Adipose transplantation improves olfactory function and neurogenesis via PKCα-involved lipid metabolism in Seipin Knockout mice

Abstract

Lipodystrophy-associated Metabolic Disorders caused by Seipin deficiency lead to not only severe lipodystrophy but also neurological disorders. However, the underlying mechanism of Seipin deficiency-induced neuropathy is not well elucidated and the possible restorative strategy needs to be explored. In the present study, we investigated the systemic lipid metabolic abnormalities of Seipin knockout (KO) mice and their effect on adult neurogenesis in the subventricular zone (SVZ) and olfactory function. It was found that KO mice presented an ectopic accumulation of lipid in the lateral ventricle, accompanied by decreased neurogenesis in adult SVZ, diminished new neuron formation in the olfactory bulb, and impaired olfactory-related memory. Transcriptome analysis showed that the differentially expressed genes (DEGs) in SVZ tissues of adult KO mice were significantly enriched in biological processes related to lipid metabolism. Mass spectrometry imaging showed that the levels of glycerophospholipid, diglyceride and ceramide were significantly increased. In the restorative study, we found that subcutaneous adipose tissue transplantation (AT) rescued the abnormality of peripheral metabolism in KO mice and ameliorated the ectopic lipid accumulation in SVZ, concomitant with restoration of the SVZ neurogenesis and olfactory function. Mechanistically, PKCα was the potential mediator of lipid dysregulation-induced phenotypes. In the brain tissue of KO mice, PKCα was upregulated, which could be mimicked by the administration of DG analogue (Dic8) into cultured neural stem cells (NSCs). Dic8 impaired proliferation and differentiation NSCs, whereas it could be recovered by PKCα inhibitor. Overall, this study demonstrates that Seipin deficiency leads to systemic lipid metabolism disorder, which impairs neurogenesis and olfactory memory. Adipose transplantation restores lipid metabolic homeostasis and neurogenesis via PKCα involved pathway. The present study paves a novel way to treat lipid metabolic dysregulation-induced neurological disorders.