Nobody likes the unpleasant feeling of hunger, which is part of the reason that some people struggle to stick to a diet. A muffin or a grumbly tummy? Hmmm. But what if there was a simple way to effectively ease hunger pangs, and thus safely aid weight loss in overweight or obese people? Researchers could well be edging towards achieving this goal after discovering a key component of a complex brain network that inhibits and controls eating.
Not only does this circuitry promote satiety in hungry mice, but it also abolishes that virtually unbearable feeling of hunger. Alongside furthering our knowledge of the neural circuitry underpinning hunger and appetite, the findings could have important implications for the development of drugs to assist weight loss. The study has been published in Nature Neuroscience.
This latest discovery builds on previous work, which revealed that a bunch of brain cells in the hypothalamus, known as AgRP neurons, sense when we’re running low on calories and subsequently drive feeding behaviors. They do this by releasing inhibitory molecules that dampen the activity of cells downstream in this neural circuit that promote feelings of fullness. Consequently, we feel hungry and eat to prevent starvation.
While this much was known, scientists were left with a big grey box: Which downstream ‘satiety’ neurons are the AgRP neurons targeting? Since the molecule AgRP, which is released by the AgRP neurons, is known to block a type of receptor known as MC4R, Harvard researchers hypothesized that the downstream neurons likely possessed high levels of this receptor. This eventually led to the discovery of a tiny bundle of MC4R-expressing neurons within the hypothalamus that is crucial in the regulation of feeding.
The researchers then genetically modified mice so that the activity of these particular neurons could be chemically controlled by the administration of a certain drug. When the researchers switched off the cells, they found that mice who had already consumed a day’s worth of calories continued to gobble down food, even though they didn’t need it. And it worked the opposite way around, too: When the researchers artificially switched the cells on using a drug, unfed hungry mice didn’t eat anything. Together, the researchers say, this indicates that this population of cells acts as a feeding brake, preventing overeating.
Taking this one step further, the researchers set out to find the next downstream component of this neural circuit that is responsible for mediating this apparent effect. To do this, they injected a dye that revealed which cells the previously identified neurons were communicating with. This was found to be a dense population located at the back of the brain known as the lateral parabrachial nucleus (LPBN).
Next, they engineered the mice so that this particular pathway, from the MC4R receptors to the LPBN, could be activated by blue light, which was delivered through a brain implant. Once again, switching on this part of the circuit significantly reduced eating behaviors.
Currently, there are conflicting ideas as to why we eat: Do we do it to abolish the unpleasant feeling of hunger, or because eating food is pleasurable and rewarding? To find out more, the researchers conducted an experiment that was designed to investigate whether the previously identified circuit would evoke feelings of reward if activated artificially and in the absence of food.
Mice were placed in a box with two chambers, one of which would deliver blue light to their brains when they entered it. Hungry engineered mice spent significantly more time in the blue-light chamber, whereas normal mice displayed no preference, suggesting the artificial stimulation was pleasurable. Taken together, these findings suggest that it could be possible to artificially switch on this same circuit using drugs, which could potentially help in the treatment of obesity.
