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Brain receptor regulates fat burning in cells

Decreasing levels of the neurotrophin p75 receptor prevented obesity and metabolic disease in mice who were fed a high-fat diet.

Scientists at the Gladstone Institutes — an independent and nonprofit biomedical research organization affiliated with the University of California at San Francisco — have discovered an unusual regulator of body weight. Interestingly, it was found in a mechanism commonly associated with brain cells.

After lowering levels of p75 a NeuroTrophin Receptor (NTR) involved in neuron growth and survival, it was found mice being fed a high-fat diet were protected from developing obesity, diabetes, and fatty liver disease. In addition to its role in the brain, p75 NTR is also in the liver and fat cells and elsewhere throughout the body.

Previous research has implicated p75 NTR in liver disease and insulin resistance, both consequences of metabolic syndrome and obesity. In the current study, published in Cell Reports, the relationship between p75 NTR and a high fat diet was examined more deeply, which is when scientists discovered it helped regulate metabolic processes controlling weight.
Reducing the level of p75 NTR in fat cells prevented weight gain in mice.

"We've identified a novel molecular mechanism that regulates energy expenditure and may help prevent obesity and the metabolic syndrome," says lead author Bernat Baez-Raja, PhD, a research scientist in the Gladstone Institute of Neurological Disease. "The complete protection from obesity and metabolic dysfunction in the study animals, without any differences in appetite or physical activity, suggests that p75 NTR is a key regulator of fat burning."

Researchers experimentally removed p75 NTR from mice — and then fed them a high-fat diet. Remarkably, the mice resisted weight gain and remained healthy and lean after several weeks on the rich diet. On the opposite spectrum, normal or "wildtype (WT)" mice fed the same diet became obese, had larger fat cells, higher insulin levels, and developed signs of fatty liver disease — even though there was no difference between the diet of wildtype and p75 NTR-depleted mice, overall energy consumption, or physical activity. Rather, experimental mice had significantly greater energy expenditure than the wildtype mice, most likely because they burned more fat.

"The robustness of the effect is quite remarkable. Since neurotrophins and their receptors control communication between the brain and peripheral organs, they could become new therapeutic targets in both metabolic and neurologic diseases."

Katerina Akassoglou PhD, senior investigator at Gladstone and Professor of Neurology, University of California, San Francisco.

In a final set of experiments, investigators found that in particular p75 NTR's role in fat cells contributed significantly to regulating body weight. Deleting p75 NTR only from fat cells produced similar outcomes as deleting those same receptors from all cell types. What's more, transplanting fat cells from experimental mice into wildtype mice protected the wildtype mice from developing obesity.

The next step is to develop small molecules or drugs to regulate p75 NTR in order to reproduce this effect and potentially serve as an intervention for obesity and metabolic syndrome.

Abstract Highlights
•p75NTR-null mice are protected from diet-induced obesity
•p75NTR regulates energy expenditure and fat oxidation
•p75NTR inhibits the dissociation of the PKA holoenzyme and suppresses cAMP
•Adipocyte-specific p75NTR knockout protects mice from diet-induced obesity

Obesity and metabolic syndrome reflect the dysregulation of molecular pathways that control energy homeostasis. Here, we show that the p75 neurotrophin receptor (p75NTR) controls energy expenditure in obese mice on a high-fat diet (HFD). Despite no changes in food intake, p75NTR-null mice were protected from HFD-induced obesity and remained lean as a result of increased energy expenditure without developing insulin resistance or liver steatosis. p75NTR directly interacts with the catalytic subunit of protein kinase A (PKA) and regulates cAMP signaling in adipocytes, leading to decreased lipolysis and thermogenesis. Adipocyte-specific depletion of p75NTR or transplantation of p75NTR-null white adipose tissue (WAT) into wild-type mice fed a HFD protected against weight gain and insulin resistance. Our results reveal that signaling from p75NTR to cAMP/PKA regulates energy balance and suggest that non-CNS neurotrophin receptor signaling could be a target for treating obesity and the metabolic syndrome.

Other Gladstone scientists on the study were Eirini Vagena, Dimitrios Davalos, Natacha Le Moan, Jae Kyu Ryu, and Justin Chan. Researchers from the University of California, San Diego, the University of Glasgow, and King's College London also took part in the research. Funding was provided by the National Institute of Neurological Disorders and Stroke, the UCSF Liver Center, the UCSF Diabetes and Endocrinology Center, the Spanish Research Foundation, and the Medical Research Council.

About the Gladstone Institutes
To ensure our work does the greatest good, the Gladstone Institutes focuses on conditions with profound medical, economic, and social impact--unsolved diseases of the brain, the heart, and the immune system. Affiliated with the University of California, San Francisco, Gladstone is an independent, nonprofit life science research organization that uses visionary science and technology to overcome disease.

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Lowering the level of p75 — a NeuroTrophin Receptor (NTR) involved in neuron growth
and survival — was found to protect mice fed a high-fat diet from becoming obese.
WT stands for "Wild Type" mice.
Image Credit: Nature Neuroscience Reviews




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