Habek Nikola, Ratko Martina, Sedmak Dora, Banovac Ivan, Crljen Vladiana, Kordić Milan, Radmilović Marina, Škokić Siniša, Tkalčić Martina, Mažuranić Anton, Bubalo Pero, Škavić Petar, Ljubić Spomenka, Rahelić Dario, Dugandžić Aleksandra
Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Zagreb, Croatia.
Centre of Excellence for Basic, Clinical and Translational Neuroscience, School of Medicine, University of Zagreb, Zagreb, Croatia.
Front Pharmacol. 2025 Apr 25;16:1569163. doi: 10.3389/fphar.2025.1569163. eCollection 2025.
Preclinical and clinical research of insulin resistance and glucose homeostasis in metabolic disorders are essential. In this study, we aim to determine the expression of uroguanylin (UGN) in the mouse and human brain, its regulatory mechanisms, and its significance to patients with obesity and type 2 diabetes (T2D).
UGN expression, regulation, and its correlation with feeding status and obesity in the mouse and human brain were analyzed at the mRNA level using RT-PCR, qPCR, and hybridization and at the protein level using Western blot, ELISA, and immunohistochemistry. Brown adipose tissue (BAT) activity was measured using infrared thermography. The volume of interscapular brown adipose tissue in mice was assessed by magnetic resonance imaging.
UGN was expressed in both the mouse and human brain, and its expression was regulated by feeding. In the human prefrontal cortex, UGN was expressed in several interneuron subpopulations across all cortical layers. In Brodmann area (BA) 10, prouroguanylin (proUGN) expression was not regulated by feeding in obesity, whereas this regulation still persisted in BA9. In mice, centrally applied UGN and its analog linaclotide, affecting the hypothalamus, induced both acute and chronic activation of BAT, which decreases the plasma glucose concentration. However, in obesity, proUGN expression was reduced in the human hypothalamus, suggesting reduced postprandial glucose consumption in BAT. Similarly, centrally applied analog of glucagon-like peptide 1 (GLP-1-liraglutide) affected proUGN expression and was associated with increased basal BAT activity but reduced BAT activation after a meal in patients with T2D receiving GLP-1 therapy.
Postprandial BAT activation is regulated by brain-derived UGN, which could serve as a novel therapeutic approach to enhance BAT activity in patients with obesity and T2D to improve postprandial glucose regulation.
胰岛素抵抗和葡萄糖稳态在代谢紊乱中的临床前和临床研究至关重要。在本研究中，我们旨在确定尿鸟苷素（UGN）在小鼠和人脑中的表达、其调节机制及其对肥胖和2型糖尿病（T2D）患者的意义。
使用逆转录聚合酶链反应（RT-PCR）、定量聚合酶链反应（qPCR）和杂交技术在mRNA水平分析UGN在小鼠和人脑中的表达、调节及其与进食状态和肥胖的相关性，并使用蛋白质印迹法、酶联免疫吸附测定（ELISA）和免疫组织化学在蛋白质水平进行分析。使用红外热成像测量棕色脂肪组织（BAT）活性。通过磁共振成像评估小鼠肩胛间棕色脂肪组织的体积。
UGN在小鼠和人脑中均有表达，其表达受进食调节。在人前额叶皮质中，UGN在所有皮质层的几个中间神经元亚群中表达。在布罗德曼区（BA）10，肥胖时前尿鸟苷素（proUGN）表达不受进食调节，而在BA9中这种调节仍然存在。在小鼠中，中枢应用UGN及其类似物利那洛肽影响下丘脑，诱导BAT的急性和慢性激活，从而降低血浆葡萄糖浓度。然而，在肥胖患者中，人下丘脑proUGN表达降低，提示BAT餐后葡萄糖消耗减少。同样，中枢应用胰高血糖素样肽1（GLP-1）类似物利拉鲁肽影响proUGN表达，并与接受GLP-1治疗的T2D患者基础BAT活性增加但餐后BAT激活减少有关。
餐后BAT激活受脑源性UGN调节，这可能是一种新的治疗方法，可增强肥胖和T2D患者的BAT活性，以改善餐后血糖调节。
