Compound Found In Red Wine, Fruit Could Help Block Fat Cell Formation

 Date: 10 Apr 2012 - 1:00 PDT

A compound found in red wine, grapes and other fruits, and similar in structure to resveratrol, is able to block cellular processes that allow fat cells to develop, opening a door to a potential method to control obesity, according to a Purdue University study. 

Kee-Hong Kim, an assistant professor of food science, and Jung Yeon Kwon, a graduate student in Kim's laboratory, reported in the Journal of Biological Chemistry that the compound piceatannol blocks an immature fat cell's ability to develop and grow. 

While similar in structure to resveratrol - the compound found in red wine, grapes and peanuts that is thought to combat cancer, heart disease and neurodegenerative diseases - piceatannol might be an important weapon against obesity. Resveratrol is converted to piceatannol in humans after consumption. 

"Piceatannol actually alters the timing of gene expressions, gene functions and insulin action during adipogenesis, the process in which early stage fat cells become mature fat cells," Kim said. "In the presence of piceatannol, you can see delay or complete inhibition of adipogenesis." 

Over a period of 10 days or more, immature fat cells, called preadipocytes, go through several stages to become mature fat cells, or adipocytes. 

"These precursor cells, even though they have not accumulated lipids, have the potential to become fat cells," Kim said. "We consider that adipogenesis is an important molecular target to delay or prevent fat cell accumulation and, hopefully, body fat mass gain." 

Kim found that piceatannol binds to insulin receptors of immature fat cells in the first stage of adipogenesis, blocking insulin's ability to control cell cycles and activate genes that carry out further stages of fat cell formation. Piceatannol essentially blocks the pathways necessary for immature fat cells to mature and grow. 

Piceatannol is one of several compounds being studied in Kim's laboratory for its health benefits, and it is also present in different amounts in red grape seeds and skin, blueberries, passion fruit, and other fruits. 

Kim would like to confirm his current finding, which is based on a cell culture system, using an animal model of obesity. His future work would also include determining methods for protecting piceatannol from degrading so that concentrations large enough would be available in the bloodstream to stop adipogenesis or body fat gain. 

"We need to work on improving the stability and solubility of piceatannol to create a biological effect," Kim said.

ABSTRACT 

Piceatannol, Natural Polyphenolic Stilbene, Inhibits Adipogenesis via Modulation of Mitotic Clonal Expansion and Insulin Receptor-dependent Insulin Signaling in Early Phase of Differentiation 

Jung Yeon Kwon, Sang Gwon Seo, Yong-Seok Heo, Shuhua Yue, Ji-Xin Cheng, Ki Won Lee and Kee-Hong Kim 

Piceatannol, a natural stilbene, is an analog and a metabolite of resveratrol. Despite a well-documented health benefit of resveratrol in intervention of the development of obesity, the role of piceatannol in the development of adipose tissue and related diseases is unknown. Here, we sought to determine the function of piceatannol in adipogenesis and elucidate the underlying mechanism. We show that piceatannol inhibits adipogenesis of 3T3-L1 preadipocytes in a dose-dependent manner at noncytotoxic concentrations. This anti-adipogenic property of piceatannol was largely limited to the early event of adipogenesis. In the early phase of adipogenesis, piceatannol-treated preadipocytes displayed a delayed cell cycle entry into G2/M phase at 24 h after initiation of adipogenesis. Furthermore, the piceatannol-suppressed mitotic clonal expansion was accompanied by reduced activation of the insulin-signaling pathway. Piceatannol dose-dependently inhibited differentiation mixture-induced phosphorylation of insulin receptor (IR)/insulin receptor substrate-1 (IRS-1)/Akt pathway in the early phase of adipogenesis. Moreover, we showed that piceatannol is an inhibitor of IR kinase activity and phosphatidylinositol 3-kinase (PI3K). Our kinetics study of IR further identified a Km value for ATP of 57.8 mM and a Ki value for piceatannol of 28.9 mM. We also showed that piceatannol directly binds to IR and inhibits IR kinase activity in a mixed noncompetitive manner to ATP, through which piceatannol appears to inhibit adipogenesis. Taken together, our study reveals an anti-adipogenic function of piceatannol and highlights IR and its downstream insulin signaling as novel targets for piceatannol in the early phase of adipogenesis.
http://www.jbc.org/content/287/14/11566.abstract
http://www.medicalnewstoday.com/releases/243843.php

Common allergy drug reduces obesity and diabetes in mice

July 26th, 2009

Crack open the latest medical textbook to the chapter on type 2, or adult-onset, diabetes, and you'll be hard pressed to find the term "immunology" anywhere. This is because metabolic conditions and immunologic conditions are, with a few exceptions, distant cousins.

However, a group of papers appearing in Nature Medicine, two of which are from Harvard Medical School researchers, have linked type 2 diabetes with immunology in a way that might persuade leading researchers to start viewing them as siblings.

In the first study, researchers used two common over-the-counter allergy medications to reduce both obesity and type 2 diabetes in mice. The medications, called Zaditor and cromolyn, stabilize a population of inflammatory immune cells called mast cells. In the second study, researchers found that a kind of white blood cell called a regulatory T cell, once thought to manage only other white blood cells, also acts as a liaison between the metabolic and immune systems—in this case, controlling inflammation in fat tissue. Fat tissue from obese and insulin-resistant mice and people is marked by a dramatic absence of this cell type, in dramatic contrast to an already reported overabundance in fat tissue of inflammatory immune cells called macrophages.

"It seems that we're seeing the emergence of a new biomedical discipline: immunometabolism," says HMS professor of pathology Diane Mathis, senior author on one of the papers.

Both papers will appear online July 26 in Nature Medicine.

Molecular garbage

Type 1 and type 2 diabetes both involve abnormalities in the insulin-producing beta cells of the pancreas, but their root causes are completely different. Type 1 diabetes is an autoimmune disease in which the immune system attacks the pancreas, destroying its ability to produce insulin. In contrast, type 2 diabetes is a strictly metabolic condition in which cells grow increasingly deaf to insulin signals and thus lose their ability to metabolize glucose. In both cases, glucose mounts in the blood, at times to fatal levels.

But it is becoming increasingly clear that we should also think of type 2 diabetes in the context of immune function, Harvard scientists assert.

Guo-Ping Shi, Biochemist from the Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, began to suspect such a connection when, in a previous study, he found mast cells present in a variety of inflammatory vascular diseases.

Mast cells are immune cells that facilitate healing in wounded tissue, primarily by increasing blood flow to the site. However, in certain conditions mast cells build up to levels far beyond what the body needs. As a result these cells become unstable and eventually, like punctured trash bags, leak molecular "garbage" into the tissue. This can result in chronic inflammation that causes asthma and certain allergies.

As Shi and postdoctoral research fellow Jian Liu discovered, mast cells were far more abundant in fat tissue from obese and diabetic humans and mice than they were in normal weight fat tissue. This led to an obvious question: by regulating mast cells, could we then control the symptoms?

To find out, Shi and colleagues took a group of obese and diabetic mice and, for a period of two months, treated them with either ketotifen fumarate (also called Zaditor) or cromolyn, both over-the-counter allergy drugs.

"We knew from published research that both cromolyn and Zaditor help stabilize mast cells in people suffering from allergy or asthma," said Shi. "It's almost as if the drugs place an extra layer of plastic on the ripped trash bag. So it seemed like a logical place to begin."

The mice were divided into four groups. The first was the control group; the second group was simply switched to a healthy diet; the third was given cromolyn or ketotifen fumarate; and the fourth was both given the drug and switched to a healthy diet.

While symptoms of the second group improved moderately, the third group demonstrated dramatic improvements in both body weight and diabetes. The fourth group exhibited nearly 100 percent recovery in all areas.

To bolster these findings, Shi and colleagues then took a group of mice whose ability to produce mast cells was genetically impaired. Despite three months of a diet rich in sugar and fat, these mice neither became obese nor developed diabetes.

"The best thing about these drugs is that we know it's safe for people," says Shi. "The remaining question now is: Will this also work for people?"

Shi now intends to test both cromolyn and ketotifen fumarate on obese and diabetic non-human primates.

Beyond friendly fire

In findings independent of Shi, researchers at Harvard Medical School and Joslin Diabetes Center discovered that a class of immune system cells called regulatory T cells, or Tregs, were abundant in the abdominal fat tissue of normal-weight humans and mice, but were virtually absent in the same tissue from obese and diabetic humans and mice.

Their numbers were inversely correlated with the numbers of a class of inflammatory immune cells, macrophages, in a sense creating parallel universes of fat. While obese and diabetic fat tissue was full of inflammatory macrophages and nearly absent of Tregs, normal-weight fat tissue was the diametric opposite.

"For immunologists this is very important, because Tregs had always been thought to control other T cells and that's it," says Markus Feuerer, a postdoctoral researcher in the lab of HMS professors of pathology Diane Mathis and Christophe Benoist. "But this is an entirely new concept." Mathis and Benoist collaborated on the study with Steven Shoelson, HMS professor of medicine at the Joslin Diabetes Center.

"I come at this studying the effects of obesity and why it can spread systemically to cause chronic health problems," says Shoelson, an endocrinologist. "It's possible that the inflammation caused by macrophages results in insulin resistance. And it's more likely, from what we've just seen, that Tregs are keeping the macrophages in check in normal fat tissue, thus preventing inflammation."

For over a decade, Tregs have been known as guardians for the immune system, ensuring that when white blood cells attack a foreign pathogen they don't become overzealous and harm healthy host tissue in a kind of friendly fire. Malfunctioning Tregs, however, have recently been implicated in diseases as diverse as multiple sclerosis and certain cancers.

"Now we're seeing that Tregs may be needed to prevent metabolic abnormalities as well," says Mathis. She adds, half joking, "As an immunologist, I always thought that type 2 diabetes was a pretty boring condition. After these findings, I'm starting to change my mind."

More information: "Genetic deficiency and pharmacological stabilization of mast cells reduce diet-induced obesity and diabetes in mice" Nature Medicine, July 26, 2009, early online publication

Source: Harvard Medical School

Source

Governor Perry Announces $250,000 in TETF for Halsa Pharmaceuticals

Posted on Monday, March 24, 2008

AUSTIN - Gov. Rick Perry today announced the state will invest $250,000 through the Texas Emerging Technology Fund (TETF) in Halsa Pharmaceuticals, Inc. of Houston for the development and pilot manufacturing of a therapeutic drug treatment for obesity. Up to $1 million total investment may be available to the company if it meets certain performance benchmarks.

"Obesity is a serious health epidemic affecting more than 10 million Texans," said Gov. Perry. "The development of effective obesity treatments, coupled with a healthy lifestyle, will not only save taxpayers billions in direct costs and lost productivity but will more importantly save lives."

Founded in 2000, Halsa Pharmaceuticals’ initial business plan was developed in the MOOT CORP Program at the University of Texas McCombs School of Business. Halsa won the Texas MOOT CORP Competition and received a $100,000 investment from the MOOT CORP Pontoon Fund. Since its establishment, the company has received significant support from BioHouston, an organization that fosters activities to spur life-science start-ups, and other private investors.

Halsa has achieved exclusive patent rights to a natural material that, when injected into an obese patient, causes immediate and substantial depletion of body fat with none of the adverse side effects that other weight loss formulas produce. The company is moving into the advanced testing stages of the product.

The Texas Emerging Technology Fund is a $200 million initiative created by the Texas Legislature in 2005 at the governor’s request and was reauthorized in 2007. A 17-member advisory committee of high-tech leaders, entrepreneurs and research experts reviews potential TETF projects and recommends funding allocations to the Governor, Lieutenant Governor and Speaker of the House. To date, the TETF has allocated $86.9 million in funds to Texas companies and universities. For more information on the TETF, please visit www.emergingtechfund.com.

Source

Halsa Pharmaceuticals
http://www.halsapharma.com/


Further article
Article Date: 26 Mar 2008 - 4:00 PDT

Houston-based Halsa Pharmaceuticals, Inc., has been awarded $250,000 from the Texas Emerging Technology Fund (TETF) to continue development and pilot manufacturing of a therapeutic treatment for obesity. The TETF may provide up to $1 million total investment if the company meets certain performance benchmarks.

Halsa holds exclusive patent rights to a natural material that, when injected by a physician into an obese patient, is expected to cause immediate and substantial depletion of body fat.

"The TETF process was an intense and constructive dialogue. Both the Texas Life Science Committee (TLSC) and the 17-member committee's analysis required Halsa's management to attain critical milestones, and we're a much better situated company for this direction and support," said Halsa CEO Phil Speros, Ph.D.

"[This] process has become a de facto vetting mechanism that funding entities use to enrich the set of early stage companies on which to focus," stated TETF Director Mark Ellison.

The TETF, a $200 million initiative created by the Texas Legislature in 2005 at the governor's request, encourages the creation of companies and jobs in new technologies and the life sciences. The fund gives preference to proposals that have the potential to result in a medical or scientific breakthrough.

"We believe that Halsa's technology has the potential to revolutionize the treatment of obesity. Halsa's obesity therapeutic is an example of the 'disruptive' technology that the Emerging Technology Fund has a mandate to commercialize. The Emerging Technology Fund can help bridge the gap between Halsa's grant funding and venture capital funding that is critical for commercialization," said Charles W. Tate, chairman of the Texas Life Science Center.

Halsa Pharmaceuticals' initial business plan was developed in the MOOT CORP Program at the UT/McCombs School of Business. Halsa won the Texas MOOT CORP Competition and received a $100,000 investment from the MOOT CORP Pontoon Fund.

According to Dr. Gary Cadenhead, former director of the MOOT CORP Program, "Halsa has the greatest potential, both in terms of benefiting the health of humans around the world and in becoming a major economic success, of any of the ventures launched during my tenure as director."

The company has also progressed with significant support from BioHouston, which facilitated a core of germane activities and symposia. Recently, private investors have provided additional seed capital.

More than 65% of American adults are overweight, and half are obese, according to the U.S. Centers for Disease Control. Over $110 billion annually is lost to obesity and overweight in the United States, 50% due to direct health care costs and 50% from loss of productivity due to illness and mortality. Obesity is highly correlated with increased incidence of heart disease, stroke, cardiovascular diseases, diabetes, kidney disease, cancer, osteoarthritis, and other diseases.

"Prevalence continues to increase with no sign of a leveling. It is difficult to overstate the magnitude of the problem of obesity. Effective, suitable treatments are lacking," stated John P. Foreyt, Ph.D., director of the Behavioral Research Center at the Baylor College of Medicine and a member of Halsa's Scientific Advisory Board.

"In our preliminary work, the candidate therapeutic has acted consistently in causing fat breakdown without showing adverse side effects," Speros said. "The pharmaceutical development process is long and full of uncertainties, but these early results lead us to believe that a product using our technology will benefit the obese and morbidly obese without the gastrointestinal distress, blood pressure increase, or mood depression encountered with existing products."

About Halsa Pharmaceuticals

Halsa Pharmaceuticals, Inc. was founded in 2000 to pursue the development of a therapeutic treatment for obesity.

Safe Harbor Statement

This release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995. Statements that are not historical facts are "forward-looking statements," which involve risks and uncertainties that could cause actual results to differ materially from any future results, performance, or achievements expressed or implied by such statements.

Halsa Pharmaceuticals