Blocking hormone uptake burns more fat

A newly discovered regulatory mechanism helps the body control the rate of fat metabolism, according to a new study publishing on January 17 in the open-access journal PLOS Biology by Ligong Chen of Tsinghua University in Beijing and colleagues. The finding may lead to new drugs to help burn stored fat and reduce weight.

Fat tissue can be white, brown, or beige, differing not only in color but also in metabolism. White fat is principally a storage tissue, with a low rate of metabolism; brown fat tissue, on the other hand, is rich in mitochondria, and burns up stored fat, releasing heat to warm the body, a process called thermogenesis. After prolonged cold exposure, brown-like fat cells develop within white fat, making it beige, and beige fat cells also burn fat to keep the body warm.

A key stimulus for thermogenesis is the hormone norepinephrine, which exerts its effects at the cell surface, and is then taken up into the cell and degraded to prevent overstimulation. A mechanism for the uptake of norepinephrine from fat cells has previously been described, but its rate of uptake is relatively low, suggesting there may be another pathway.

In the new study, the authors found that beige fat cells in mice have high levels of a protein called organic cation transporter 3 (Oct3), which can import norepinephrine into the cells for degradation. The authors showed that reducing the level of Oct3, and thus slowing norepinephrine degradation, led to a higher rate of fat metabolism in beige fat and a higher body temperature. When exposed to prolonged cold, mice deficient in Oct3 increased beige fat content faster than their littermate controls, accompanied by increased activity of thermogenic and mitochondrial biogenic genes.

Gratifyingly, when they looked at human genetic association databases, the authors found that possessing versions of the OCT3 gene that make OCT3 protein with a reduced transport function was associated with a higher metabolic rate. Together, these results indicate that OCT3 plays an important role in regulating the rate of beige fat production and thermogenesis in both mice and humans.

“Our finding that a reduction in OCT3 activity can lead to more beige fat and increased thermogenesis indicating the importance of this transporter in catecholamine recycling in adipose tissues.,” Chen said. “Developing specific OCT3 inhibitors would open up new therapeutic possibilities for metabolic diseases.”

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Story Source:

Materials provided by PLOS. Note: Content may be edited for style and length.

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Journal Reference:

1. Wenxin Song, Qi Luo, Yuping Zhang, Linkang Zhou, Ye Liu, Zhilong Ma, Jianan Guo, Yuedong Huang, Lili Cheng, Ziyi Meng, Zicheng Li, Bin Zhang, Siqi Li, Sook Wah Yee, Hao Fan, Peng Li, Kathleen M. Giacomini, Ligong Chen. Organic cation transporter 3 (Oct3) is a distinct catecholamines clearance route in adipocytes mediating the beiging of white adipose tissue. PLOS Biology, 2019; 17 (1): e2006571 DOI: 10.1371/journal.pbio.2006571

https://www.sciencedaily.com/releases/2019/01/190117142127.htm

Gene therapy may block peripheral nerve damage

Nerve axons serve as the wiring of the nervous system, sending electrical signals that control movement and sense of touch. When axons are damaged, whether by injury or as a side effect of certain drugs, a program is triggered that leads axons to self-destruct. This destruction likely plays an important role in multiple neurodegenerative conditions, including peripheral neuropathy, Parkinson’s disease and amyotrophic lateral sclerosis (ALS).

Now, scientists have developed a gene therapy that blocks this process, preventing axon destruction in mice and suggesting a therapeutic strategy that could help prevent the loss of peripheral nerves in multiple conditions.

The study, from Washington University School of Medicine in St. Louis, appears in the Journal of Experimental Medicine.

The strategy could help prevent peripheral neuropathy, a disease that currently affects about 20 million people in the United States. Peripheral neuropathy can result from chemotherapy for cancer treatment or poorly controlled diabetes, and it causes persistent pain, numbness, burning, itching and muscle weakness.

“Peripheral neuropathies are the most common neurodegenerative diseases in the world,” said first author Stefanie Geisler, MD, an assistant professor of neurology. “Many peripheral neuropathies are caused by breakdown of nerve fibers, but we currently don’t have therapies that can directly block this process. For many neuropathies, we can’t halt progression of the disease and are limited to trying to treat the symptoms. We are somewhat successful decreasing neuropathic pain, but it is very difficult to alleviate numbness.

“I see many patients with chemotherapy-induced neuropathy, and it can severely impact their quality of life,” she said. “To benefit patients, we will need to test this treatment in human clinical trials, but our current finding is significant because we have shown for the first time that we can effectively block nerve fiber breakdown in mice with a standard viral gene therapy.”

When an axon is injured, whether cut or crushed by injury or damaged by drugs, a protein called SARM1 becomes active. In healthy nerves, this protein is switched off. Past studies by this research team have shown that activated SARM1 triggers axons to self-destruct, kicking off a chain of events that quickly consumes all of a nerve cell’s energy supply. The axons of such cells break into pieces.

In this study, scientists used a virus — one that can’t cause disease — to deliver into cells a mutated version of the SARM1 protein that blocks axon destruction.

This mutated SARM1 prevents the characteristic rapid energy loss and subsequent destruction of axons, even in the most extreme form of injury — a complete severing of the axon.

“With our viral gene therapy, we delivered a mutated form of SARM1 that is not only inactive itself but also blocks normal SARM1 proteins that have become activated in mice with nerve injuries,” said senior author Jeffrey D. Milbrandt, MD, PhD, the James S. McDonnell Professor and head of the Department of Genetics. “For a long time, viral gene therapy was a pipe dream, but there are now a number of ongoing clinical trials in other disorders that suggest we are on a promising track.”

For example, a similar viral gene therapy is now in clinical trials for a genetic disorder called Duchenne muscular dystrophy. In that case, a different protein is delivered to address muscle loss, but the virus is the same.

In theory, it could be possible to change the viral packaging to direct the viruses to deliver their gene payload to different types of cells — sensory neurons for peripheral neuropathy or motor neurons for ALS, for example.

“This has the potential to be transformative because it cuts across so many diseases,” said co-senior author Aaron DiAntonio, MD, PhD, the Alan A. and Edith L. Wolff Professor of Developmental Biology. “Rather than addressing a single disease, it is potentially a treatment for a disease process that is shared among many different neurodegenerative disorders.”

In addition to this viral gene therapy, the researchers are studying other possible ways to block SARM1, including small molecules for drug development.

This work was supported by the National Institutes of Health (NIH), grant numbers K08NS091448, R01CA219866, R01NS087632 and R01CA218263; the Muscular Dystrophy Association, grant number MDA344513; the Thompson Family Foundation Initiative; and the Hope Center Viral Vector Core at Washington University School of Medicine in St. Louis.

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Story Source:

Materials provided by Washington University School of Medicine. Original written by Julia Evangelou Strait. Note: Content may be edited for style and length.

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Journal Reference:

1. Stefanie Geisler, Shay X. Huang, Amy Strickland, Ryan A. Doan, Daniel W. Summers, Xianrong Mao, Jiwoong Park, Aaron DiAntonio, Jeffrey Milbrandt. Gene therapy targeting SARM1 blocks pathological axon degeneration in mice. The Journal of Experimental Medicine, 2019; jem.20181040 DOI: 10.1084/jem.20181040

https://www.sciencedaily.com/releases/2019/01/190117142144.htm

Engineered light to improve health, food

People who believe light-emitting diodes, or LEDS, are just an efficient upgrade to the ordinary electric light bulb are stuck in their thinking, suggest Sandia National Laboratories researcher Jeff Tsao and colleagues from other institutions in a Nature“Perspectives” article published in late November.

“LED lighting is only in its infancy,” the authors write. “We now stand at the threshold of what might be called engineered light.”

Light intentionally controlled in time, space and spectral content can reward not just human optics with better lighting but also can help regulate human health and productivity by eliciting various hormonal responses.

Moreover, with plants, the authors write, tailored LED wavelengths and intensities can efficiently stimulate their growth, alter their shapes and increase their nutritional value, opening a new world of scientific and technological possibilities for indoor farming.

“That’s not to ignore the integration of LEDs with the internet of things,” Tsao said, “which is already happening with LED integration with electronics, sensors and communications.” The so-called internet of things refers to electronic circuits that can communicate with each other while embedded in a variety of everyday devices.

In short, the inevitable broadening of LED usage could add value to society far greater than the energy saved in lighting homes and buildings, the authors write.

The research was supported by the Department of Energy’s Solid State Lighting Program.

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Story Source:

Materials provided by DOE/Sandia National Laboratories. Note: Content may be edited for style and length.

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Journal Reference:

1. P. M. Pattison, J. Y. Tsao, G. C. Brainard, B. Bugbee. LEDs for photons, physiology and food. Nature, 2018; 563 (7732): 493 DOI: 10.1038/s41586-018-0706-x

https://www.sciencedaily.com/releases/2019/01/190116115527.htm

Proteus launches its first digital cancer chemotherapy pill

Smart-pill maker Proteus Digital Health has launched an oral chemotherapy equipped with its ingestible sensor, which aims to help oncologists track treatment effectiveness and adherence in their cancer patients.

The digital pill is first being offered as part of a collaboration between the former Fierce 15 winner, the University of Minnesota health system and Fairview Health Services, a nonprofit network of Minnesota clinics.

They will be prescribing digital capecitabine to treat patients with stages 3 and 4 colorectal cancer, with the opportunity to better intervene if patients are not taking their medication correctly or miss a dose. The pill’s embedded sensor activates in stomach acid and sends an electronic signal before being dissolved.

“Proteus’ digital medicine technology provides a more direct connection to the patient,” said Edward Greeno, who directs the University of Minnesota Health oncology service line.

“It creates a way for us to achieve a lot of things that happen when a patient is in the clinic for infusions without them coming in person,” Greeno said in a statement. “Also, we can gain insights about the patient that we can’t learn from an office visit, like how the patient is doing with their treatment regimen while at home, on a daily basis.”

According to Proteus, the digital medicine program can help optimize oral regimens by recording the time, dose and type of chemotherapy taken, and merge with data on rest, activity and resting heart rate. The information can also be shared with pharmacists or caretakers through Proteus’ secure mobile platform.

“Currently, providers make decisions about oral chemotherapy based on patients’ best knowledge of their medication taking,” said Andrew Thompson, Proteus CEO and co-founder. “For the first time, digital oncology medicines give providers and caregivers new insights and ability to engage with more specific information in the remote care of colorectal cancer patients.”

“Based on our data around the use of digital medicines in other treatment areas, we believe this will enable oncology patients to stay on their therapy longer, avoid hospital admissions, and have better response to therapy overall,” Thompson added. Proteus also plans to launch a digital medication registry study, gathering real-world experience data from multiple sites to share best practices for oral chemotherapies.

https://www.fiercebiotech.com/medtech/proteus-launches-its-first-digital-cancer-chemotherapy-pill

Apple, J&J to put the Apple Watch’s ECG through large-scale clinical test

Apple and Johnson & Johnson are teaming up on a multi-year research study to see if the latest Apple Watch can help catch and diagnose elderly people with atrial fibrillation earlier and faster than before.

The watch, with its ECG function and irregular heartbeat notifications that went live last month, will be paired with a patient engagement app developed by J&J, to gauge its potential for improving cardiovascular outcomes and preventing strokes.

The two companies plan to launch the large-scale project in the U.S. later this year, with a controlled, randomized study enrolling participants age 65 and older. The study will also assess the impacts of a medication adherence program, through J&J’s Janssen Pharmaceuticals arm.

“We’re excited about the potential of common, wearable technology to aid in the earlier detection and prevention of a frequent cause of stroke,” said J&J’s chief scientific officer, Paul Stoffels.

“Too many people living with AFib are unaware of their risk, and earlier detection, diagnosis and treatment of AFib could significantly improve outcomes,” Stoffels said. “Based on the insights generated through this research program, we may be able to develop new ways to detect other health conditions earlier in the future that also exhibit measurable physiological symptoms.”

According to J&J, 33 million people worldwide have atrial fibrillation, which is responsible for about 130,000 deaths and 750,000 hospitalizations annually.

“Utilizing wristwatch-based optical heart sensor and ECG monitoring is a logical evolution of this research and may also lead to increased AFib diagnosis and improved clinical outcomes for patients,” said Paul Burton, Janssen’s vice president of medical affairs.

Earlier this week, a report from CNBC described how Apple has had talks with at least three private Medicare plans, including some of the market’s largest insurance companies, about subsidizing the cost of the Apple Watch for people over age 65.

With the latest version’s ECG and fall monitoring hardware, the device appears to be designed as useful health tracker for seniors, and not just for tech-focused adopters.

In addition, Apple CEO Tim Cook told CNBC’s Jim Cramer this week that the company plans to announce new additions to its services in 2019.

“I believe, if you zoom out into the future, and you look back, and you ask the question, ‘What was Apple’s greatest contribution to mankind?’ it will be about health,” Cook said on Mad Money, but did not offer further details. “We are taking what has been with the institution and empowering the individual to manage their health. And we’re just at the front end of this.”

https://www.fiercebiotech.com/medtech/apple-j-j-to-put-apple-watch-s-ecg-through-large-scale-clinical-testing

Viking Therapeutics Regains Ground After Bearish Citron Report

Viking Therapeutics, Inc. (VKTX) shares rose more than 4% on Thursday after analysts defended the company against a bearish report from Citron Research. Earlier this week, Citron published a negative report on licensor Ligand Pharmaceuticals Incorporated (LGND), saying that Viking Therapeutics accounts for over half of Ligand’s milestones. Despite the significant portion of its valuation attributable to Viking, Ligand has been repurchasing its own stock and selling its Viking Therapeutics holdings. Citron also pointed out that Viking Therapeutics insiders have been net sellers over the past year.

Raymond James analysts called the report “ridiculous” and maintained its Outperform rating and price target of $43.00 per share on Viking Therapeutics, which represents a massive premium to the current market price. At the same time, STAT’s Adam Feuerstein tweeted that Citron’s short thesis relies on Viking “blowing up,” adding that if Viking pans out, short sellers would be “toast.”

StockCharts.com 

From a technical standpoint, the stock is trading down more than 65% from its 52-week highs made back in mid-September. The stock bottomed out at its then-S2 support level in mid-December before rebounding to a pivot point near $8.76. The relative strength index (RSI) remains somewhat oversold at 45.74, while the moving average convergence divergence (MACD) remains in a bullish uptrend. These indicators suggest that the stock could have more room to run higher.

Traders should watch for a breakout toward upper trendline and 200-day moving average resistance near $10.00. If the stock breaks out from these levels, traders could see a move higher toward R2 resistance at $13.45 over the coming weeks. If the stock breaks down from trendline support, traders could see a move to fresh lows near S1 support at $5.86. Traders will be keeping an eye on VK2809 and other clinical programs as well as potential acquisition possibilities.

https://www.investopedia.com/viking-therapeutics-stock-regains-ground-4584185?utm_campaign=quote-yahoo&utm_source=yahoo&utm_medium=referral&yptr=yahoo

Activity Tied to Cognition, Despite Brain Pathologies

Higher levels of physical activity and motor abilities were independently associated with better cognition in older adults, even when brain lesions or biomarkers linked to dementia were present, a post-mortem study showed.

The study also showed no evidence that a more active lifestyle or better motor abilities modified associations between dementia pathologies and cognitive function, suggesting the cognitive reserve associated with activity may be unrelated to them, Aron Buchman, MD, of the Rush University Medical Center in Chicago, and colleagues wrote in Neurology.

“Physical activity may provide cognitive reserve to maintain function independent of accumulating brain pathologies,” Buchman told MedPage Today.

“Similar findings have been reported for late-life cognitive activities,” he added. “Together, these suggest that even in the absence of treatment for Alzheimer’s disease and related disorders, a more active lifestyle including physical and cognitive activities may help maintain cognition in older adults.”

Numerous observational studies have supported an association between physical exercise and reduced cognitive decline, but the mechanisms remain unknown, noted James Mortimer, PhD, of the University of South Florida in Tampa, and Yaakov Stern, PhD, of Columbia University in New York, in an accompanying editorial.

“The results of randomized trials of physical exercise suggest that exercise leads to increases in brain tissue, including in the hippocampus, where atrophy is an early and important finding in Alzheimer’s disease,” they wrote. One trial showed aerobic exercise led to increased levels of brain-derived neurotrophic factor (BDNF) and increased hippocampal volume; other studies suggested higher BDNF gene expression may help slow cognitive decline. “Alternatively, physical exercise itself might reduce brain pathology,” Mortimer and Stern added: mouse models have shown that higher physical activity levels reduce Alzheimer’s pathology accumulation.

The study drew on data from the Rush Memory and Aging Project, a community-based cohort of older adults who agreed to annual detailed clinical examination and brain donation at the time of death. The analysis included 454 participants with an average age at death of 91; 73% were female. A total of 191 participants had been diagnosed with dementia and 263 with no dementia.

The researchers incorporated 10 supervised motor performance tests to determine a global motor ability score and relied on continuous multi-day accelerometer recordings to monitor physical activity. Activity results were collected about 2 years before death and were measured in counts/day. The overall average was 156,000 counts/day, with participants without dementia averaging 180,000 counts/day, and people with dementia averaging 130,000 counts/day.

At autopsy, the researchers assessed brain tissue for:

• Alzheimer’s disease pathology (neuritic plaques, diffuse plaques, and neurofibrillary tangles)
• Nigral neuronal loss
• Lewy body disease pathology
• TAR DNA-binding protein 43
• Hippocampal sclerosis
• Macroscopic cerebral infarcts
• Cerebral atherosclerosis
• Microscopic cerebral infarcts
• Cerebral arteriolosclerosis
• Cerebral amyloid angiopathy

On average, participants had three different brain pathologies, with one or more pathologies observed in nearly all cases.

Buchman and colleagues performed regression analyses to “examine whether motor abilities or the quantity of daily physical activity attenuates the association of indices of AD pathology with the level of cognitive function proximate to death,” they wrote. Higher levels of total daily activity (estimate 0.148 ± 0.049, 95% CI 0.053–0.0.244, P=0.003) and better motor abilities (estimate 0.283 ± 0.055, 95% CI 0.175–0.390, P<0.001) both were independently associated with better global cognition proximate to death. These independent associations remained significant when interaction terms for Alzheimer’s disease and other pathologies were added.

Each standard deviation increase of total daily activity or motor capacity was associated with a reduction of dementia risk (total daily activity 31%; motor abilities 55%). These associations were additive, as the association of total daily physical activity with cognition did not vary with motor abilities.

“These data provide support for the idea that strategies or behaviors that lead to a more active lifestyle and better motor abilities may provide cognitive reserve, which may maintain cognitive function in older adults despite the accumulation of Alzheimer’s disease and other common brain pathologies,” the researchers wrote. “Further work is needed to clarify to what extent the risk factors and the types and duration of interventions to increase total daily physical activity and motor abilities are distinct and can be disentangled.”

The authors noted several limitations to their research: the data were cross-sectional and causal inferences cannot be drawn. It’s possible some of the association resulted from reverse causality (that lower cognitive function led to less activity). Accelerometers used in the study did not differentiate between various physical activities (such as steps vs arm movements) And the researchers assessed activity only at one point later in life; whether physical activity in early life may have played a role is unknown.

The study was supported by the National Institutes of Health, the Illinois Department of Public Health, and the Robert C. Borwell Endowment Fund.

Buchman reported no disclosures relevant to the manuscript. Other researchers reported relationships with Grifols, Lilly, Genentech, the Michael J. Fox Foundation, and the National Hockey League.

The editorialists reported no relationships.

• Primary Source

  Neurology

  Source Reference: Buchman A, et al “Physical activity, common brain pathologies, and cognition in community-dwelling older adults” Neurology 2019; DOI: 10.1212/WNL.0000000000006954.

• Secondary Source

  Neurology

  Source Reference: Mortimer J, Stern Y “Physical exercise and activity may be important in reducing dementia risk at any age” Neurology 2019; DOI: 10.1212/WNL.0000000000006935.

https://www.medpagetoday.com/neurology/dementia/77478