AAPS, American Association of Plastic Surgeons
AAPS, American Association of Plastic Surgeons
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2008 Annual Meeting Abstracts

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A Mechanism For Liporemodeling Through Manipulation of the NPY2 Receptor
Stephen B. Baker, MD, DDS, Michael Cohen, MD, Ali Al-Attar, MD, PhD, Lydia Kuo, PhD, Michael Johnson, PhD, Zofia Zukowska, MD, PhD.
Georgetown University, Washington, DC, USA.

PURPOSE:
Our previous in vitro work has found stimulation of the neuropeptide Y2 receptor (Y2R) to be adipogenic and antagonism of the Y2 receptor to be adipolytic. This study evaluates the in vivo effects of Y2R manipulation on nonsurgical peripheral fat remodeling in animal models.
METHODS:
To evaluate the adipolytic effects of Y2R antagonists, normal and multiple obese murine models were injected with 0.1µg Y2R antagonist daily for 14 days. A murine model of metabolic syndrome underwent the same daily injections for three months. Controls were used. 3-D MRI was used to quantify specific fat depots of body fat at 3 month follow up. Vital signs and metabolic parameters were evaluated. Histology and immunohistochemistry were used to evaluate the tissue samples. Toxicology was performed on the animals.
Adipogenic effects of a Y2R agonist were evaluated using murine and primate models as well as nude mice with human xenografts. NPY was placed in a cholesterol pellet that steadily released NPY for 14 days in the subcutaneous abdomen of six mice and two primates. Adipogenesis was evaluated using immunohistochemistry and MRI. A second group of nude mice had the NPY pellet placed subcutaneously with 0.25cc of human fat. Fat graft maintenance was evaluated using 3-D ultrasound and dissected weight at three months.
RESULTS:
Y2R antagonist resulted in the following volume reductions in peripheral body fat: 50% in ob/ob and 60% in high fat/stressed. NPY2 knockout mice showed a comparable loss in peripheral body fat. Serum cholesterol and glucose tolerance were improved, and there was no change in insulin resistance in the Y2R antagonist group. No tissue abnormalities were noted on histopathologic examination. In a murine model of metabolic syndrome, visceral adiposity was almost entirely eliminated by 3 months of Y2R antagonist injections. All metabolic parameters of metabolic syndrome were reversed or eliminated: hypertension, diabetes, serum cytokine levels, fatty liver, and fatty muscle.
At 3 month follow up, MRI showed fat retention circumferentially around the agonist pellet; the control pellet showed no retention of fat. In the nude mice with human fat grafts, NPY was injected into the grafts and saline was injected to serve as a control. At 3 months, there was over 90% retention of grafted fat in the experimental group but only 40% retention in the control group. PECAM staining revealed increased angiogenesis and ultrasound showed less vacuolization of fat grafted with NPY2 agonist as compared to the saline injected control.
CONCLUSION:
This study is the first to demonstrate the adipogenic effects of NPY on peripheral Y2 receptors in vivo. Antagonism of these receptors produces local and global adipolytic effects in murine models including reversal of metabolic syndrome and elimination of visceral adiposity in a murine model. It is felt that translational development of the NPY-Y2R pathway could lead to a nonsurgical means to remodel adipose tissue in reconstructive and cosmetic surgery as well as a potential role in obesity therapy.


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