High dietary fat, cholesterol linked to increased risk of breast cancer

High Dietary Fat, Cholesterol Linked to Increased Risk of Breast Cancer


ScienceDaily (Jan. 7, 2011) — Elevated fat and cholesterol levels found in a typical American-style diet play an important role in the growth and spread of breast cancer, say researchers at the Kimmel Cancer Center at Jefferson.



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The study, published in the January issue of The American Journal of Pathology, examines the role of fat and cholesterol in breast cancer development using a mouse model. The results show that mice fed a Western diet and predisposed to develop mammary tumors, can develop larger tumors that are faster growing and metastasize more easily, compared to animals eating a control diet.
The research team led by cancer biologist Philippe G. Frank, Ph.D., Assistant Professor in the Department of Stem Cell Biology and Regenerative Medicine at Thomas Jefferson University, was interested in learning about the link between diet and breast cancer. The incidence rate of this cancer is five times higher in Western countries than in other developed countries. Moreover, studies have shown an increase in breast cancer incidence in immigrant populations that relocate from a region with low incidence. "These facts suggest strong environmental influence on breast cancer development," says Dr. Frank.
Dietary fat and cholesterol have been shown to be important risk factors in the development and progression of a number of tumor types, but diet-based studies in humans have reached contradictory conclusions. This has led Dr. Frank to turn to animal models of human cancer to examine links between cholesterol, diet, and cancer.
The research team turned to the PyMT mouse model to determine the role of dietary fat and cholesterol in tumor development. This mouse model is believed to closely parallel the pathogenesis of human breast cancer. PyMT mice were placed on a diet that contained 21.2 percent fat and 0.2 percent cholesterol, reflective of a typical Western diet. A control group of PyMT mice was fed a normal chow that had only 4.5 percent fat and negligible amounts of cholesterol.
The researchers found that tumors began to develop quickly in mice fed the fat/cholesterol-enriched chow. In this group, the number of tumors was almost doubled, and they were 50 percent larger than those observed in mice that ate a normal diet. "The consumption of a Western diet resulted in accelerated tumor onset and increased tumor incidences, multiplicity, and burden, suggesting an important role for dietary cholesterol in tumor formation," Dr. Frank says. There was also a trend towards an increased number of lung metastasis in mice fed the fatty diet, he adds.
To confirm the aggressive nature of the cancer in animals fed a cholesterol-rich diet, the researchers examined the levels of several biomarkers of tumor progression and found a signature of a more advanced cancer stage, compared to tumors that developed in the control group.
The researchers also showed that plasma cholesterol levels in experimental mice that developed tumors were significantly reduced compared to a group of "wild-type" mice -- animals with no predisposition to develop tumors -- that was also fed a cholesterol-rich diet. "This suggests that tumor formation was responsible for the reduction in blood cholesterol levels observed in our animals," indicates Dr. Frank.
Dr. Frank explains the use of cholesterol in breast tumors this way: "In a neighborhood, if you want to build more houses, you need more bricks. In tumors, cholesterol provides the bricks that are the foundation for further growth, and this cholesterol comes from the blood. A drop in blood cholesterol may signify that some tumors are growing as cholesterol provides support for breast cancer growth."
"These data provide new evidence for an increase in cholesterol utilization by breast tumors and thus provides many new avenues for prevention, screening, and treatment," indicates Dr. Frank. These findings suggest that use of cholesterol-lowering drugs, such as statins, may both protect against breast cancer as well as treat patients carrying tumors. Since researchers also found that blood cholesterol levels dropped significantly as tumors began to develop, the study indicates measuring blood cholesterol levels may also be an effective method of screening cancer development.
This research team also discovered the same association between cholesterol and growth of prostate cancer in mice in a study published in the December issue of The American Journal of Pathology. The results of these two new studies indicate, according to Dr. Frank that, "Cholesterol does indeed seem to be an important factor in the regulation of tumor formation in several cancer types."

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The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Thomas Jefferson University.

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Weight-loss surgery improved female urinary problems but male erection issues got worse

Weight-Loss Surgery Improved Female Urinary Problems but Male Erection Issues Got Worse


ScienceDaily (Jan. 6, 2011) — Women who underwent gastric band surgery to lose weight reported significant improvements in urinary function and quality of life after the operation, according to research published in the January issue of the urology journal BJUI.



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However, men undergoing the procedure did not enjoy the same significant urinary function improvements as the women. They also reported that erectile function was slightly worse after surgery, unlike studies following non-surgical weight loss where sexual function actually improved.
Researchers surveyed 176 patients -- 142 women and 34 men -- who had undergone laparoscopic gastric banding surgery (LGB) at a single centre in Newcastle, Australia.
"We were keen to see what effect weight loss surgery had had on the patients' sexual and urinary functions, as these are common problems in people who are very obese" says study lead Dr Weranja Ranasinghe from the Department of Urology at Austin Hospital in Melbourne.
"Just under two-thirds of the women (65 per cent) and 24 per cent of the men had some urinary incontinence, while the majority of the men (83 per cent) had erection problems before surgery."
Estimates suggest that 1.6 billion adults worldwide are overweight and 400 million are obese. In 2007-8, 68 per cent of men and 55 per cent of women in Australia were overweight or obese. In Europe alone, obesity accounts for up to eight per cent of healthcare costs and up to 13 per cent of deaths.
"Gastric band surgery is increasingly being used to tackle the most severe cases of obesity, because carrying excess weight increases the risk of life-threatening conditions such as heart disease, high blood pressure and diabetes" says Dr Ranasinghe.
"However it is still regarded as a last resort by many surgeons, after non-surgical options like diet and exercise have failed, and there is limited data to show its effect on sexual and urinary function."
All the patients who had undergone surgery in the last ten years were invited to take part in the study and equal percentages of men and women agreed, providing the researchers with data on 34 males and 142 females. The average time that had elapsed since their surgery was just under 32 months.
The women had an average age of just under 48 years and the men averaged just under 53. The women averaged 118kg before surgery and the men averaged 146kg.
Weight loss following surgery was similar for both sexes, averaging just over 23kgs for the men and just under 23kgs for the women. However the women had a slightly higher BMI loss than the men (8.3 versus 7.5).
Key findings of the study included:

The women in the study reported that weight loss had led to significant improvements in their urinary problems, possibly due to a reduction in intra-abdominal pressure, as soon as three to four months after surgery. And every kilogram lost led to a slight improvement in their quality of life score.
Although women reported an overall improvement in urinary function, urge incontinence worsened. However, the authors say that this condition can be caused by a number of factors and the deterioration may be down to the time elapsed since surgery, not the weight loss.
The men in the study did not show any improvement when it came to urinary function and the authors suggest that raised intra-abdominal pressure may not affect male urinary problems in the same way as females.
Despite the men's significant weight-loss, the overall scores for erectile and orgasmic function declined over time. Age was not a factor in this reduction. This is at odds with the findings of other studies following non-surgical weight loss where sexual function actually improved.

"Urinary incontinence is common in people who are very obese and this study shows that gastric band surgery did improve the majority of urinary problems in women, with the exception of urge incontinence" concludes Dr Ranasinghe. "Our results highlight an added benefit of weight loss surgery, apart from the known improvements in cardiovascular mortality and diabetes risk etc.
"However the anticipated improvement in the men's sexual function, which has been observed in studies on non-surgical weight loss, did not materialise. In fact, the men in our study reported that their erection and orgasm problems worsened after surgery.
"A number of factors could have influenced this decline in sexual function after surgery. Our study looked at the short-term results of sexual function and these problems may improve in the long term. There is always a dip in sexual function after any form of surgery, due to psychological issues and fluctuating hormone levels. It is likely, therefore, that sexual function will improve over time.
"It is clear from our study that further research is needed to investigate the effects of gastric band surgery on urinary and sexual function, as such problems can be very distressing and cause a number of health and quality of life issues for patients."
The collaborative study also drew on the expertise of urology surgeon Mr Raj Persad from Bristol Royal Infirmary, UK, and upper gastrointestinal surgeon Dr Tim Wright from John Hunter Hospital, Australia, as well as the School of Medicine and Public Health at the University of Newcastle, Australia.

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Weranja K.B. Ranasinghe, Timothy Wright, John Attia, Patrick McElduff, Terrence Doyle, Meegan Bartholomew, Katrina Hurley, Rajendra A. Persad. Effects of bariatric surgery on urinary and sexual function. BJU International, 2011; 107 (1): 88 DOI: 10.1111/j.1464-410X.2010.09509.x

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Tomatoes found to contain nutrient which prevents vascular diseases

Tomatoes Found to Contain Nutrient Which Prevents Vascular Diseases


ScienceDaily (Jan. 6, 2011) — They are the most widely produced fruit in the world and now scientists in Japan have discovered that tomatoes contain a nutrient which could tackle the onset of vascular diseases. The research, published in the journal Molecular Nutrition & Food Research, reveals that an extracted compound, 9-oxo-octadecadienoic, has anti-dyslipidemic affects.



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The team led by Dr Teruo Kawada, from Kyoto University and supported by the Research and Development Program for New Bio-industry Initiatives, Japan, focused their research on extracts which tackle dyslipidemia, a condition which is caused by an abnormal amount of lipids, such as cholesterol or fat, in the blood stream.
"Dyslipidemia itself usually causes no symptoms," said Kawada, "however; it can lead to symptomatic vascular diseases, such as arteriosclerosis and cirrhosis. In order to prevent these diseases it is important to prevent an increased build up of lipids."
Tomatoes are already known to contain many compounds beneficial to health. In this study the team analyzed 9-oxo-octadecadienoic acid, to test its potential anti-dyslipidemia properties.
The compound was found to enhance fatty acid oxidation and contributed to the regulation of hepatic lipid metabolism. These findings suggest that 9-oxo-octadecadienoic acid has anti-dyslipidemia affects and can therefore help prevent vascular diseases.
"Finding a compound which helps the prevention of obesity-related chronic diseases in foodstuffs is a great advantage to tackling these diseases," concluded Kawada. "It means that the tomato allows people to easily manage the onset of dyslipidemia through their daily diet."

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Young-Il Kim, Shizuka Hirai, Haruya Takahashi, Tsuyoshi Goto, Chie Ohyane, Taneaki Tsugane, Chiaki Konishi, Takashi Fujii, Shuji Inai, Yoko Iijima, Koh Aoki, Daisuke Shibata, Nobuyuki Takahashi, Teruo Kawada. 9-oxo-10(E),12(E)-octadecadienoic acid derived from tomato is a potent PPAR α agonist to decrease triglyceride accumulation in mouse primary hepatocytes. Molecular Nutrition & Food Research, 2010; DOI: 10.1002/mnfr.201000264

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Metabolic cost of human sleep deprivation quantified by researchers

Metabolic Cost of Human Sleep Deprivation Quantified by Researchers


ScienceDaily (Jan. 5, 2011) — In the first-ever quantification of energy expended by humans during sleep, a University of Colorado team has found that the metabolic cost of an adult missing one night of sleep is the equivalent of walking slightly less than two miles.



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The new findings will help researchers further understand one of the important functions of sleep in humans, said CU-Boulder Associate Professor Kenneth Wright. Wright, who led the study, said the goal was to measure and quantify energy expenditure during both sleep and wakeful periods.
"We found that people do expend more energy when they are awake in bed than when they are asleep," he said. The findings showed the eight hours of sleep saved roughly 135 calories over eight hours of wakefulness.
"While the amount of energy savings for humans during sleep may seem relatively small, it actually was a little more than we expected," said Wright, a faculty member in CU-Boulder's integrative physiology department and director of CU-Boulder's Sleep and Chronobiology Laboratory.
A paper on the subject was published in the January issue of the Journal of Physiology. Co-authors included CU-Boulder's Christopher Jung and Emily Frydenall, as well as Assistant Professor Edward Melanson, Dr. Leigh Perreault and Dr. Robert Eckel of the University of Colorado School of Medicine. Jung, first author on the paper, got his doctorate from CU-Boulder in 2009 and is now at the University of Alaska.
The study showed that compared to a typical night of sleep, the amount of energy expended by study subjects during 24 hours of sleep deprivation was up about 7 percent. In contrast, energy expenditure decreased by about 5 percent during the recovery episode, which included 16 hours of wakefulness following the sleep deprivation night, then eight hours of recovery sleep, Wright said.
"Understanding the function of sleep, especially in humans, is considered one of the most important scientific enigmas," said Wright, who also is an adjunct faculty member at the University of Colorado School of Medicine.
The study, which included seven young adult subjects, was tightly controlled. All participants were required to stay in bed for the entire three-day study. Their diets met individual daily energy requirements, and the content and timing of each meal was exactly at the same time each day during the lab study. The subjects spent the sleep deprivation night in bed watching movies, reading and talking, said Wright.
The first day of the study consisted of a typical 16 hours of wakefulness followed by eight hours of sleep. Days two and three included 40 hours of total sleep deprivation followed by eight hours of recovery sleep.
As part of the study, the researchers studied the effects of sleep stages ranging from light sleep to rapid-eye movement sleep to deep, "slow wave" sleep and awakenings from sleep on whole body energy expenditure, Wright said. The study indicated the most energy was expended during natural arousals from sleep, which occurred less often during the eight-hour sleep episodes following sleep deprivation.
The amount of energy saved during sleep by the study subjects likely would have been higher if they were allowed to continue sleeping after the eight hours of recovery sleep rather than being awakened, which was the final step in the study, said Wright.
The study may have implications for those with sleep disorders such as insomnia or sleep apnea. Insomnia, marked by difficulty going to and staying asleep, and sleep apnea, marked by frequent arousals from sleep, may mean such people "are burning the furnace at a higher rate at night because their sleep is disturbed," said Wright. He noted that more research is needed to address this issue in patients with sleep disorders.
It's likely that the metabolic costs of sleep deprivation would have been higher if the subjects had not been restricted to bed rest and had opportunities to walk around and perform various tasks, said Wright. Other studies have shown that sleep deprivation reduces the levels of leptin -- a hormone responsible for telling the brain that the body is satiated -- which could mean late-night snacking by "free-ranging" humans, he said.
"One question we have is why humans don't conserve more energy during sleep," he said. "We think there are multiple functions of sleep, and that some energy conserved during sleep may be redistributed to support other important physiological processes." Some energy conserved by sleep might be used for nighttime physiological activities like immune-system function, the strengthening of connections between neurons in the brain as a result of daily learning and experience, and hormone synthesis and release.
One of the health areas scientists are very interested in is how sleep loss may contribute to weight gain and obesity, said Wright. He stressed that energy expenditure during sleep deprivation is neither a safe or effective strategy for weight loss, and that other studies have shown chronic sleep deprivation is associated with impaired cognition. He said more research is needed to understand how short nighttime sleep schedules, typically six hours or less a night across many days, contribute to weight gain and obesity.
Wright said about a half dozen undergraduate research assistants helped in the study. The Sleep Research Society Foundation, the National Institutes of Health, CU-Boulder's Undergraduate Research Opportunities Program and the Bioscience Undergraduate Research Skills and Training programs of the Biological Sciences Initiative at CU-Boulder funded the study.
A 2006 study by Wright and his colleagues showed that people awakened after eight hours of sound sleep have more impaired thinking and memory skills than they do after being deprived of 24 hours of sleep.

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Birch bark ingredient comes with many metabolic benefits

Birch Bark Ingredient Comes With Many Metabolic Benefits


ScienceDaily (Jan. 5, 2011) — An ingredient found in abundance in birch bark appears to have an array of metabolic benefits, according to new studies in animals that are reported in the January issue of Cell Metabolism, a Cell Press publication. In mice, the compound known as betulin lowered cholesterol, helped prevent diet-induced obesity, and improved insulin sensitivity. Betulin-treated mice were also more resistant to developing atherosclerotic plaques in their arteries.



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Betulin works by targeting so-called sterol regulatory element-binding proteins (SREBPs), transcription factors that are known to be important for activating the expression of genes involved in the biosynthesis of cholesterol, fatty acids, and triglycerides.
"Our study shows that the SREBP pathway is a good target for several metabolic diseases," said Bao-Liang Song of the Shanghai Institutes for Biological Sciences. "We also identify a leading compound."
In the new study, Song and his colleagues went in search of a compound that might act directly on SREBP. That chemical screen turned up betulin as a top contender. They then confirmed in cells that betulin lowered the activity of genes that are normally switched "on" by SREBP. It also lowered lipid levels within cells.
Song's team then treated mice on a high-fat, Western diet with betulin, the cholesterol-lowering statin known as lovastatin, or a placebo (saline) for 6 weeks. Compared to placebo, both drugs led the mice to gain less weight on the high-fat diet, though by different means. Betulin caused the animals to burn more calories while lovastatin appeared to reduce the amount of lipid taken up from the diet.
Further investigations showed that betulin also lowered lipid levels in blood, liver, and fat tissue. Betulin also made the animals more sensitive to insulin. Mice with a mutation that makes them prone to develop atherosclerosis showed fewer plaques when treated with either lovastatin or betulin.
"Betulin has several major metabolic effects," Song said.
The researchers say that their findings suggest that betulin may have similar or even better effects than lovastatin, a member of the most widely prescribed drug class for treating high cholesterol. For instance, in their studies betulin decreased lipids in liver and fat to a greater extent than lovastatin did. Betulin also improved insulin resistance through its effects on fatty acid and triglyceride synthesis.
Song notes that betulin is a readily available compound and is already in use as a precursor in the manufacture of other drugs.
Although betulin appears to have very low toxicity, he says future studies will need to further investigate the safety of betulin and its metabolic effects. Researchers will also explore the possibility that a derivative of betulin might have even greater potency. "That may be the path forward to move this clinically," Song said.

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The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Cell Press, via EurekAlert!, a service of AAAS.




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Jing-Jie Tang, Jia-Gui Li, Wei Qi, Wen-Wei Qiu, Pei-Shan Li, Bo-Liang Li, Bao-Liang Song. Inhibition of SREBP by a Small Molecule, Betulin, Improves Hyperlipidemia and Insulin Resistance and Reduces Atherosclerotic Plaques. Cell Metabolism, 2011; 13 (1): 44-56 DOI: 10.1016/j.cmet.2010.12.004

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Fueling the body on fat: Critical tuning dial for controlling energy found

Fueling the Body on Fat: Critical Tuning Dial for Controlling Energy Found


ScienceDaily (Jan. 5, 2011) — Researchers have found what appears to be a critical tuning dial for controlling whole body energy, according to a new report in the January issue of Cell Metabolism, a Cell Press publication. When energy levels within cells drop, it sets off a series of events designed to increase the amount of calorie-rich dietary fat that the body will absorb.



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This energy reset mechanism is surely critical for survival under natural conditions of scarcity to ensure a steady supply of fuel, the researchers say. Today, many of us who enjoy a Western diet loaded with fat might do better if we could find a way to turn the activity of the so-called AMPK-SRC-2 pathway down.
"Thousands of years ago, this would have been crucial," said Bert O'Malley of Baylor College of Medicine. "Now it's trouble because we eat so much fatty food."
Earlier studies had shown the enzyme AMPK to be an ancient energy sensor. The enzyme causes cells to consume less energy in the form of ATP and to produce more. AMPK also drives appetite.
The new work shows that AMPK also allows for the optimal absorption of the most energy-rich fuel from the diet: fat. That effect of AMPK depends on its activation of SRC-2, a master control gene whose job is to switch other genes on.
When SRC-2 springs into action, it controls genes that lead to the secretion of bile from the gall bladder into the intestine. "You need bile to emulsify and absorb fat," O'Malley explained.
Mice lacking SRC-2 fail to absorb fat normally, they report. Those deficiencies can be corrected by restoring bile acids to the gut.
Together with earlier work, the findings present a "pretty picture" in which SRC-2 is involved in absorbing and storing fat. SRC-2 is also known to play a role in releasing stored glucose from the liver. "It's all about energy accretion, storage and delivery," O'Malley says.
This process takes place on a daily basis even when there is already plenty of fat stored in the body. "It's designed to get in more fat," he says. "Over evolutionary time, when you didn't know when the next meal would be, you really couldn't get enough fat. Now, our next meal is at the corner McDonald's."
The discovery reveals a key mechanism linking the cellular energy state with the whole-body energy state and may ultimately have important clinical implications, the researchers say.
"Obesity is all about fat absorption and storage," O'Malley said. "If you could turn that down, you could have a major effect on a disease that is slowly killing the population." He says his team is now conducting studies in search of SRC-2 inhibitors that might do exactly that.

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The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Cell Press, via EurekAlert!, a service of AAAS.




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Atul R. Chopra, Ramakrishna Kommagani, Pradip Saha, Jean-Francois Louet, Christina Salazar, Junghun Song, Jaewook Jeong, Milton Finegold, Benoit Viollet, Franco DeMayo, Lawrence Chan, David D. Moore, Bert W. O'Malley. Cellular Energy Depletion Resets Whole-Body Energy by Promoting Coactivator-Mediated Dietary Fuel Absorption. Cell Metabolism, 2011; 13 (1): 35-43 DOI: 10.1016/j.cmet.2010.12.001

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Obesity research targets brain's use of fatty acids

Obesity Research Targets Brain's Use of Fatty Acids


ScienceDaily (Jan. 4, 2011) — Researchers at the University of Colorado School of Medicine have created a new and exciting mouse model to study how lipid sensing and metabolism in the brain relate to the regulation of energy balance and body weight.



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The research team, led by Hong Wang, PhD, created mice with a deficiency of lipoprotein lipase (LPL) in neurons, and observed two important reactions. First, the mouse models ate less and second, they became sedentary. Because LPL is important to the delivery of fatty acids to the brain, these responses spotlight the importance of fatty acid delivery to the brain in the regulation of body weight.
"This work may have important impact in understanding the causes of obesity and providing new treatments for this epidemic of our time," said Robert H. Eckel, MD, corresponding and senior author of "Deficiency of Lipoprotein Lipase in Neurons Modifies the Regulation of Energy Balance and Leads to Obesity" which was published in Cell Metabolism.
The genetically-modified mouse (NEXLPL) has a defect in the breakdown of dietary lipoprotein triglycerides into fatty acids in the brain. These mice became obese on a standard chow diet between three and six months. At that point, the mice ate less and were less active.
The research also looked at which areas of the brain have the greatest impact on regulating body weight and learned that the hypothalamus may be the key area to observe as NEXLPL mice have increases in hypothalamic AgRP/NPY gene expression before obesity. AgRP/NPY cause increases in food intake and decreases in energy expenditure. Researchers also noted that the NEXLPL mice demonstrate deficiencies in n-3 fatty acids in the hypothalamus. Overall, this research indicates that the lipoproteins are sensed in the brain by an LPL-dependent pathway and provide lipid signals for the central regulation of body weight and energy balance.
The research team included scientists in the Division of Endocrinology, Metabolism and Diabetes in the Department of Medicine at the CU School of Medicine; the Department of Pharmacology at the University of California Irvine; the Department of Neurogenetics at the Max-Planck-Institute of Experimental Medicine in Germany; the Italian Institute of Technology in Genoa, Italy and the Department of Medicine at Columbia University in New York.

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The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by University of Colorado Denver.




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Hong Wang, Giuseppe Astarita, Matthew D. Taussig, Kalyani G. Bharadwaj, Nicholas V. DiPatrizio, Klaus-Armin Nave, Daniele Piomelli, Ira J. Goldberg, Robert H. Eckel. Deficiency of Lipoprotein Lipase in Neurons Modifies the Regulation of Energy Balance and Leads to Obesity. Cell Metabolism, 2011; 13 (1): 105-113 DOI: 10.1016/j.cmet.2010.12.006

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