October 2002 Blog with Durk and Sandy

"I have yet to see any problem, however complicated, which, when you looked at it in the right way, did not become still more complicated."
- Poul Anderson
New Scientist, September 25, 1969

"A committee is a cul-de-sac down which ideas are lured and then quietly strangled."
- Sir Bennett Cocks 
New Scientist, 1973

"In a democracy, it's hard to get turkeys to vote for Christmas."
- John Lawton, chief executive of Britain's Environmental Research Council
Nature 418:813-4 (2002)

He was complaining about how hard it is to get voters to spend huge sums of money now for alleged environmental benefits that will not be apparent for decades (if ever). Well, Mr. Lawton, you reveal (perhaps unwittingly) a rather low opinion of taxpayers by calling them "turkeys," but they may not be stupid enough to vote for Christmas.

"According to a cable dispatch from Vienna, a newspaper for nervous persons is projected, which will handle startling occurrences in such an unexciting way as to permit sensitive individuals to keep au courant with the times without the needless shock liable to be produced by usual chronicles."
- From the Journal of the American Medical Association
October 25, 1902

Sounds good, but on the basis of the popularity of newspapers and TV news, most people prefer their news to be startling and even frightening. Years ago, we hypothesized that people have what we call a "conservation of paranoia," meaning that people have an innate urge to search for and focus on dangers (we wouldn't be here if we didn't) and that when a major danger, such as war, suddenly vanishes, there is a swift shift of people's focus to some other alleged danger.

Preventing Cancer, Atherosclerosis, and Obesity Through Antiangiogenesis

Angiogenesis, the growth of new blood vessels, is known to be a major basis for the growth of cancers, and considerable research, including human clinical trials, is being done to discover effective antiangiogenic agents. A 1998 paper¹ reported that the hormone leptin, released largely by adipocytes (fat cells), acts as an angiogenic factor. Leptin is known to affect fat mass by regulating food intake and energy expenditure; it modulates lipid metabolism, hematopoiesis, pancreatic beta-cell function (these are the cells that release insulin), ovarian function, thermogenesis, and wound repair.

The authors of the 1998 paper showed that the leptin receptor (OB-Rb) that is expressed primarily in the hypothalamus is also expressed in human vasculature and in primary cultures of human endothelial cells. In vitro and in vivo assays revealed that leptin has angiogenic activity. They reported that leptin caused cultured endothelial cells to aggregate and form tubes that resemble early-stage blood vessels. Leptin also caused new blood vessels to form in the corneas of rats. The authors proposed that leptin stimulates an angiogenic response that maintains an appropriate balance between blood supply and fat depot size.

In an interview (Reuters, Sept. 11, 1998), the lead author, Dr. M. Rocio Sierra-Honigmann, suggested that "Tumors make angiogenic factors, so it's not at all remote to think that they may be making leptin." Although the second article in reference 1 mentioned that Judah Folkman's team "is checking to see if any tumors make leptin," we haven't seen anything published on this.

In a 1999 paper,² researchers report that human umbilical-vein endothelial cells, which express leptin receptors, are subject to oxidative stress in response to leptin. They showed that reactive oxygen species act as second messengers to carry leptin-induced signals in endothelial cells. Increased JNK activity and AP-1 DNA binding in the cells were sensitive to antioxidant treatment with N-acetylcysteine. Leptin-increased NF-kappaB DNA binding activity was also prevented in nuclear extracts from cells pretreated with N-acetylcysteine.²

Moreover, leptin led to an upregulation of MCP-1. MCP-1, the authors explained, belongs to the class of chemotactic cytokines shown to elicit the direct migration of monocytes to inflammatory sites and is increased in response to mitogenic signals (which includes oxidative stress) in a variety of cells, including smooth muscle cells and endothelial cells. The MCP-1 upregulation was suppressed in the presence of antioxidants. The authors speculate that the actions of leptin that lead to MCP-1 expression in endothelial cells may play a key role in the inflammatory process linked to atherosclerosis.

Another paper reported that leptin regulates proinflammatory immune responses.³ The study indicated that leptin enhances the synthesis of proinflammatory cytokines, such as tumor necrosis factor-alpha and IL-6, by cultured macrophages when the cells are treated with LPS, a bacterial lipopolysaccharide. Inflammation is associated with cellular proliferation, such as occurs in cardiovascular disease (smooth muscle cell proliferation in plaques) and cancer.

A recent paper⁴ proposes that adipose tissue mass is regulated by vasculature. This tissue is highly vascularized and depends upon growth of blood vessels in order to increase in mass. The authors hypothesized that "adipose tissue growth is angiogenesis-dependent and, therefore, may be inhibited by antiangiogenesis agents."⁴

The researchers used a fat (ob/ob) mouse model. This animal lacks the hormone leptin (which regulates appetite and metabolism), overeats, expends less energy, and rapidly accumulates adipose tissue, becoming morbidly obese. Fat loss in these mice can be induced by treating them with leptin. However, rather than using leptin, the researchers treated the ob/ob mice with various angiogenesis inhibitors, such as angiostatin, endostatin, TNP-470, Bay-12-9566, and thalidomide. The body and adipose tissue weights of treated mice were significantly less than those of controls. In fact, loss of adipose tissue mass was similar to that resulting from leptin treatment. (This supports the hypothesis that leptin may act on adipose tissue mass largely via its angiogenic effects.) There was decreased endothelial cell proliferation and increased apoptosis of adipose tissue cells compared to controls. These results suggest that fat tissue is angiogenesis-dependent, as the researchers predicted.

This is a very exciting finding. Although the specific angiogenesis inhibitors used by the researchers in this study are either not available or, in the case of thalidomide, may not be suitable for general use in obese people (also, the antiangiogenic mechanism of thalidomide is not known⁵), there is a large number of nutritional antiangiogenic substances, as well as NSAIDs (nonsteroidal anti-inflammatory drugs, including aspirin), which inhibit various steps in the angiogenic pathway, such as COX-2 and VEGF (vascular endothelial growth factor).⁸

Angiogenesis has been reported to be inhibited by tea, especially green tea,⁶resveratrol (a natural compound found in red wine and grapes),^7,9 N-acetylcysteine,^8,10epigallocatechin-3-gallate (a constituent of green tea),⁸ genistein,⁸ flavonoids,⁸silymarin,⁸ selenium, phytoestrogens, lignans, vitamins B3, D, and E, capsaicin, and curcumin, among others, and possibly glucoraphanin (found in broccoli), arginine, and omega-3 fatty acids (fish oils).⁹

Rather than a calorie-restricted diet that leaves you hungry, we would suggest that you alter your diet to include more of these antiangiogenic foods and food constituents. Although we do not know how well any particular combination of antiangiogenic foods will perform in a weight-loss (to be more precise, fat-loss) program, it is something that is well suited to safe self-experimentation.¹⁰ Please let us know how your personal program works out.

References

1. Sierra-Honigmann et al. Biological action of leptin as an angiogenic factor.Science 281:1683-6 (1998). Barinaga. Leptin sparks blood vessel growth.Science 281:1582 (1998).
2. Bouloumie et al. Leptin induces oxidative stress in human endothelial cells.FASEB J 13:1231-8 (1999). See also Maulik, Das. Redox signaling in vascular angiogenesis. Free Rad Biol Med 33(8):1047-60 (2002).
3. Loffreda et al. Leptin regulates proinflammatory immune responses. FASEB J12:57-65 (1998).
4. Rupnick et al. Adipose tissue mass can be regulated through the vasculature.Proc Natl Acad Sci 99(16):10730-5 (2002).
5. Trends in Pharmacological Sciences 19 (June 1998).
6. Cao, Cao. Angiogenesis inhibited by drinking tea. Nature 398:381 (1999).
7. Brakenhielm et al. Suppression of angiogenesis, tumor growth, and wound healing by resveratrol, a natural compound in red wine and grapes. FASEB J(June 8, 2001).
8. Tosetti et al. "Angioprevention": angiogenesis is a common and key target for cancer chemopreventive agents. FASEB J 16:2-14 (2002).
9. Losso. Preventing degenerative diseases by anti-angiogenic functional foods.Food Technol 56(6):78-88 (2002). Many other food substances were mentioned in this article.
10. CAUTION: N-acetylcysteine can inhibit blood clotting by increasing prothrombin time. If you are taking a prescription "blood thinner," do not use N-acetylcysteine without having your physician check your prothrombin time. Be cautious if you are taking low-dose aspirin, ginkgo, or both (and also, possibly, fish oil), all of which inhibit blood clotting. Sandy was taking ginkgo along with low-dose aspirin and fish oil and had to discontinue ginkgo (and reduce her dose of fish oil) when she developed nosebleeds at night. Pol, Lebray. N-acetylcysteine for paracetamol poisoning: effect on prothrombin. Lancet 360:1115 (2002).