Brain-derived uroguanylin as a regulator of postprandial brown adipose tissue activation: a potential therapeutic approach for metabolic disorders

Nikola Habek ^1,2 Martina Ratko ¹ Dora Sedmak ³ Ivan Banovac ³ Vladiana Crljen ^1,2 Milan Kordić ⁴ Marina Dobrivojević Radmilović ¹ Siniša Škokić ¹ Martina Tklčić ⁵ Anton Mažuranić ⁵ Pero Bubalo ⁵ Petar Škavić ⁵ Spomenka Ljubić ⁶ Dario Rahelic ⁶ Aleksandra Dugandzic ^1,7*

• ¹ Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Zagreb, Croatia
• ² Department of Physiology, School of Medicine, University of Zagreb, Zagreb, Croatia, Zagreb, Croatia
• ³ Department for Anatomy and Clinical Anatomy, School of Medicine, University of Zagreb, Zagreb, Croatia
• ⁴ MKP Ltd., Zagreb, Croatia
• ⁵ Institute for Forensic Medicine, School of Medicine, University of Zagreb, Zagreb, Croatia
• ⁶ Department of Diabetes, Vuk Vrhovac University Clinic for Diabetes, Endocrinology and Metabolic Diseases, Merkur University Hospital, Zagreb,, Zagreb, Croatia
• ⁷ School of Medicine, University of Zagreb, Zagreb, Croatia

Background: Preclinical and clinical research of insulin resistance and glucose homeostasis in metabolic disorders are essential. This study aims to determine 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).Methods: 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 in situ 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.Results: UGN was expressed in both the mouse and human brain, and its expression was regulated by feeding. In human prefrontal cortex, UGN was expressed in several interneuron subpopulations across all cortical layers. In Brodmann area (BA) 10, proUGN expression was not regulated by feeding in obesity, whereas this regulation still persisted in BA9. In mice, centrally applied UGN and its analogue linaclotide, affecting hypothalamus, induced both acute and chronic activation of BAT which decreases plasma glucose concentration. However, in obesity, proUGN expression was reduced in the human hypothalamus suggesting reduced postprandial glucose consumption in BAT. Similarly, centrally applied analogue 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.