Scientists at Baylor College of Medicine, the National Institutes of Health and Virginia Tech Carilion Research Institute have discovered a new mechanism in the mouse brain that regulates obesity. The study shows that this new mechanism can potentially be targeted to treat obesity.

“It’s well known that the brain is involved in the development of obesity, but how a high-fat diet changes the brain so it triggers the accumulation of body fat is still unclear,” said senior author Dr. Makoto Fukuda, assistant professor of paediatrics at Baylor and the USDA/ARS Children’s Nutrition Research Center at Baylor and Texas Children’s Hospital.

Fukuda and colleagues studied the mouse Rap1 gene, which is expressed in a variety of tissues, including the brain where it is involved in functions such as memory and learning. Little was known, however, of the role brain Rap1 plays in energy balance.

To explore the role Rap1 plays in a mouse model, the scientists selectively deleted the Rap1 gene in a group of neurons in the hypothalamus, a region of the brain that is involved in regulating whole-body metabolism.

The scientists had two groups of mice. In one group, the mice were genetically engineered to lack the Rap1 gene, while the control group had a functional Rap 1 gene. Then, the scientists fed the mice in both groups a high-fat diet in which 60 percent of the calories came from fat. As expected, the control mice with a working Rap1 gene gained weight, but, in comparison, the mice that lacked Rap 1 had markedly reduced body weight and less body fat. Interestingly, when both groups of mice were fed a normal diet, both showed similar weights and body fat. 

The scientists then looked closer at why the mice lacking the Rap1 gene had not gained weight despite eating a high-fat diet.
“We observed that the mice lacking Rap1 were not more physically active. However, they ate less and burned more body fat than mice with Rap1,” said Fukuda. “These observations were associated with the hypothalamus producing more of a hormone that reduces appetite, called POMC, and less of hormones that stimulate appetite, called NPY and AgRP.” These mice also had lower levels of blood glucose and insulin than controls.
The scientists also were interested in studying whether leptin changed in mice lacking Rap1. Leptin, the ‘satiety hormone’ produced by fatty tissue, helps regulate body weight by inhibiting appetite. Obese people, however, do not respond to leptin’s signals of satiety, and the blood levels of leptin are higher than those in non-obese people. Leptin resistance is a hallmark of human obesity.

Mice that lacked Rap1 and ate a high-fat diet, on the other hand, did not develop leptin resistance; they were able to respond to leptin, and this was reflected in the hormone’s lower blood levels.

Fukuda and colleagues also tested the effect of inhibiting Rap1 with drugs instead of deleting the gene on mice on a high-fat diet. The scientists inhibited RAP1 action with inhibitor ESI-05.

“When we administered ESI-05 to obese mice, we restored their sensitivity to leptin to a level similar to that in mice eating a normal diet. The mice ate less and lost weight,” said Fukuda.

The scientists have shown a new mechanism by which the brain can affect the development of obesity triggered by consuming a high-fat diet. Consuming a high-fat diet results in changes in the brain that increase Rap1 activity, which in turn leads to a decreased sensitivity to leptin, and this sets the body on a path to obesity.
“This new mechanism involving Rap1 in the brain may represent a potential therapeutic target for treating human obesity in the future,” said Fukuda.

Baylor College of Medicine www.bcm.edu/news/nutrition/rap1-potential-new-target-to-treat-obesity

Researchers have identified two new genetic risk factors for Alzheimer’s disease (AD) among African Americans.  The findings may lead to the development of new therapies specifically targeting those genes.

Despite the fact that AD is more common in African Americans than Caucasians, the AD genetic risk profile for African Americans is more poorly understood. While more than 20 genes have been identified as risk factors for AD in Caucasians, fewer than five have been identified for African Americans.

In 2013, a genome-wide association study of AD in more than 5,500 African Americans identified two genetic risk factors for AD. This study looked at genetic variants across subjects’ entire genome and compared their frequency in cases versus controls. Researchers from Boston University School of Medicine (BUSM) used these same subjects, but added additional AD risk information (smoking status, diabetes status, education level) to their statistical modelling to increase the power of the study. By doing so they were able to identify two new genes (COBL and SLC10A2) associated with risk of AD in African Americans.

Mez_Jesse-432×636-2“There are currently no medications for AD that slow or stop the progression of the disease. Genes that increase risk for AD are potential targets for new disease-modifying AD drug therapies. Our study identifies two potentially “drugable” targets,” explains corresponding author Jesse Mez, MD, MS, assistant professor of neurology  and associate director of the BU Alzheimer’s Disease & CTE Center Clinical Core.

According to the researchers the methodology they employed for this study allowed them to make an important discovery without investing more money in genotyping or more effort to recruit volunteers. They believe that a similar methodology could be used for many other diseases to make new genetic discoveries without new large investments.

“Despite the fact that Alzheimer’s disease is more common in African Americans than Caucasians, we understand less about the genes that influence risk of Alzheimer’s in African Americans. Our hope is that this study begins to eliminate that disparity and that ultimately these newly identified genes become targets for Alzheimer’s disease drug development,” added Mez.

Boston University Medical Center www.bumc.bu.edu/busm/2016/10/25/new-genes-responsible-for-alzheimers-among-african-americans-identified/

Researchers at the University at Buffalo Research Institute on Addictions have discovered how a gene in the brain’s dopamine system can play an important role in prolonging lifespan: it must be coupled with a healthy environment that includes exercise.

The study was led by Panayotis (Peter) K. Thanos, senior research scientist at RIA.

Thanos and his team studied the genes in dopamine to assess their impact on lifespan and behaviour in mice. Dopamine is a neurotransmitter that helps control the brain’s reward and pleasure centres and helps regulate physical mobility and emotional response.

The researchers found that the dopamine D2 receptor gene (D2R) significantly influences lifespan, body weight and locomotor activity, but only when combined with an enriched environment that included social interaction, sensory and cognitive stimulation and, most critically, exercise.

“The incorporation of exercise is an important component of an enriched environment and its benefits have been shown to be a powerful mediator of brain function and behaviour,” Thanos says.

The mice in the enriched environment lived anywhere from 16 to 22 percent longer than those in a deprived environment, depending on the level of D2R expression.

“These results provide the first evidence of D2R gene-environment interaction playing an important role in longevity and aging,” Thanos says. “The dichotomy over genes versus environment has provided a rigorous and long debate in deciphering individual differences in longevity. In truth, there exists a complex interaction between the two which contribute to the differences.”

Research exploring this genetic-environmental interaction should lead to a better understanding and prediction of the potential benefits of specific environments, such as those including exercise, on longevity and health during aging.

University at Buffalo Research Institute on Addictions www.buffalo.edu/ria/news_events/latest_news.host.html/content/shared/university/news/news-center-releases/2016/04/056.detail.html

Scientists at The University of Nottingham have demonstrated for the first time that it is possible to selectively sequence fragments of DNA in real time, greatly reducing the time needed to analyse biological samples.

A paper describes a novel technique for highly selective DNA sequencing, called ‘Read Until’.  The method, used with real-time nanopore sequencing, enables the user to analyse only DNA strands that contain pre-determined signatures of interest.

Dr Matt Loose, of the Cell and Developmental Biology Research Group in the University’s School of Life Sciences, has been working with the MinION, a new portable DNA sequencing technology produced by biotech company Oxford Nanopore Technologies. All sequencing was carried out at The University of Nottingham Next Generation Sequencing Facility, DeepSeq.

“This is the first time that direct selection of specific DNA molecules has been shown on any device,” said Dr Loose. “We hope that it will enable many future novel applications, especially for portable sequencing. This makes sequencing as efficient as possible and will provide a viable, informatics based alternative to traditional wet lab enrichment techniques. The application of this approach to a wide number of problems from pathogen detection to sequencing targeted regions of the human genome is now within reach.”

The pocket-sized MinION device – the same technology which NASA recently sent to the International Space Station in an effort to investigate whether DNA sequencing is possible in microgravity – employs tiny molecular pores in a membrane that ‘sense’ the sequence of DNA fragments passing through these nanopores, producing minute fluctuations in a current trace. These current traces, termed ‘squiggles’ then need to be converted to DNA bases using base caller software, often located in the cloud. The University of Nottingham team used signal processing techniques to map these squiggles to reference sequences, by passing this step.

In the paper, the Nottingham team go further, showing that this squiggle matching technique can be performed at a rate that enables decisions to be made about the fragment of DNA that is being sequenced before it has completely passed through the nanopore. Depending on the sequence, individual nanopores within the MinION can then be instructed to continue sequencing or to eject the current DNA fragment and start sequencing another. The Nottingham team show that this ‘real-time selective sequencing’, or as some have called it ‘DNA tasting’, can reduce the time needed to sequence key DNA fragments or enable the analysis of pathogen samples where there is host and other DNA present in the sample.

The Read Until method/technique was developed by applying dynamic time warping to match short query current traces to references, demonstrating selection of specific regions of small genomes, individual amplicons from a group of targets, or normalisation of amplicons in a set.

Nottingham University www.nottingham.ac.uk/news/pressreleases/2016/july/nottingham-researchers-show-novel-technique-that-can-‘taste’-dna.aspx

Researchers have identified a new pathway and with it a protein, BRD4, necessary for breast cancer cells to spread.

The findings may provide a new target to suppress breast cancer metastasis.

Triple-negative breast cancer is considered the worst subgroup of breast cancer. It is highly aggressive and responds poorly to the current therapeutic tools resulting in a dismal prognosis for patients. Furthermore, the lack of identified targets has limited the development of new drug strategies.

Researchers from Boston University School of Medicine (BUSM) used breast cancer cell lines that present the clinical characteristics of an aggressive breast cancer subtype (clinically described as a triple-negative breast cancer). They then used an experimental design to model cancer cell metastasis. By suppressing the expression of the protein BRD4 in these cell lines, they observed that their dissemination capabilities were blocked, indicating that BRD4 drives breast cancer dissemination. In addition, they conducted a screening analysis of human breast tumours and found that tumours with a high expression of BRD4 were more likely to metastasize.

“The current treatment options for a triple-negative cancer are unacceptably limited. It is crucial to identify new therapeutic targets to tackle challenging cancer types, including triple negative breast cancer. BDR4 targeting represents an innovative strategy to ablate breast cancer metastasis,” explained lead investigator Guillaume Andrieu, PhD, a post-doctoral research associate at Boston University School of Medicine.

Although obesity per se is not thought of as a carcinogen, the abnormal, inflamed microenvironments found in obesity are critical for progression, invasion and metastasis of triple negative breast cancer. “Bromodomain and ExtraTerminal domain (BET) proteins, which include BRD2, BRD3 and BRD4, are known to regulate production of inflammatory mediators. Our study proposes that BRD4 couples inflammation to breast cancer dissemination. Thus, small molecules that block BET proteins possess anti-inflammatory properties that can be useful for therapy,” he added.

Although these findings primarily focus on breast cancer and metastasis, the researchers plan to expand their results to the treatment of prostate cancer, which they believe has similar pathways involved in its metastasis.

Boston University Medial Center www.bu.edu/news/2016/11/15/researchers-identify-protein-required-for-breast-cancer-metastasis/