery Research Council
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PSRC 60th Annual Meeting
Program and Abstracts

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SDF-1 mediates pre-adipocyte neovascular potential and slows progression of Type 2 Diabetes
Janos Barrera, BS, Zeshaan Maan, MBBS, MSc, MRCS, Alexander J. Whittam, BA, Robert Rennert, MD, Dominik Duscher, MD, Kevin Paik, BA, Michael Hu, MD, MS, MPH, Graham Walmsley, BA, Michael T. Longaker, MD, MBA, Geoffrey C. Gurtner, MD, FACS.
Stanford School of Medicine, Palo Alto, CA, USA.

Purpose:
In the setting of obesity, discrete regions of fat become relatively hypoxic, activating the HIF-1 pathway and initiating both neovascular and inflammatory responses. Constitutive HIF-1 activation, likely due to inadequate vascular supply, results in chronic adipose tissue inflammation, and is associated with the progression to Type 2 Diabetes Mellitus (T2DM). Interestingly, the loss of HIF-1α expression within adipose tissue inhibits the development of T2DM in mice fed a high fat diet (HFD)[1]. The role of HIF-1α in diabetes pathogenesis may be linked to its downstream effector, stromal-cell derived factor 1 (SDF-1), which plays a critical role in neovascularization and mediates pre-adipocyte function and fate [2-4]. Specifically, SDF-1 expression is reduced in diabetes[5], suggesting a possible mechanism for disease progression via inadequate pre-adipocyte-mediated vascularization and subsequently uncorrected hypoxia and inflammation in fat tissue. Using a Cre-Lox gene knockout model in mice, we studied the effect of SDF-1 knockout (KO) on the development of T2DM in response to HFD, and investigated the effects of SDF-1 KO on pre-adipocyte function.
Methods:
eKO and WT mice were placed on a HFD (60% by weight) and progression to diabetes was assessed using serial glucose tolerance tests. Inguinal fat pads were harvested from wild type (WT), diabetic, global SDF-1 KO (gKO) and endothelial cell specific SDF-1 KO (eKO) mice. Whole tissue, representing the pre-adipocyte niche, was processed for qRT-PCR. Primary cells were harvested from the fat for FACS analysis and cell culture. BrdU proliferation assay, human umbilical vein endothelial cell (HUVEC) co-culture tubulization assay in growth factor reduced (GFR) matrigel and adipogenic differentiation assays were carried out on cells in passage 1.
Results:
Serial glucose tolerance testing revealed that after commencing HFD, eKO mice became diabetic by week 8, compared to week 12(60%)-16(40%) in WT mice. eKO and gKO adipose tissue, representing the niche environment, demonstrated dramatic downregulation of FGF-2, VEGF, PDGF and their complimentary receptors (*p<0.001). Pre-adipocytes from eKO and gKO mice demonstrated decreased proliferative capacity (*p<0.001) and decreased ability to induce tubulization of HUVECs (*p<0.01) compared to WT. Adipogenic differentiation was significantly increased in eKO and gKO groups compared to WT (*p<0.01).
Conclusions:
The accelerated progression to diabetes in SDF-1 knockout mice suggests that by promoting neovascularization, SDF-1 may also protect against diabetes. The loss of SDF-1 from endothelial cells alone disrupts the transcriptional and functional homeostasis of adipose tissue. Pre-adipocytes are shunted towards adipogenesis, with reduced proliferative and pro-angiogenic capacity. This change alters their functional role within adipose tissue and hinders their potential for promoting new vessel formation in response to hypoxia. These findings suggest a possible mechanism for accelerated progression to T2DM in the absence of endothelial SDF-1. Further investigation is ongoing to refine the role of the HIF-1α/SDF-1 pathway in the context of diabetes.


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