International Business Department           Liu Bojia           September 4, 2023

  We often think that our appetite is determined by our mouths and stomachs, and that if we feel good, we eat more, and if we get a little full, we don't eat any more. But when we look beyond the surface of appetite, we end up directing clues to the hypothalamus, the region of the brain that strictly controls the complex balance between eating and energy expenditure.

  For example, some past studies have found that neurons in the lateral hypothalamus connect to fat tissue and can participate in fat metabolism.

  In a new study in Nature Metabolism, scientists further explored the mechanisms involved. They found a cluster of specialized neurons in the hypothalamus, cells that express receptors for the inhibitory neurotransmitter GABA. Based on their properties, the researchers named these neurons GABRA5, and they can project to the surrounding brown and white adipose tissue, linking them to fat metabolism.

  The study authors constructed a group of obese mice with a high-fat diet and observed that the electrical activity of GABRA5 neurons in these obese mice would be significantly reduced. And if one artificially tries to inhibit the neuronal activity of GABRA5, it makes the thermogenesis process in the brown adipose tissue of the mice weaker, which means that energy expenditure becomes less and the mice are more likely to accumulate fat and gain weight. Conversely, if the GABRA5 neurons were stimulated, the mice could easily "lose weight".

  The researchers viewed the GABRA5 neurons as a switch to control body weight. However, these neurons do not work alone, but also have cooperative connections with other cells in the brain. For example, astrocytes in the lateral hypothalamus regulate the activity of GABRA5 neurons, which are not neurons, but rather supportive cells that fill the space between nerve cells and also participate in intercellular communication.

  In the neural circuits observed in the study, astrocytes highly express monoamine oxidase (MAO-B), which synthesizes and releases GABA, which is then received by GABRA5 neurons, decreasing neuronal activity and ultimately producing a similar fattening effect as before. The authors then found that obese mice had a significant increase in the number and size of astrocytes, meaning they produced more GABA to inhibit GABRA5 neurons.

  In this series of participants, modulating any one of these would be expected to stop the mice from gaining weight, such as increasing GABRA5 neuron activity, inhibiting astrocytes, or decreasing the release of GABA from astrocytes.

  In the new study, the authors set their sights on inhibiting the gene that encodes for the MAO-B enzyme, i.e., reducing the final output of GABA. They found that by silencing this gene, or by using a MAO-B enzyme inhibitor, they were able to significantly slow down the rate of weight gain in mice. Even when the conditions of the high-fat diet were not altered, and the mice were fed ad libitum, they did not gain weight, and the amount of calories produced in adipose tissue increased.

  One of the MAO-B inhibitors used in the study, KDS2010, is already in Phase 1 clinical trials, and the researchers noted that many obesity therapies in the past have focused more on hypothalamic neurons, but they found that even if it's not the nerve cells, they're still able to be used for weight loss. This could be a novel strategy for achieving weight loss without compromising appetite.