Mutations in the Neuropeptide Y (NPY) gene have been linked to an elevated body mass index, although this does not seem to influence eating behaviors. NPY has been identified as having a protective function against obesity within sympathetic neurons and plays a role in the formation of thermogenic fat cells by encouraging the proliferation of mural cells. However, obesity induced by diet has been found to result in damage to NPY+ axons and a decrease in mural cells. This underscores the conflicting roles of NPY released from sympathetic nerves in weight regulation and points to the limitations of current obesity interventions.
Zhu and colleagues explored the impact of the peripheral form of the NPY gene, originating from sympathetic neurons, on body weight. For this purpose, single-cell RNA sequencing (scRNA-seq) data from sympathetic ganglia were analyzed, revealing that two subgroups of sympathetic neurons exhibited high NPY levels. These observations were verified through immunofluorescence staining. The research demonstrated that 40% of sympathetic neurons in inguinal white adipose tissue (iWAT) were NPY+, and these axons formed networks associated with blood vessels. NPY was shown to promote mural cell proliferation, which allowed for their conversion into thermogenic adipocytes, thus playing a protective role against obesity. However, it was noted that diet-induced obesity caused nerve damage in NPY+ axons and a reduction in mural cell populations. The study emphasized the importance of NPY from sympathetic nerves in maintaining energy expenditure and combating obesity.
The methods employed in the study were comprehensive, investigating the impact of the NPY gene on obesity through mouse models. The energy expenditure and respiratory exchange ratios of the mice were assessed using an indirect calorimetry system, with mice housed separately, and their body weights and food intake monitored. Activity levels were recorded with the Panlab device, which collected behavioral data via its sensitive sensors. Body composition was evaluated through low-field magnetic resonance spectroscopy (NMR). Throughout the experiments, molecular biology techniques, including cell culture, immunofluorescence staining, and quantitative polymerase chain reaction (qPCR), were utilized. For sequencing and flow cytometry analyses, adipose tissues were enzymatically digested to create single-cell suspensions. To study NPY’s effects on adipocytes, viral injections were performed in mice, and cell proliferation tests were conducted. Microscopy was carried out using the Zeiss LSM880 confocal microscope.
These methodologies were applied thoroughly to examine the peripheral effects of NPY derived from sympathetic nerves both in vivo and in vitro. The impact of obesity-induced nerve damage on NPY+ axons was explored, and the results confirmed that NPY is pivotal in energy expenditure and affects the progression of obesity. According to the study, NPY released from sympathetic neurons promotes mural cell proliferation, leading to their conversion into thermogenic fat cells. This process boosts energy expenditure and provides a defense against obesity. However, in mice fed a high-fat diet, nerve damage in NPY+ axons and a decline in mural cell numbers were noted, contributing to obesity-related dysfunction in adipose tissue.
In summary, the findings illustrate that the peripheral actions of NPY play a critical role in regulating energy expenditure and body weight. Unlike NPY in the brain, NPY from sympathetic nerves enhances energy consumption and helps prevent obesity. These results suggest that NPY could be a promising target for obesity treatment and that nerve damage linked to obesity disrupts the protective role of NPY. The findings provide new perspectives on energy regulation and present potential strategies for managing obesity.
Author: Defne Saral
Editor: Elif Duymaz
Reference: Zhu, Y., Yao, L., Gallo-Ferraz, A. L., Bombassaro, B., Simões, M. R., Abe, I., Chen, J., Sarker, G., Ciccarelli, A., Zhou, L., Lee, C., Sidarta-Oliveira, D., Martínez-Sánchez, N., Dustin, M. L., Zhan, C., Horvath, T. L., Velloso, L. A., Kajimura, S., & Domingos, A. I. (2024). Sympathetic neuropeptide Y protects from obesity by sustaining thermogenic fat. Nature. https://doi.org/10.1038/s41586-024-07863-6
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