MRI reveals brain damage in obese teens

November 25, 2019

Science Daily/Radiological Society of North America

Researchers using MRI have found signs of damage that may be related to inflammation in the brains of obese adolescents, according to a study being presented next week at the annual meeting of the Radiological Society of North America (RSNA).

Obesity in young people has become a significant public health problem. In the U.S., the percentage of children and adolescents affected by obesity has more than tripled since the 1970s, according to the Centers for Disease Control and Prevention. Data from the World Health Organization indicates that the number of overweight or obese infants and young children ages five years or younger increased from 32 million globally in 1990 to 41 million in 2016.

While obesity is primarily associated with weight gain, recent evidence suggests that the disease triggers inflammation in the nervous system that could damage important regions of the brain. Developments in MRI like diffusion tensor imaging (DTI), a technique that tracks the diffusion of water along the brain's signal-carrying white matter tracts, have enabled researchers to study this damage directly.

For the new study, researchers compared DTI results in 59 obese adolescents and 61 healthy adolescents, ages 12 to 16 years. From DTI, the researchers derived a measure called fractional anisotropy (FA), which correlates with the condition of the brain's white matter. A reduction in FA is indicative of increasing damage in the white matter.

The results showed a reduction of FA values in the obese adolescents in regions located in the corpus callosum, a bundle of nerve fibers that connects the left and right hemispheres of the brain. Decrease of FA was also found in the middle orbitofrontal gyrus, a brain region related to emotional control and the reward circuit. None of the brain regions in obese patients had increased FA.

"Brain changes found in obese adolescents related to important regions responsible for control of appetite, emotions and cognitive functions," said study co-author Pamela Bertolazzi, a biomedical scientist and Ph.D. student from the University of São Paulo in Brazil.

This pattern of damage correlated with some inflammatory markers like leptin, a hormone made by fat cells that helps regulate energy levels and fat stores. In some obese people, the brain does not respond to leptin, causing them to keep eating despite adequate or excessive fat stores. This condition, known as leptin resistance, makes the fat cells produce even more leptin.

Worsening condition of the white matter was also associated with levels of insulin, a hormone produced in the pancreas that helps regulate blood sugar levels. Obese people often suffer from insulin resistance, a state in which the body is resistant to the effects of the hormone.

"Our maps showed a positive correlation between brain changes and hormones such as leptin and insulin," Dr. Bertolazzi said. "Furthermore, we found a positive association with inflammatory markers, which leads us to believe in a process of neuroinflammation besides insulin and leptin resistance."

Dr. Bertolazzi noted that additional studies are needed to determine if this inflammation in young people with obesity is a consequence of the structural changes in the brain.

"In the future, we would like to repeat brain MRI in these adolescents after multi-professional treatment for weight loss to assess if the brain changes are reversible or not," she added.

https://www.sciencedaily.com/releases/2019/11/191125100405.htm

Gut-brain connection helps explain how overeating leads to obesity

August 12, 2019

Science Daily/Baylor College of Medicine

A multi-institutional team reveals a previously unknown gut-brain connection that helps explain how those extra servings lead to weight gain.

Eating extra servings typically shows up on the scale later, but how this happens has not been clear. A new study published today in the Journal of Clinical Investigation by a multi-institutional team led by researchers at Baylor College of Medicine reveals a previously unknown gut-brain connection that helps explain how those extra servings lead to weight gain.

Mice consuming a high-fat diet show increased levels of gastric inhibitory polypeptide (GIP), a hormone produced in the gut that is involved in managing the body's energy balance. The study reports that the excess GIP travels through the blood to the brain where it inhibits the action of leptin, the satiety hormone; consequently, the animals continue eating and gain weight. Blocking the interaction of GIP with the brain restores leptin's ability to inhibit appetite and results in weight loss in mice.

"We have uncovered a new piece of the complex puzzle of how the body manages energy balance and affects weight," said corresponding author Dr. Makoto Fukuda, assistant professor of pediatrics at Baylor and the USDA/ARS Children's Nutrition Research Center at Baylor and Texas Children's Hospital.

Researchers know that leptin, a hormone produced by fat cells, is important in the control of body weight both in humans and mice. Leptin works by triggering in the brain the sensation of feeling full when we have eaten enough, and we stop eating. However, in obesity resulting from consuming a high-fat diet or overeating, the body stops responding to leptin signals -- it does not feel full, and eating continues, leading to weight gain.

"We didn't know how a high-fat diet or overeating leads to leptin resistance," Fukuda said. "My colleagues and I started looking for what causes leptin resistance in the brain when we eat fatty foods. Using cultured brain slices in petri dishes we screened blood circulating factors for their ability to stop leptin actions. After several years of efforts, we discovered a connection between the gut hormone GIP and leptin."

GIP is one of the incretin hormones produced in the gut in response to eating and known for their ability to influence the body's energy management. To determine whether GIP was involved in leptin resistance, Fukuda and his colleagues first confirmed that the GIP receptor, the molecule on cells that binds to GIP and mediates its effects, is expressed in the brain.

Then the researchers evaluated the effect blocking the GIP receptor would have on obesity by infusing directly into the brain a monoclonal antibody developed by Dr. Peter Ravn at AstraZeneca that effectively prevents the GIP-GIP receptor interaction. This significantly reduced the body weight of high-fat-diet-fed obese mice.

"The animals ate less and also reduced their fat mass and blood glucose levels," Fukuda said. "In contrast, normal chow-fed lean mice treated with the monoclonal antibody that blocks GIP-GIP receptor interaction neither reduced their food intake nor lost body weight or fat mass, indicating that the effects are specific to diet-induced obesity."

Further experiments showed that if the animals were genetically engineered to be leptin deficient, then the treatment with the specific monoclonal antibody did not reduce appetite and weight in obese mice, indicating that GIP in the brain acts through leptin signaling. In addition, the researchers identified intracellular mechanisms involved in GIP-mediated modulation of leptin activity.

"In summary, when eating a balanced diet, GIP levels do not increase and leptin works as expected, triggering in the brain the feeling of being full when the animal has eaten enough and the mice stop eating," Fukuda said. "But, when the animals eat a high-fat diet and become obese, the levels of blood GIP increase. GIP flows into the hypothalamus where it inhibits leptin's action. Consequently, the animals do not feel full, overeat and gain weight. Blocking the interaction of GIP with the hypothalamus of obese mice restores leptin's ability to inhibit appetite and reduces body weight."

These data indicate that GIP and its receptor in the hypothalamus, a brain area that regulates appetite, are necessary and sufficient to elicit leptin resistance. This is a previously unrecognized role of GIP on obesity that plays directly into the brain.

Although more research is needed, the researchers speculate that these findings might one day be translated into weight loss strategies that restore the brain's ability to respond to leptin by inhibiting the anti-leptin effect of GIP.

https://www.sciencedaily.com/releases/2019/08/190812160533.htm