SerpinA3N in leptin-sensitive neurons is required for energy and glucose homeostasis and autonomic regulation

IF 11.9 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental Pub Date : 2025-09-09 DOI:10.1016/j.metabol.2025.156387

Deng Fu Guo , Zili Luo , Alexis Olson , Donald A. Morgan , Elizabeth A. Newell , Kamal Rahmouni

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引用次数: 0

Abstract

Aims

SerpinA3N (Serpin peptidase inhibitor clade A member 3) is a serine protease inhibitor upregulated in the hypothalamus by leptin and obesity, yet its role in physiological regulation remains poorly understood. This study aims to elucidate the role of hypothalamic SerpinA3N in regulation of energy balance, glucose homeostasis, and autonomic and cardiovascular functions.

Methods and results

Immunostaining revealed that SerpinA3N is primarily expressed in neurons, including those expressing the leptin receptor (LepRb). Targeted deletion of SerpinA3N in LepRb neurons reduced body weight and adiposity and improved insulin sensitivity in female mice. SerpinA3N deficiency also enhanced leptin sensitivity, evidenced by amplified leptin-induced anorexia, weight loss, and LepRb signaling in the hypothalamic arcuate nucleus. Upon exposure to an obesogenic diet, mice lacking SerpinA3N in LepRb neurons exhibited attenuated weight gain, hepatic lipid accumulation and microgliosis. Notably, SerpinA3N deletion in LepRb neurons impaired baroreflex sensitivity and elevated renal sympathetic nerve activity, with dietary obesity further exacerbating sympathetic tone.

Conclusions

These findings identify neuronal SerpinA3N as a key regulator of energy balance, leptin and insulin sensitivity, and autonomic function.

查看原文本刊更多论文

瘦素敏感神经元中的SerpinA3N是能量和葡萄糖稳态和自主调节所必需的。

目的：SerpinA3N（丝氨酸肽酶抑制剂分支A成员3）是一种丝氨酸蛋白酶抑制剂，在下丘脑中被瘦素和肥胖上调，但其在生理调节中的作用尚不清楚。本研究旨在阐明下丘脑SerpinA3N在调节能量平衡、葡萄糖稳态、自主神经和心血管功能中的作用。方法和结果：免疫染色显示，SerpinA3N主要表达在神经元中，包括表达瘦素受体（LepRb）的神经元。在LepRb神经元中靶向删除SerpinA3N可以降低雌性小鼠的体重和肥胖，并改善胰岛素敏感性。SerpinA3N缺乏也增强了瘦素敏感性，这可以通过瘦素引起的厌食症、体重减轻和下丘脑弓状核中的LepRb信号传导放大来证明。暴露于致肥性饮食后，LepRb神经元中缺乏SerpinA3N的小鼠表现出体重增加减轻、肝脏脂质积累和小胶质细胞增生。值得注意的是，LepRb神经元中SerpinA3N的缺失损害了压力反射敏感性和肾交感神经活动的升高，饮食肥胖进一步加剧了交感神经张力。结论：这些发现表明神经元SerpinA3N是能量平衡、瘦素和胰岛素敏感性以及自主神经功能的关键调节因子。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Metabolism: clinical and experimental 医学-内分泌学与代谢

CiteScore

18.90

自引率

3.10%

发文量

310

审稿时长

16 days

期刊介绍： Metabolism upholds research excellence by disseminating high-quality original research, reviews, editorials, and commentaries covering all facets of human metabolism. Consideration for publication in Metabolism extends to studies in humans, animal, and cellular models, with a particular emphasis on work demonstrating strong translational potential. The journal addresses a range of topics, including: - Energy Expenditure and Obesity - Metabolic Syndrome, Prediabetes, and Diabetes - Nutrition, Exercise, and the Environment - Genetics and Genomics, Proteomics, and Metabolomics - Carbohydrate, Lipid, and Protein Metabolism - Endocrinology and Hypertension - Mineral and Bone Metabolism - Cardiovascular Diseases and Malignancies - Inflammation in metabolism and immunometabolism