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Perineurium integrates leptin with its sympathetic outflow to protect against obesity

ABSTRACT: The regulatory mechanism of leptin's afferent action in the brain is contingent upon the efferent sympathetic innervation of white and brown adipose tissues. Nonetheless, the peripheral regulation governing the the afferent-efferent balance remains ambiguous. Here, we show the enriched expression of both leptin receptor (Lepr) and β2 adrenergic receptor (Adrb2) in perineurial cells that form a barrier around sympathetic ganglia and nerve bundles in adipose tissues, using single-cell RNA sequencing on murine sympathetic ganglia. Lepr+ Sympathetic Perineurial Cells (SPCs) are molecularly similar to endothelial cells. Conditional knockout of Adrb2 in Lepr+ cells, including SPCs predisposes male mice to obesity, by lowering energy expenditure and thermogenesis without affecting food intake. Notably, obesity-associated hyperleptinemia causes apoptosis in SPCs, disrupting the perineurial barrier and concomitant adipose sympathetic neuropathy. This deleterious effect can be reversed by partial reduction of leptin or sympathomimetic β2 adrenergic receptor agonism. Clinically, we observed a male-specific synergistic effect of LEPR and ADRB2 polymorphisms on increased BMI risk in a large European population. We propose that SPCs coordinate the afferent and efferent arms of the neuroendocrine loop of leptin action to regulate energy expenditure and body weight.

ORGANISM(S): Mus musculus

PROVIDER: GSE233163 | GEO | 2026/05/26

REPOSITORIES: GEO

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Project description:Leptin receptors (Lepr) are expressed by various types of stem cells including mesenchymal stem cells, hematopoietic stem cells, embryonic stem cells, and induced pluripotent stem cells. Leptin/lepr signaling is also a central regulator of metabolism. However, the role of Lepr in pluripotency, metabolic disease progression and growth development is still controversial and poorly understood. In the present study, we explored the Lepr function in disease progression, pluripotency and metabolism using day 14.5 mouse embryonic fibroblasts (MEFs) and their reprogrammed induced pluripotent stem cells (iPSCs) as model system. We successfully reprogrammed mouse embryonic fibroblasts into iPSCs from control and db/db (Lepr deficient) mice. Using a global quantitative proteomic approach, we identified key pathways regulating pluripotency, metabolic homeostasis and protein synthesis during fetal growth and development. The Lepr MEFs show abnormal metabolic abnormalities and mitochondrial dysfunction as compared to control MEFs, while Lepr iPSCs show upregulated elongated factor 4 e (eIF4e) protein synthesis pathway and altered Oct4 and Stat3 pathways which are involved in normal fetal growth development. Furthermore, chip analysis revealed that higher Stat3 binding on the promoter of eIF4e in Lepr iPSCs leads to higher protein synthesis in these cell types as compared to control iPSCs. Finally, point mutation corrected Lepr iPSCs using CRISPR/Cas9 gene editing method showed recovered pluripotency, metabolic and protein synthesis pathways. In conclusion, we have shown that Lepr signaling is involved in the regulation of the metabolic properties and key developmental pathways in MEFs and stemness of pluripotent stem cells. Disruption of Lepr signaling has been shown to involve in the pathophysiology of various diseases including obesity and diabetes. The generated MEFs and iPSCs in this present study provide valuable tools to explore the role of Lepr in the progression of obesity, diabetes and metabolic abnormalities, and to find the putative targets of Lepr signaling during the development of these diseases.

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Perineurium integrates leptin with its sympathetic outflow to protect against obesity

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