Obesity-induced modulation of MFSD2a in hypothalamic nuclei

Abstract

Background

MFSD2a is the primary omega-3 (ω3) fatty acid transporter from the blood to the central nervous system, which also contributes to the maintenance of blood-brain barrier (BBB) permeability. Studies have shown that the BBB is heterogeneous across brain regions, leading to differences in its properties. Previously, we demonstrated that total hypothalamic MFSD2a content is changed under obesity induced by high-fat food intake. Specifically, immune-guided histology suggested that this enhancement occurred differently in hypothalamic zones, which could differently impact the control of food intake and energy expenditure. However, no further evidence exists regarding how obesity specifically alters MFSD2a in each hypothalamic nucleus, nor how transcriptional factors are involved in it. Some studies suggest that peroxisome proliferator-activated receptors (PPARs) may regulate MFSD2a transcription; however, this has not yet been conclusively confirmed.

MFSD2a is the primary omega-3 (ω3) fatty acid transporter from the blood to the central nervous system, which also contributes to the maintenance of blood-brain barrier (BBB) permeability. Studies have shown that the BBB is heterogeneous across brain regions, leading to differences in its properties. Previously, we demonstrated that total hypothalamic MFSD2a content is changed under obesity induced by high-fat food intake. Specifically, immune-guided histology suggested that this enhancement occurred differently in hypothalamic zones, which could differently impact the control of food intake and energy expenditure. However, no further evidence exists regarding how obesity specifically alters MFSD2a in each hypothalamic nucleus, nor how transcriptional factors are involved in it. Some studies suggest that peroxisome proliferator-activated receptors (PPARs) may regulate MFSD2a transcription; however, this has not yet been conclusively confirmed.

Objective

Evaluate the modulation of MFSD2a by diet-induced obesity in the different hypothalamic nuclei, and the participation of PPARs in its transcription.

Evaluate the modulation of MFSD2a by diet-induced obesity in the different hypothalamic nuclei, and the participation of PPARs in its transcription.

Methods

Obesity was induced in mice fed with a high-fat diet for 12 weeks (35% w/w fat) ad libitum. Using the immunofluorescence and microdissection technique, MFSD2a content of arcuate, paraventricular, ventromedial, and lateral hypothalamic nuclei was mapped and quantified. To determine the role of PPAR in hypothalamic MFSD2a transcription, oral PPARα and PPARγ pharmacological agonists were used, as well as PPARα knockout mice, to evaluate MFSD2a gene expression and content. All experimental procedures were approved by the local animal ethics committee (protocols 6721-1/2025 and 6801-1/2025).

Obesity was induced in mice fed with a high-fat diet for 12 weeks (35% w/w fat) ad libitum. Using the immunofluorescence and microdissection technique, MFSD2a content of arcuate, paraventricular, ventromedial, and lateral hypothalamic nuclei was mapped and quantified. To determine the role of PPAR in hypothalamic MFSD2a transcription, oral PPARα and PPARγ pharmacological agonists were used, as well as PPARα knockout mice, to evaluate MFSD2a gene expression and content. All experimental procedures were approved by the local animal ethics committee (protocols 6721-1/2025 and 6801-1/2025).

Preliminary results

The HF diet successfully mimics the obese phenotype, changing the MFSD2a content differently across hypothalamic areas. PPARγ agonist for 5 days did not alter hypothalamic MFSD2a expression, but PPARα agonist increased MFSD2a compared to vehicle. Interestingly, PPARα knockout mice did not exhibit alterations in the MFSD2a content.

The HF diet successfully mimics the obese phenotype, changing the MFSD2a content differently across hypothalamic areas. PPARγ agonist for 5 days did not alter hypothalamic MFSD2a expression, but PPARα agonist increased MFSD2a compared to vehicle. Interestingly, PPARα knockout mice did not exhibit alterations in the MFSD2a content.

Partial conclusion

Obesity outcomes modulate the hypothalamic MFSD2a distribution in different nuclei, followed by partial control of MFSD2a expression induced by PPARα.

Obesity outcomes modulate the hypothalamic MFSD2a distribution in different nuclei, followed by partial control of MFSD2a expression induced by PPARα.