Bariatric surgery lowers cancer risk for severely obese patients

Severely obese patients who undergo bariatric surgery lower their risk of developing cancer by at least a third, according to a University of Cincinnati (UC) College of Medicine researcher leading a large retrospective cohort study of patients in the western United States.

“We found having bariatric surgery is associated with a reduced risk of cancer, especially obesity-associated cancers including postmenopausal breast cancer, endometrial cancer, pancreatic cancer and colon cancer,” explains Daniel Schauer, MD, associate professor in the UC Division of General Internal Medicine and lead researcher. “What’s surprising is how great the risk of cancer was reduced.”

The findings were recently published online in the Annals of Surgery.

The study reviewed medical data of 22,198 individuals who had bariatric surgery and 66,427 nonsurgical patients between 2005 and 2012 with follow-up through 2014. It pulled data from large integrated health insurance and health care delivery systems from five study sites operated by Kaiser Permanente–Southern California, Northern California, Oregon, Colorado and Washington.

More than 80 percent of patients in the study were women.

Patients undergoing bariatric surgery had a 33 percent lower risk of developing any cancer during follow-up, according to the published findings. Schauer says the benefit is greatest among obesity-associated cancers. The risk of postmenopausal breast cancer dropped by 42 percent and while the risk for endometrial cancer dropped 50 percent in severely obese patients. The risk of colon cancer dropped 41 percent while the risk of pancreatic cancer was lowered by 54 percent.

“Cancer risks for postmenopausal breast cancer and endometrial cancer are closely related to estrogen levels,” says Schauer. “Having weight loss surgery reduces estrogen level.”

Bariatric surgery helps reduce the risk of diabetes and insulin levels which may be a risk factor for pancreatic cancer, while the mechanisms for colon cancer are more complicated, says Schauer.

“I think considering cancer risk is one small piece of the puzzle when considering bariatric surgery, but there are many factors to consider. Reductions in diabetes, hypertension and improvements in survival and quality of life are reason enough,” says Schauer. “The study provides an additional reason to consider bariatric surgery.”

The study found no significant association between bariatric surgery and cancer risk among men. Schauer says that may be because the vast majority of study patients are female and at least two of the cancers most impacted by bariatric surgery, postmenopausal breast cancer and endometrial cancer, affect women only.

Multivariable Cox proportional-hazards models were used to examine the incidence of cancer up to 10 years after bariatric surgery compared to the matched nonsurgical patients. After a mean follow-up of 3.5 years, researchers identified 2,543 incident cancers.

About 15 million adults in the United States suffer from severe obesity, which is defined as having a body mass index of greater than 35 kg/m2. Obesity and cancer are closely linked. Obesity is associated with up to 40 percent of all cancers diagnosed in the United States, says Schauer.

Scientists Discover Common Obesity and Diabetes Drug Reduces Rise in Brain Pressure

Research led by the University of Birmingham, published today in Science Translational Medicine, has discovered that a drug commonly used to treat patients with either obesity or Type II diabetes could be used as a novel new way to lower brain pressure.

Raised brain pressure is common in emergency situations such as traumatic brain injury, hydrocephalus and stroke, and is also the cardinal feature of Idiopathic Intracranial Hypertension (IIH). IHH causes disabling daily headaches and severely raised pressure around the nerves in the eye. It also causes permanent vision loss in 25% of untreated people.

Over a three-year period, researchers at the University of Birmingham examined whether GLP-1 agonist drugs – existing drugs used in the treatment of diabetes and obesity – could reduce intracranial pressure in an animal model of raised brain pressure.

Corresponding author Dr Alexandra Sinclair, of the University of Birmingham’s Institute of Metabolism and Systems Research, said: “Treatments to lower brain pressure are lacking and new treatments are desperately needed.

“The current primary treatment in IIH is acetazolamide and this does not work well for many patients, while also having such severe side effects that our previous trials have shown that 48 per cent of patients stop taking it.

“We have shown that the GLP-1 agonist extendin-4 significantly reduces brain pressure rapidly and dramatically, by around 44 per cent with significant effects from just 10minutes of dosing – the biggest reduction we have seen in anything we have previously tested. What’s more, we found that the effects last at least 24 hours.

“These findings are rapidly translatable into a new novel treatment strategy for IIH as GLP-1 agonists are safe and widely-used drugs used to treat diabetes and obesity. They are also potentially game-changing for other conditions featuring raised brain pressure, including stroke, hydrocephalus and traumatic brain injury.

“We are very excited that this novel treatment strategy could make a landmark change for future patient care.”

The findings are due to be presented on September 8th and 9th in Vancouver at the International Headache Society Meeting, followed by the British Endocrine Society meeting in the UK from November 6th to 8th.

The research was carried out in collaboration with Birmingham Health Partners, the University of Copenhagen, and the Department of Neurology at University Hospitals Birmingham NHS Foundation Trust.

The University of Birmingham is now due to begin a clinical trial to test GLP-1 agonist drug in patients with raised brain pressure.

  • The University of Birmingham is ranked amongst the world’s top 100 institutions. Its work brings people from across the world to Birmingham, including researchers, teachers and more than 5,000 international students from over 150 countries.
  • Botfield et al (2017). ‘Glucagon-like peptide-1 receptor agonists as a therapeutic to reduce intracranial pressure’. Science Translational Medicine.
  • The research was funded by a variety of supporters including the National Institute for Health Research, Medical Research Council, the West Midlands Neuroscience Teaching and Research Fund and the University of Birmingham Research Development Fund.
  • The cause of IIH is unknown and it mainly affects obese women in their 20s and 30s, and has been associated with hormone problems. IIH is becoming an increasingly frequent problem and now affects 20 per 100,000 of obese women.

New combination of anti-obesity drugs may have beneficial effects

Research conducted in the Perelman School of Medicine at the University of Pennsylvania has revealed that a unique combination of hormone-based drugs can produce enhanced weight loss in laboratory tests with obese animals. The research is to be presented this week at the Annual Meeting of the Society for the Study of Ingestive Behavior (SSIB), the foremost society for research into all aspects of eating and drinking behavior.

“Imagine a drug regimen where an obese person would cycle between different drug therapies over the course of a month to achieve a greater degree of body weight loss compared to the effects achieved with either a single drug or the continuous combination of drugs,” said senior author Dr. Matthew Hayes. His team studied the combination of two different drug classes that target different hormones: amylin and glucagon-like peptide-1 (GLP-1). They found that combined treatments acted synergistically to suppress feeding and body weight. They also discovered that the weight loss effects of chronic amylin- and GLP-1-based combination therapies could be enhanced when obese lab animals are cycled through their drug treatments. “The idea of drug-cycling is nothing new,” says lead author Kieran Koch-Laskowski. “Millions of women on birth control pills, for example, already take daily pills that cycle between drug and placebo throughout the month,” she goes on to say.

Perhaps the most exciting finding of the current data coming out of Penn is the fact that the research finds these enhanced weight loss effects with a combination of drugs that are either already FDA approved or in clinical trials for metabolic diseases, “making the translational impact of our work extremely timely and highly clinically relevant!” says Hayes. The authors are now finalizing their research to demonstrate mechanically how these two hormonal systems interact to achieve greater weight loss in the hopes of fast-tracking their findings to new clinical treatments for obesity.

Obesity risk factors dropped in preschoolers in prevention program

Preschoolers from low-income families living in cities that took part in a two-year community-wide intervention to foster healthy eating and lifestyle habits consumed fewer sugary drinks, got more sleep, and showed improvement in weight, according to a study led by a researcher at NewYork-Presbyterian/Columbia University Medical Center (CUMC).

The study–one of a trio of studies published today in Obesity–was designed to test a childhood obesity-prevention program known as the Massachusetts Childhood Obesity Research Demonstration (MA-CORD) initiative among families in low-income communities, where high obesity rates persist.

Obesity, which remains historically high in the U.S., showed recent declines in preschool-age children. However, obesity prevalence is two to three times higher in children from low-income families compared to higher-income counterparts.

“Evidence strongly suggests that instilling healthy habits in young children is a necessary cornerstone in efforts to prevent obesity and its sequelae,” said study leader Jennifer Woo Baidal, MD, MPH, assistant professor of pediatrics and Director of Pediatric Weight Management at CUMC and a pediatric gastroenterologist in the Comprehensive Adolescent Bariatric Surgery Program at NewYork-Presbyterian/Columbia University Medical Center. “Though some progress has been made in reducing childhood obesity, not all families are aware that certain strategies–like eliminating sugary drinks, limiting screen time, and getting enough physical activity and sleep–help young children achieve and maintain a healthy weight. Solutions that can be scaled-up are urgently needed to prevent obesity in young children at highest risk.”

To increase adoption of these strategies, the researchers in this study implemented the MA-CORD initiative at two community-wide offices of the Special Supplementation for Women, Infants and Children (WIC) program in Massachusetts, which provides healthy foods, nutrition assessment and education, breastfeeding support, and referrals to healthcare and other services for low-income families with very young children. WIC providers were trained to deliver consistent messages during office visits about how much sugar-sweetened beverage, juice, junk food, screen time, and exercise young children should get. Families at a third community WIC site did not get the intervention.

At the end of the study, children from the intervention sites reduced their intake of sugary beverages and juice and got more sleep compared to children who did not receive the intervention. Children from the intervention sites also engaged in more physical activity and less screen time than their counterparts in the comparison group, though these differences were not statistically significant.

In one intervention site, non-Asian children also had small decreases in adjusted BMI scores compared with children in the comparison group.

“Overall, the intervention had a positive impact on reducing obesity risk factors among the children in our study, but the smaller impact on reducing BMI may be due to factors that can’t be easily controlled, such as access to high-quality, nutritious foods in the community and the challenge of measuring rapid changes in growth during early childhood,” said Rachel Colchamiro, MPH, RD, Director of Nutrition Services for the Nutrition Division at the Massachusetts Department of Public Health and a co-author of the paper. “Because obesity disproportionately affects lower-income families, incorporating WIC providers and community systems into multi-sector obesity prevention efforts could yield high results at a national level.”

The two related studies published today examined the effectiveness of the whole-of-community intervention at local health clinics and in schools.

“Ultimately, we think that durable and effective childhood obesity-prevention efforts will require the implementation of evidence-informed interventions and sustained coordination across multiple sectors to reach vulnerable populations,” said Elsie Taveras, MD, MPH, Chief of the Division of General Pediatrics and Director of Pediatric Population Health Management at Massachusetts General Hospital and a professor of pediatrics and population medicine at Harvard Medical School. “There is an urgency to find solutions for childhood obesity that will reach populations that need it most. Our findings suggest that community-wide initiatives such as MA-CORD are particularly promising in these efforts.”

Study reveals sweetened drinks during pregnancy puts infants at higher risk for obesity

A recent Danish study of children born to women with gestational diabetes, found that maternal daily consumption of artificially-sweetened beverages during pregnancy was associated with a higher body mass index score and increased risk of overweight/obesity at 7 years.

Artificial sweeteners are widely replacing caloric sweeteners, due to the health concern related to sugar-sweetened beverages (SSBs) within the general population. Artificially sweetened beverages have been considered as potential healthier alternatives, although this study suggests contrary. This study looks to investigate the long-term impact of ASBs consumption during pregnancy on offspring obesity risk in relation to offspring growth through age 7 years among children born to women with gestational diabetes .

In particular, children born to women with gestational diabetes –the most common pregnancy complication affecting approximately 16% of pregnancies worldwide–represent a high-risk phenotype, which may serve as a unique model to study the early origins of obesity. Further evidence has linked nutritional biological disruptions during pregnancy to fetal development and obesity risk in later life. Thus, the authors argue it is important to identify modifiable dietary factors that may prevent offspring obesity and maternal complications.

The study investigated 918 mother and child pairs from the Danish National Birth Cohort. Enrolled participants completed four telephone interviews at gestational weeks 12 and 30, and 6 and 18 months postpartum, which collected data on sociodemographic, perinatal, and clinical factors. In addition, maternal dietary intake was assessed by a food questionnaire during pregnancy. Offspring body mass index scores and overweight/obesity status were calculated using weight and length/height at birth, 5 and 12 months, and 7 years. When the children were 7 years old, a follow-up questionnaire about the child’s health and development was delivered to the parents.

Results showed that approximately half (45.4%) of women reported consuming artificially sweetened beverages during pregnancy. Whereas 68.7% reported consuming SSBs, artificially sweetened beverage consumption–compared to never consuming artificially sweetened beverages–by pregnant women with gestational diabetes was associated with a 1.57 increased risk of being overweight for gestational age babies and a 1.93-fold increase in overweight/obesity risk at 7 years after adjustment for major maternal and offspring risk factors.

Associations were more pronounced in male than female offspring. Substituting SSBs with artificially sweetened beverages was associated with an increased risk of offspring overweight/obesity at 7 years whereas substitution of artificially sweetened beverage with water was associated with a 17% reduced risk. The findings illustrated a positive association between uterus exposure to artificially sweetened beverages and birth size and risk of overweight/obesity at 7 years.

Childhood obesity causes lasting damage to the body

Obesity in childhood has long term health implications stretching into adulthood, a new study in the journal Obesity Reviews reveals.

Examining data collected from over 300,000 participants across 18 studies, researchers from the University of Surrey identified increased arterial damage and enhanced likelihood of pre diabetes in participants who were obese in childhood. The damage, an increased thickness of these vital arteries, heightens the likelihood of an individual suffering from a cardiovascular ailment, such as heart disease, in later life.

Body mass index (BMI), waist circumference and skin fold thickness measurements of over 300,000 children (average age of 10) were assessed and compared with results gathered from the same participants on average 25 years later.

Researchers discovered that obese children were pre disposed to ‘pre-diabetes’ (an inability to adequately metabolise glucose, which can later lead to diabetes) and thickening of arteries in adulthood, both of which can be detrimental to their adult health. Childhood BMI also proved to be an indicator of adult hypertension demonstrating that this indicator is useful in predicting illnesses associated with obesity in adulthood. Due to limited data it is unknown if waist circumference and skin fold thickness are indicators to future ailments.

Childhood obesity has become increasingly prevalent in the UK, with figures from the NHS National Child Measurement Programme indicating that 19.8 per cent of 10-11 year olds being classed as obese in 2015/16, a rise of 0.7 per cent on the previous year. The long term implications of childhood obesity to adult health and resulting cost to the NHS is unknown.

Lead author Dr Martin Whyte from the University of Surrey, said: “It is worrying that obesity is becoming endemic in our society.

“The adverse effects of adult obesity are well known but what we have found is that obesity in childhood can cause lasting arterial damage which could potentially lead to life threatening illness. This is something that we need to address to protect adult health and reduce pressure on the NHS.”

Urine Metabolites May Help Predict Which Obese Teens Will Develop Diabetes

Researchers have discovered a unique metabolic “signature” in the urine of diabetic, obese black teenagers that they say may become a way to predict the development of type 2 diabetes in people at risk. They will present their results Tuesday at the Endocrine Society’s 99th annual meeting in Orlando, Fla.

In detailed metabolic analyses, the level of the main metabolite, or byproduct, of serotonin was “strikingly lower” in obese youth with type 2 diabetes than in nondiabetic obese adolescents, said Pinar Gumus Balikcioglu, M.D., the study’s lead investigator and an assistant professor of pediatric endocrinology at Duke University School of Medicine, Durham, N.C. Also, levels of several other metabolites were reportedly much higher than in the teenagers without diabetes.

“The major determinant of type 2 diabetes is obesity, which causes resistance to the effects of insulin. Yet many obese people do not become insulin resistant, and only a minority go on to develop Type 2 diabetes,” Gumus Balikcioglu said. “To identify those at highest risk, it is essential to find metabolic markers that predict the development of insulin resistance and diabetes.”

To attempt to do that, she and her colleagues have turned to the new field of studying the chemical “fingerprints” that small-molecule metabolites leave in blood and urine. In previous studies in obese teenagers, they analyzed hormone levels and metabolites in blood samples and identified several factors associated with the development of insulin resistance, she said.

In this study, they performed metabolic profiling of urine specimens obtained over a 24-hour period from 33 obese African-American teenagers ages 8 to 18: 13 with type 2 diabetes and 20 without. Both groups were comparable in age, sex and body mass index (an estimate of body fat). Participants who took the diabetes drug metformin were asked to stop taking it the day before the study, but those taking insulin were allowed to continue it for safety reasons.

Metabolic analysis, the researchers said, found that a much lower level of 5-hydroxy-indoleacetic acid (5-HIAA), the main metabolite of the neurotransmitter serotonin, was associated with diabetes. Although serotonin is perhaps best known for mood regulation, it has multiple functions, including controlling the development and function of the pancreatic beta cells that make insulin.

“A low level of serotonin or its byproducts could reduce insulin secretion, causing obese people to progress from insulin resistance to type 2 diabetes,” Gumus Balikcioglu said.

In addition, she said the diabetic teenagers had significantly higher levels of three metabolites than nondiabetic participants did. Among these were metabolites related to dysfunction of mitochondria, the “power unit” of the cell responsible for converting food to energy, and defects of the mitochondrial respiratory chain, which also lead to decreased energy production.

“Validation of our findings in larger clinical trials could provide a new noninvasive approach to identification of biomarkers for metabolic risk in in both children and adults,” she said. “More importantly, analysis of serotonin metabolism may provide new therapeutic targets for diabetes prevention and treatment.”

This study received funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health; and the Children’s Miracle Network Hospitals partnerships and programs benefiting Duke Children’s Hospital and ENABLE career development program.

Humans have three times more brown body fat

Compared to white fat, brown body fat burns through energy at an extraordinary rate. However, until now the proportion of brown fat in humans was thought to be quite small. Now a study conducted by researchers at the Technical University of Munich (TUM) has shown: The quantity of brown fat in humans is three times greater than previously known. As a consequence, new obesity and diabetes drugs that activate brown adipose tissue are expected to be more effective.

For the study, published in the Journal of Nuclear Medicine, nearly 3,000 PET scans of 1644 patients were analyzed. PET is an acronym for positron emission tomography, a method widely used in oncology. PET scans enable the visualization of metabolic activity in the body. Since a tumor often has a different energy metabolism to healthy tissue, PET scans can be used to demonstrate the presence of metastases.

“A byproduct of PET scans is that they allow us to see active brown adipose tissue,” according to Dr Tobias Fromme from the Else-Kröner-Fresenius Center at the Technical University of Munich — “brown adipose tissue absorbs lots of sugar, and we can observe this activity through the scans.” For example, it is conceivable that a drug could reduce excessive blood sugar levels in diabetics by increasing the activity of the brown fat.

Similarly, it is conceivable that patients with obesity could use the high rate of energy combustion through brown fat to melt away their excess weight — at least to a certain extent. “In any event, the outlook for the efficacy of drugs in brown adipose tissue can be adjusted upwards,” said the researcher.

Some people activate brown body fat more than others

The analysis of the PET scans also revealed that some groups of persons have an easier time activating their brown fat than others, or even have more of it in the first place. As several previous studies have already shown, women more frequently have active brown fat than men. Similarly, thinner and younger persons have larger proportions of brown fat. Furthermore, brown fat does not react with the same level of activity in overweight individuals or in the elderly. “However, active brown fat occurs with far greater frequency in about five percent of patients than in the general population,” said Fromme — “in these patients, 50% of the scans showed these active fatty tissue proportions.”

The researcher suggested that this may point to a possible explanation for the phenomenon that some persons seem to gain weight after only one extra piece of cake, while others can gorge on sweets without gaining at all — different body weights despite having the same diet. “Ultimately, with medication that activates brown adipose tissue, we must anticipate that some groups of people are likely to benefit from an additional activation of brown fat more than others,” the author of the study explained. “So far, we don’t know the causes for a particular individual to have especially active brown fat.”

A newly discovered factor may prove key to solving this riddle: The researchers showed for the first time that brown fat activity is affected by a variable known as creatinine clearance, which is related to renal function. “Further basic research is still needed,” said Fromme” — but one hypothesis is that there may be signaling substances that affect both brown fat and the kidneys.”

Children with Asthma May Be at Higher Obesity Risk

Children with asthma may be more likely to become obese later in childhood or in adolescence, according to new research published online ahead of print in the American Thoracic Society’s American Journal of Respiratory and Critical Care Medicine.

In “Effects of Childhood Asthma on the Development of Obesity among School-Aged Children,” researchers report that young children with asthma were 51 percent more likely to become obese over the next decade as children who did not have asthma. The researchers also found that the use of asthma rescue medications reduced the risk of becoming obese by 43 percent.

“Asthma and obesity often occur together in children, but it is unclear whether children with asthma are at higher risk for onset of obesity or whether obese children develop asthma, or both, said Zhanghua Chen, PhD, lead study author and a postdoctoral research associate of preventive medicine at the Keck School of Medicine at the University of Southern California. “Our findings add to the literature that early-life asthma history may lead to increased risk of childhood obesity.”

In their prospective study, Dr. Chen and her colleagues analyzed the records of 2,171 kindergarteners and first graders who were not obese at the time they enrolled in the Southern California Children’s Health Study (CHS). At enrollment, 13.5 percent of the children had asthma. The children were followed for up to 10 years (average: 6.9 years). During that time, 15.8 percent of all the children enrolled in the study developed obesity. Researchers confirmed study results in a different group of children, recruited in the 4th grade to participate in the CHS.

The researchers accounted for a number of factors that might have biased results, including whether the children had health insurance or were overweight at enrollment, ethnicity, family income, smoking exposure at home and physical activity.
These confounding factors also did not explain the finding that the use of rescue asthma medications appeared to reduce the risk of developing obesity.

Frank D. Gilliland, MD, PhD, senior study author and Hastings Professor of Preventive Medicine at the university, said the fact that rescue, but not controller, asthma medications reduced obesity was a surprise and warranted further study. He added, however, that overall study findings reinforce the importance of early diagnosis and treatment of asthma, which may short circuit “the vicious cycle of asthma increasing the development of obesity and obesity causing increased asthma symptoms.”

Study limitations include relying on parents to report asthma diagnosis, limited information about exercise and no information about diet. Still, study findings, the authors said, suggest commonsense strategies for children with asthma that can improve their overall health while reducing the risk of obesity. Among those strategies, they said, are eating a healthy diet, increasing physical activity and achieving asthma control through medication and better understanding of symptom triggers.

The Role of Common Risk Factors in ER-Positive, ER-Negative Breast Cancer

Karla Kerlikowske, MD, and team recently published a paper in the Journal of the National Cancer Institute that examined the role of common risk factors in the development of ER-positive and ER-negative breast cancers. The study sheds new light on how a woman’s age, weight, and menopausal status affect her risk for breast cancer. Dr. Kerlikowske discusses the findings below.


What was the aim of the study?
The goal of the study was to examine how common breast cancer risk factors play a role in the development of estrogen receptor (ER)-positive versus ER-negative invasive breast cancer. Some breast cancer cells contain receptors that attach to the hormone estrogen that can fuel the growth of breast cancer cells. ER-positive tumors have receptors that attach to the hormone estrogen, whereas ER-negative breast cancers do not.

What led you to pursue this question?
Primary prevention with hormone therapy (selective estrogen receptor modulators or aromatase inhibitors) blocks the effects of estrogen in the breast tissue so cells don’t receive the hormone estrogen’s signals to grow and multiply. Hormone therapy leads to a decrease in the risk of estrogen receptor positive- but not estrogen receptor negative breast cancer.
It is important to know which women are at increased risk for each cancer subtype so women at increased risk of ER-positive cancer can discuss with their provider hormone therapy as an option for prevention.

Does the study address gaps in existing research?
Most studies examining the role of risk factors in the development of breast cancer have examined risk of breast cancer overall, rather than by ER cancer subtype. Studies that have examined risk factors for ER cancer subtype have been small and inconsistent in their results.
Our large prospective Breast Cancer Surveillance Consortium (BCSC) cohort study was able to examine risk for ER-positive and ER-negative invasive cancer with strong, prevalent risk factors according to a woman’s age and menopausal status.

What are your chief findings?
We found family history of breast cancer in a first degree relative, benign breast disease, and breast density increased the risk for both ER-positive and ER-negative invasive breast cancer, but the level of risk varied by age. We also found postmenopausal women who were overweight or obese were similarly at increased risk of ER-positive and ER-negative cancer while peri/premenopausal women who were overweight or obese were at increased risk of ER-negative cancer to a greater extent than ER-positive cancer.
Women at highest risk in our study had benign breast lesions with proliferative changes (overgrowth of the cells that line the ducts or the milk glands). These women were at high risk of ER-positive cancer.

Why is this new information? And why is it significant?
Prior studies show premenopausal women who are overweight or obese are not at increased risk of ‘premenopausal’ breast cancer because assessment of weight is measured close to the time of diagnosis.
We found premenopausal women who are overweight or obese are at increased risk of breast cancer in the next ten years, and at greatest risk of ER-negative breast cancer which is more difficult to treat than ER-positive breast cancer.

Premenopausal covers a huge age variance — is there heightened risk for overweight women in their 20s, 30s?
Premenopausal was defined as women who reported a menstrual period within the last 180 days, were under age 40, or birth control hormone users. Perimenopausal women were not sure if their periods had stopped; or their last menstrual period was 180-364 days ago.

What is the link between extra weight and increased risk?
Postmenopausal women who are overweight or obese have elevated circulating estrogens to promote breast tumor growth. Premenopausal women who are overweight or obese have high blood levels of insulin and insulin-like growth factor and chronic low-grade inflammation. It has been hypothesized that they are possible mechanisms by which obesity increases breast cancer risk in these women.

What are the implications of the findings?
These findings provide new information for women and providers about which women are at increased risk of ER-positive versus ER-negative breast cancer. This will aid discussions about preventive measures such as losing weight or the option of preventive hormone therapy.

Can the findings be incorporated into clinical practice?
Peri/premenopausal and postmenopausal women who are overweight or obese should be encouraged to lose weight to decrease breast cancer risk.
Women with benign lesions that show proliferative changes on breast biopsies are at increased risk of ER-positive breast cancer and should calculate their 5-year risk of breast cancer using the BCSC risk calculator (https://tools.bcsc-scc.org/BC5yearRisk/). If risk is >3%, women should be counseled on preventive measures such as taking hormone therapy.

How much do premenopausal women have to be overweight to have higher risk? Can it be just 5 or 10 lbs. or does it have to be significant, say, 30 or more lbs.?
Overweight is six to seven pounds or more above what is considered ideal body weight for a woman’s height.

What should women do to lower their risk?
Maintain ideal body weight for their height and exercise regularly.

There Are at Least 59 Types of Obesity, According to Researchers

It’s a strange fact that if two obese people have the same amount of excess weight, one diet might work really well for one and do nothing for the other. Even weight-loss experts are stumped as to why this happens. But increasingly, they think that it’s because obesity isn’t one disease — rather, it has many different subtypes all with their own methods of prevention and treatment. (The New York Times made an analogy to cancer: Lung cancer and skin cancer are part of the same group, but they couldn’t be more different.)

Researchers are trying to figure out exactly how many, but there are 59 kinds of obesity that we know of, according to Lee Kaplan, director of the obesity, metabolism, and nutrition institute at Massachusetts General Hospital. There are also more than 25 genes that directly affect obesity risk and more than 300 that can lead to a few extra pounds each — bad news for people who inherit a collection of the latter altered genes. Add to these genetic links other weight-gain inducing factors like sleep deprivation and certain medications and health conditions and you have many roads to the same destination.

The Times profiled six people who struggled to lose weight, all of whom went through trial and error with their doctors. Some people had success with certain diets, others by religiously counting calories, and others still with obesity drugs and even combinations of drugs that lead to weight loss and control appetite. The entire story is worth a read, but the overarching message is that if you find something right away that helps you lose weight and keep it off, you are very, very lucky.

Rare Obesity Syndrome Therapeutic Target Identified

Columbia University Medical Center (CUMC) researchers have discovered that a deficiency of the enzyme prohormone covertase (PC1) in the brain is linked to most of the neuro-hormonal abnormalities in Prader-Willi syndrome, a genetic condition that causes extreme hunger and severe obesity beginning in childhood. The discovery provides insight into the molecular mechanisms underlying the syndrome and highlights a novel target for drug therapy.

The findings were published online today in the Journal of Clinical Investigation.

“While we’ve known for some time which genes are implicated in Prader-Willi syndrome, it has not been clear how those mutations actually trigger the disease,” said lead author Lisa C. Burnett, PhD, a post-doctoral research scientist in pediatrics at CUMC. “Now that we have found a key link between these mutations and the syndrome’s major hormonal features, we can begin to search for new, more precisely targeted therapies.”

An estimated one in 15,000 people have Prader-Willi syndrome (PWS). The syndrome is caused by abnormalities in a small region of chromosome 15, which leads to dysfunction in the hypothalamus—which contains cells that regulate hunger and satiety—and other regions of the brain. A defining characteristic of PWS is insatiable hunger. People with PWS typically have extreme obesity, reduced growth hormone and insulin levels, excessive levels of ghrelin (a hormone that triggers hunger), and developmental disabilities. There is no cure and few effective treatments for PWS.

Dr. Burnett and her colleagues used stem cell techniques to convert skin cells from PWS patients and unaffected controls into brain cells. Analysis of the stem cell-derived neurons revealed significantly reduced levels of PC1 in the patients’ cells, compared to the controls. The cells from PWS patients also had abnormally low levels of a protein, NHLH2, which is made by NHLH2, a gene that also helps to produce PC1.

To confirm whether PC1 deficiency plays a role in PWS, the researchers examined transgenic mice that do not express Snord116, a gene that is deleted in the region of chromosome 15 that is associated with PWS. The mice were found to be deficient in NHLH2 and PC1 and displayed most of the hormone-related abnormalities seen in PWS, according to study leader Rudolph L. Leibel, MD, professor of pediatrics and medicine and co-director of the Naomi Berrie Diabetes Center at CUMC.

“The findings strongly suggest that PC1 is a good therapeutic target for PWS,” said Dr. Burnett. “There doesn’t seem to be anything wrong with the gene that makes PC1—it’s just not getting activated properly. If we could elevate levels of PC1 using drugs, we might be able to alleviate some of the symptoms of the syndrome.”

“This is an outstanding example how research on human stem cells can lead to novel insight into a disease and provide a platform for the testing of new therapies,” said Dieter Egli, PhD, a stem cell scientist who is an assistant professor of developmental cell biology (in Pediatrics) and a senior author on the paper.

“This study changes how we think about this devastating disorder,” said Theresa Strong, PhD, chair of the scientific advisory board of the Foundation for Prader-Willi Research and the mother of a child with PWS. “The symptoms of PWS have been very confusing and hard to reconcile. Now that we have an explanation for the wide array of symptoms, we can move forward with developing a drug that addresses their underlying cause, instead of treating each symptom individually.”

Following the findings reported in this paper, the Columbia research team began collaborating with Levo Therapeutics, a PWS-focused biotechnology company, to translate the current research into therapeutics.

Fatty Liver: Turning Off TAZ Reverses Disease

Scientists at Columbia University Medical Center (CUMC) have identified a factor in liver cells that is responsible for turning a relatively benign liver condition, present in 30 percent of U.S. adults, into a serious disease that can lead to liver failure.

The study was published online today in Cell Metabolism.

With the rise of obesity in the U.S., the incidence of nonalcoholic fatty liver disease (NAFLD)—in which excess fat fills the liver—has risen to epidemic levels. The extra liver fat is generally benign, but in one in five people, NAFLD evolves into a more serious condition, nonalcoholic steatohepatitis (NASH).

In NASH, the liver becomes inflamed and criss-crossed by fibrous scar tissue, and liver cells start dying. Patients with NASH are at risk of liver failure and liver cancer, but there are no drugs on the market that can slow or stop the disease.

Because the amount of fibrosis in the liver is associated with a greater risk of death from NASH, Xiaobo Wang, PhD, associate research scientist in the Department of Medicine at CUMC working in the lab of Ira Tabas, MD, PhD, looked for ways to stop fibrosis in a mouse model of NASH.

He found that in liver cells, TAZ, a previously unknown factor in NASH, plays a critical role in initiating fibrosis, and that fibrosis stops in mice with NASH when TAZ is inactivated in liver cells. With TAZ shut down, existing fibers in the liver also dissolved, essentially reversing the disease. Two other critical features of NASH, inflammation and cell death, were also reduced when TAZ was turned off. Fat accumulation in the liver was unaffected.

Based on their examination of liver biopsies from NAFLD and NASH patients, Drs. Wang and Tabas believe that TAZ works in the same way in people.

“We think that by stopping fibrosis through TAZ and its partners, we may be able to prevent the serious consequences of NASH, including liver failure and liver cancer,” said Ira Tabas, Richard J. Stock Professor and vice-chair of research in the Department of Medicine and professor of pathology & cell biology (in physiology and cellular biophysics) at CUMC.

The Complex Crosstalk Between Obesity and Breast Cancer

A new study published in the Journal of Cell Physiology describes how inflammation that characterizes fatty tissue is one of the main microenvironment actors responsible for promoting cancer. The authors also describe the involvement of steroid hormones and others factors produced by adipose tissue in breast cancer development.

The study, “Multifaceted breast cancer: the molecular connection with obesity,” appeared in the July 1, 2016 edition of the international, per-reviewed journal focused on cancer-related issues. The authors belong to a multidisciplinary Italian-American-Tunisian team with a long and productive history of collaboration with Prof. Antonio Giordano, Director of the Sbarro Institute for Cancer Research, Temple University of Philadelphia, Pennsylvania, USA.

A novel approach was developed to analyze cell culture systems by professor Pietro Formisano from the University of Naples “Federico II” (NA, Italy), in order to study interactions between adipose tissue and tumors, and the molecular mechanism of insulin action. The contribution of professor Angelina Di Carlo, University of Rome “La Sapienza” (Rome, Italy), was to underline the role of matrix metalloproteinases in obesity-related mechanisms of breast carcinogenesis. The work by Professor Soumaya Kouidhi, of Manouba Thabet University (Aryanah,Tunisia), suggests that the small circulating RNA could be important in the diagnosis and prognosis of breast cancer. Finally, professor Marina Di Domenico from the Second University of Naples (Italy) and PI of IRCCS “La salute della donna” of “Malzoni Clinic ” (AV, Italy), describes the “non genomic” actions of estrogen receptors in relation to breast cancer, with particular reference to the main roles of p85 / PI3K, in differentiation and cell migration.

UK Study Shows New Potential Marker for Obesity

A new study led by University of Kentucky researchers and published in Nature shows a potential new biological marker for the development of obesity and a possible target for obesity prevention and treatment.

Neurotensin (NT), a peptide produced mainly in the gastrointestinal tract and central nervous system, is released with fat ingestion and facilitates fatty acid absorption in the intestine. Previous research has shown that NT can also stimulate the growth of various cancers and increased fasting levels of pro-NT (an NT precursor hormone) are associated with development of cardiovascular disease and breast cancer.

The new Nature study examined data from the Malmö Diet and Cancer Study, a population-based, prospective epidemiologic cohort of 28,449 men and women who were followed for an average of 16.5±1.5 years. The analysis showed that obese and insulin-resistant subjects have significantly elevated levels of fasting pro-NT, and the risk of developing obesity was doubled in non-obese subjects who had fasting pro-NT at the highest concentrations compared to subjects with the lowest concentrations.

The study further used animal models to show that a deficiency in NT protects against obesity, insulin resistance and fatty liver disease associated with high fat consumption, thus identifying NT as a potential early marker of future obesity and a novel therapeutic target for this disease.

University of Kentucky Markey Cancer Center Director Dr. Mark Evers, a surgical oncologist and professor in the UK Department of Surgery, led the study in collaboration with other investigators from the University of Kentucky, the University of Massachusetts, and the University of Lund in Malmö, Sweden.

“Our findings have redefined how we view the role of NT,” said Evers, whose laboratory has been studying this peptide for over two decades. “NT appears to be a metabolically ‘thrifty’ peptide which increases the absorption of ingested fats; however, with the abundance of fats in typical Western diets, NT can have a detrimental effect by contributing to increased obesity and related metabolic disorders.”

Additionally, because NT can contribute to the growth of certain cancers and is now linked with obesity, Evers speculates that increased NT may contribute to the higher incidence of certain cancers associated with obesity. Building on the findings from this study, future research at the University of Kentucky will examine this possible link.

Worldwide, more than 1.7 billion people are overweight, with a body mass index (BMI) higher than 25, or obese (BMI higher than 30). Additionally, more than 2.5 million deaths are attributed to the consequences of obesity each year.

Brain Cells That Aid Appetite Control Identified

It’s rare for scientists to get what they describe as “clean” results without spending a lot of time repeating the same experiment over and over again. But when researchers saw the mice they were working with doubling their weight within a month or two, they knew they were on to something.

“About twenty years ago there was a big step forward in our understanding of obesity when researchers discovered that our appetite is controlled by a key molecule called leptin. Leptin is a hormone which is produced by our fat cells, and is delivered by the blood to the brain to signal the brain that we are full and can stop eating,” explains Dr. Maia Kokoeva who is affiliated both with McGill University and the Research Institute of the McGill University Health Centre. “But even though receptors for leptin were discovered soon after in the hypothalamus, a brain area that regulates food intake and body weight, it has remained unclear how exactly leptin is detected.”

So about four years ago, Kokoeva and her team set out to explore which brain cells might play a role in the process of leptin sensing and weight gain. The answer, it turns out, lies in the median eminence.

“Protection” and “preservation” cells in a busy place
The median eminence is a brain structure at the base of the hypothalamus. It is a bit like a busy hub or market place through which hormones and molecules of various kinds travel in both directions between the brain and the bloodstream to ensure that the body functions smoothly.

The McGill research team has now discovered that without a particular group of cells (known as NG2-glia cells) in place in the median eminence, the leptin receptors in the brain never receive the messages from the body telling it that it is sated.

“Most of the brain is a well-protected fortress, designed to shelter delicate nerve cells,” says Kokoeva. “The median eminence is outside these protections, and so can be a dangerous environment for the nerve cells that detect leptin. We think that the NG2-glia cells act to support and shelter the leptin receptor neurons, enabling them to instruct the body when to stop eating.”

Crucial role of the median eminence in weight gain
“We developed an interest in NG2-glia cells in this specific part of the brain because unlike neurons, during much of our adult lives these cells are constantly dividing and they do so most actively in the median eminence,” says Tina Djogo, a McGill doctoral student and one of two lead authors on the study which was published this week in Cell Metabolism. “But though these cells were first described about thirty years ago it has been difficult so far to pinpoint their exact functions in the adult brain.”

Because of their particularly high turnover in the median eminence, the researchers wondered if the NG2-glia cells might play a role in leptin sensing and therefore in appetite control. So they used a drug to kill the NG2-glia cells in the median eminence of a group of mice and then watched to see whether there was a difference in food intake. The results were stunning.

Within three days after they started to receive the medication, some of the mice dubbed “gainers” had already started to eat more compared with the control group of mice who had not received medication. And by 30 days afterwards, the weight of some of the mice had doubled – from 25 grams to around 50 grams.

“But what was most exciting to us, was that even though NG2-glia are found across the brain” explains Sarah Robins, a research associate who was also a lead author on this study, “it was only when we removed these cells from the median eminence that we saw this clear increase in body weight.”

A possible explanation for weight gain in brain tumour patients
The researchers then corroborated the role of the NG2-glia cells in the median eminence in appetite control through experiments using genetically modified mice, and also by using irradiation. This latter discovery suggested an explanation for a previously unexplained phenomenon in human brain cancer survivors.

“People who have been treated for brain tumours using radiation to block cell proliferation often become overweight,” says Kokoeva. “However, there has never been any satisfactory explanation, but our experiments in mice now suggests that the reason for this weight gain may be the loss of NG2-glia in the median eminence as a result of radiation.”

The researchers are hopeful that the identification of NG2-glia in the median eminence as crucial elements in body weight and appetite control will pave the way to new targeted anti-obesity approaches directed towards maintaining or raising the NG2-glia population in the median eminence.

Study Suggests Link Between Obesity and Kidney Cancer

Receptors for leptin, a protein hormone, may be associated with tumor recurrence in patients with renal cell carcinoma (RCC), providing further understanding about molecular links between obesity and RCC tumor formation and prognosis, according to a study at The University of Texas MD Anderson Cancer Center.

The findings are being presented April 18 at the annual meeting of the American Association of Cancer Research (AACR) in New Orleans.

The leptin receptors, called LEPR, were found to be hypermethylated in tumors in a study involving 240 newly diagnosed and previously untreated Caucasian RCC patients. Methylation is a mechanism by which cells control gene expression and both hypomethylation and hypermethylation are known to play roles in silencing of tumor suppressor genes or over-expression of oncogenes in cancer cells. LEPR was one of 20 obesity-related genes that the research team examined.

“Obesity is an established risk factor for RCC with more than 40 percent of these cases attributed to excessive body weight,” said Xifeng Wu, M.D., Ph.D., professor of Epidemiology and principal investigator for the study. “Growing evidence suggests that obesity also may be associated with the prognosis of RCC. The molecular mechanism LEPR and two other genes, NPY and LEP, are involved in RCC tumorigenesis. LEPR methylation in tumors is associated with recurrence in RCC patients and thus, LEPR may provide a functional link between obesity and RCC.”

The study evaluated the association between methylation of 20 obesity-related genes and RCC. For the discovery portion of the study, 63 tissue pairs of RCC tumors and normal adjacent tissues from the surrounding kidney were used. An additional 177 pairs were included for the validation component of the study.

The patients were mostly males with an average age of 59 years who had never smoked. Most of the patients had clear cell RCC and were at the earliest stage of disease.

“Patients were classified into high- and low-LEPR methylation groups,” said Julia Mendoza-Perez, Ph.D., a visiting scientist of Epidemiology at MD Anderson who presented the findings at AACR. “We found that high LEPR methylation was associated with a significantly higher risk of tumor recurrence.”

The results were adjusted by age, gender, pathologic stage of disease, grade, smoking status, body mass index, hypertension and histology.

“In addition, high LEPR methylation in tumors was associated with more advanced tumor features, such as high pathologic stage, high grade, and clear cell RCC histology,” said Wu.

The researchers add that future studies are needed to further understand the biology underlying the ties between LEPR methylation and RCC recurrence.