Scientists discover key to manipulating fat
Washington, D.C. − In what they call a "stunning research advance," investigators at Georgetown University Medical Center have been able to use simple, non-toxic chemical injections to add and remove fat in targeted areas on the bodies of laboratory animals. They say the discovery, published online in Nature Medicine on July 1, could revolutionize human cosmetic and reconstructive plastic surgery and treatment of diseases associated with human obesity.
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Neuropeptide Y (NPY) is a neurotransmitter in the brain and in the periphery (including the sympathetic nervous system). In the latter locale, NPY is released from sympathetic neurons in abdominal fat during times of chronic stress, which can lead to abdominal obesity (Kuo et al., 2007; Warne & Dallman, 2007). NPY also appears to be involved in an unbelievable array of processes (including effects on vascular smooth muscle cells and endocardial endothelial cells, the immune system, estrogen-induced synapse formation in the hippocampus, bone remodeling, vascular remodeling, and energy homeostasis), and is viewed as a potential drug development target for neuroblastomas and other cancers, alcohol abuse, major depression, pain, and gene therapy in epilepsy, as well as obesity [why not examine the entire Feb 2007 issue of Peptides, NPY AND COHORTS IN HUMAN DISEASE, which has papers from the Proceedings of the 8th International NPY meeting]. These actions are mediated by at least four different NPY receptor subtypes (Y1, Y2, Y4, Y5).
In the paper, the Georgetown researchers describe a mechanism they found by which stress activates weight gain in mice, and they say this pathway -- which they were able to manipulate − may explain why people who are chronically stressed gain more weight than they should based on the calories they consume.
This pathway involves two players -- a neurotransmitter (neuropeptide Y, or NPY) and the receptor (neuropeptide Y2 receptor, or Y2R) it activates in two types of cells in the fat tissue: endothelial cells lining blood vessels and fat cells themselves. In order to add fat selectively to the mice they tested, researchers injected NPY into a specific area. The researchers found that both NPY and Y2R are activated during stress, leading to apple-shape obesity and metabolic syndrome. Both the weight gain and metabolic syndrome, however, were prevented by administration of Y2R blocker into the abdominal fat.
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"We couldn’t believe such fat remodeling was possible, but the numerous different experiments conducted over four years demonstrated that it is, at least in mice; recent pilot data also suggest that a similar mechanism exist in monkeys as well," said the study's senior author, Zofia Zukowska, M.D., Ph.D., professor and chair of the Department of Physiology & Biophysics at Georgetown University Medical Center.
"We are hopeful that these findings might eventually lead to control of metabolic syndrome, which is a huge health issue for many Americans," she said. "Decreasing fat in the abdomen of the mice we studied reduced the fat in their liver and skeletal muscles, and also helped to control insulin resistance, glucose intolerance, blood pressure and inflammation. Blocking Y2R might work the same way in humans, but much study will be needed to prove that."
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Fig. 1 (Warne & Dallman, 2007) - A new role for neuropeptide Y.
Kuo et al. focus on the direct effects of neuropeptide (NPY) on adipocyte physiology in repeatedly stressed animals fed a palatable high-fat diet. NPY acts on preadipocytes, endothelial cells and macrophages to promote adipocyte proliferation and maturation as well as to induce new capillaries to supply nutrients to the increased fat mass. NPY is secreted from sympathetic nerve terminals in response to stressors. The blockade of either NPY receptors or glucocorticoid receptors blocks the abdominal obesity that occurs with stressors and a high-fat diet. [Katie Ris]
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And perhaps the most rapid clinical application of these results will be in both cosmetic [see Nip/Tuck] and reconstructive plastic surgery, said co-author Stephen Baker, M.D., D.D.S, associate professor of plastic surgery at Georgetown University Hospital. The ability to add fat as a graft would be useful for facial rejuvenation, breast surgery, buttock and lip enhancement, and facial reconstruction, he said, and using injections like those tested in this study could make fat grafts predictable, inexpensive, biocompatible and permanent.
Equally important, blocking Y2R resulted in local elimination of adipose, or fat, tissue, said Baker. "This is the first well-described mechanism found that can effectively eliminate fat without using surgery,” he said. “A safe, effective, non-surgical means to eliminate undesirable body fat would be of great benefit to our patients."
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References
Kuo LE, Kitlinska JB, Tilan JU, Li L, Baker SB, Johnson MD, Lee EW, Burnett MS, Fricke ST, Kvetnansky R, Herzog H, Zukowska Z. (2007). Neuropeptide Y acts directly in the periphery on fat tissue and mediates stress-induced obesity and metabolic syndrome. Nat Med. 13:803-11.
The relationship between stress and obesity remains elusive. In response to stress, some people lose weight, whereas others gain. Here we report that stress exaggerates diet-induced obesity through a peripheral mechanism in the abdominal white adipose tissue that is mediated by neuropeptide Y (NPY). Stressors such as exposure to cold or aggression lead to the release of NPY from sympathetic nerves, which in turn upregulates NPY and its Y2 receptors (NPY2R) in a glucocorticoid-dependent manner in the abdominal fat. This positive feedback response by NPY leads to the growth of abdominal fat. Release of NPY and activation of NPY2R stimulates fat angiogenesis, macrophage infiltration, and the proliferation and differentiation of new adipocytes, resulting in abdominal obesity and a metabolic syndrome-like condition. NPY, like stress, stimulates mouse and human fat growth, whereas pharmacological inhibition or fat-targeted knockdown of NPY2R is anti-angiogenic and anti-adipogenic, while reducing abdominal obesity and metabolic abnormalities. Thus, manipulations of NPY2R activity within fat tissue offer new ways to remodel fat and treat obesity and metabolic syndrome.
Warne JP, Dallman MF. (2007). Stress, diet and abdominal obesity: Y? Nat Med. 13(7):781-3.
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Make me beautiful
Make me beautiful
Perfect soul
Perfect mind
Perfect face
A perfect lie
Make me beautiful
Make me beautiful
Perfect soul
Perfect mind
Perfect face
A perfect, perfect soul
Perfect mind
Perfect face
A perfect lie
A perfect lie
A perfect lie
A perfect lie
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