Researchers have identified a peptide and hormone that when administered to a specific area of the brain may reduce the desire for food. The study, which appears in the journal Neuropsychopharmacology, may one day lead to medications that treat obesity and binge eating disorders.
Obesity is a complex disorder affecting more than 78 million Americans which involves an excessive amount of body fat. It increases your risk of diseases and health problems such as heart disease, diabetes and high blood pressure. Binge-eating disorder is a prevalent illness in America characterized by periods of excessive uncontrolled consumption of food, followed by uncomfortable fullness and feelings of self-disgust.
Using an experimental model, the researchers found when administering pituitary adenylate cyclase-activating peptide (PACAP), a peptide and hormone produced by neurons, in a specific area of the brain called the “central amygdala,” it reduced the intake of food and led to weight loss.
According to the researchers PACAP is known for its food intake and body weight effects in the hypothalamus (the area of the brain known for controlling appetite). However, this is the first report of PACAP effects in the amygdala, a region of the brain outside the hypothalamus, involved in fear but also in the emotional component of eating.
The researchers also discovered how PACAP decreases food intake when injected in the amygdala. In general, food intake can be decreased in two ways: eating fewer meals of normal size during the day, or smaller meals. “We found that amygdalar PACAP reduces the amount of food eaten within meals, but not how many meals are consumed. In addition, we found that PACAP reduced the rate of intake of food. This means that, following administration of PACAP, models were eating more slowly,” explained Valentina Sabino, PhD, assistant professor of pharmacology and psychiatry, and co-director of the Laboratory of Addictive Disorder at Boston University School of Medicine (BUSM).
In addition, they found that PACAP effects on food intake and body weight were dependent on another brain factor: the growth-hormone called brain-derived neurotrophic factor (BDNF). “The effects of PACAP on food intake and body weight were absent when it was given together with another drug that blocks BDNF signaling, suggesting that PACAP acts through BDNF,” said Sabino.
The researchers believe these findings have implications for a variety of conditions, since they found not only how much food subjects ate but also how fast they ate them. “The PACAP system may hypothetically be the target of medications to treat not only obesity but also binge-eating, a disease characterized by excessive, uncontrollable consumption of food within brief periods of time,” added coauthor Pietro Cottone, PhD, associate professor of pharmacology and psychiatry and co-director of the Laboratory of Addictive Disorder at BUSM.
The field of molecular machines has taken a new bio-inspired turn to assemble another molecule, in this case linking up individual amino acids into a peptide. While this molecular peptide synthesiser isn’t going to rival a ribosome for speed any time soon, it does suggest a way to make multicomponent polymers.
The project involved David Leigh’s groups at the University of Edinburgh and then at the University of Manchester, where he is now based. His group decided to mimic the ribosome, a cellular machine that can build proteins. ‘The ribosome uses a track where a machine moves along it processively,’ Leigh says. So when the group started thinking about how to build a synthetic version they naturally thought of the rotaxane architecture of a ring on a track. However, Leigh is keen to stress this is not intended as an artificial alternative for the ribosome, especially as his machine is much slower than its biological counterpart – it took 36 hours to synthesise a three amino acid peptide. Instead, Leigh says the work is a proof-of-concept for a molecular machine.
That’s something that Fraser Stoddart, father of rotaxane-based machines at Northwestern University in California, US, agrees with. Stoddart describes the work as ‘way out there in conception’, but that the idea of using molecules to build other molecules is ‘the direction that chemistry has got to go in’.
But while Leigh and Stoddart focus on the applications of the approach, Dean Astumian of the University of Maine, US, cautions against simple descriptions of molecular mechanical machines. ‘One of the big controversies is whether we should look for a mechanical description or whether it is predominantly a chemical phenomenon,’ he says.
For Astumian, the exciting thing about this work is the potential insights the molecule might bring to the workings of molecular machines. Does the ring move along the track smoothly, Astumian wonders, or is it a stochastic process with the ring moving back and forth until it overcomes an energy barrier and moves to the next amino acid on the track?
Whatever the answer, Leigh has a number of plans for the device, including increasing the number of amino acids that can be strung together. As the peptide sequence grows, says Leigh, ‘it will be very interesting to, at the single molecule level, see how these things fold as they are made’. There are also different chemistries and polymers to try, and Leigh also says he’d like to investigate keeping the information on the track so that it can be read again, just as RNA can be read more than once by a ribosome.
But Stoddart is clear that whilst molecular machines are starting to find applications this is just the beginning. ‘Chemistry is by far the youngest of the sciences and we haven’t scraped the surface yet. There’s so much we have to learn,’ he says.
B Lewandowski et al, Science, 2013, DOI: 10.1126/science.1229753