Leucine Deprivation Leads to Antidepressant Effects

Depression is a leading cause of disability around the world and contributes greatly to the global burden of disease. Nutrition is essential for the maintenance of normal emotional states. Nutritional therapy is rising up in many disease treatments, but little is known in the depression field. Unbalanced nutrition is implicated in the etiology of depression, potentially hindering treatment. For example, many essential amino acids (EAAs) in serum are changed in patients with depression, such as tryptophan, threonine, leucine, isoleucine, and valine. However, whether EAAs contribute to depression and the possible underlying mechanisms remain largely unknown. Now, researchers in China, led by Feifan Guo, PhD, Professor in the Institute for Translational Brain Research at Fudan University, have found that a leucine-deficient diet has antidepressant effects on chronic restraint stress-induced depression-related behaviors and revealed the mechanism of amino acid sensing in hypothalamic agouti-related peptide (AgRP) neurons. The scientists published their results entitled “Leucine Deprivation Results in Antidepressant Effects Via GCN2 in AgRP Neurons” (DOI: 10.1093/lifemeta/load004) on February 4, 2023 in an open-access article in Life Metabolism.

In this study, a leucine-deficient diet was found to have antidepressant effects on chronic restraint stress-induced depression-related behaviors in both genders of mice. Interestingly, the amino acid deficiency effects apply to all essential amino acids. By intracerebroventricular injection, the researchers found that the response to leucine deprivation is mediated by the hypothalamus, a specific region that mainly regulates appetite and energy metabolism. Moreover, scientists found a group of neurons in the hypothalamus, AgRP neurons, that were activated during leucine deprivation, and silencing AgRP neurons abolished the leucine deprivation-induced antidepressant effects. Furthermore, general control of  non-derepressible 2 (GCN2), an amino acid sensor, in AgRP neurons, was activated during leucine deficiency after stress, and GCN2 knockdown in AgRP neurons blocked leucine deficiency-induced behavioral alterations, which was reversed by activating AgRP neurons.

This study established that an unexpected dietary pattern, leucine deprivation, not nutrition supplement, results in antidepressant effects, and this regulation is mediated by a group of orexigenic neurons, AgRP neurons. Furthermore, these results suggest a new function of GCN2 signaling in AgRP neurons under imbalanced amino acid and chronic stress. As leucine deprivation could also lower weight and improve glucose metabolism, this diet pattern may help to relieve the antidepressant drug-induced obesity in future application. This study provides a new perspective for exploring the relation of nutrition, hypothalamus, and depression.

About Life Metabolism

Life Metabolism is a fully open-access, peer-reviewed journal that publishes one volume per year online, providing a platform for the publication of works of high significance and broad interest in all areas of metabolism. Life Metabolism welcomes several different article types, including original article, review article, research highlight, letter, editorial, perspective, and so on. Once a paper is accepted, Life Metabolism can publish a pre-copy-edited, pre-proofed version of the paper online within 48 hours of receiving a signed license, and this will be replaced by a copy-edited, proofed version of the paper as soon as it is ready. The Editors-in-Chief are professors Peng Li at Tsinghua University and John R Speakman at University of Aberdeen, UK. In the first three years, there will be no publication costs for publishing in Life Metabolism, and Open Access fees will be waived.

[News release] [Life Metabolism article]

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