Activation of brown adipose tissue in diet-induced thermogenesis is GC-C dependent
Uroguanylin (UGN) is released from the intestine after a meal. When applied in brain ventricles, UGN increases expression of markers of thermogenesis in brown adipose tissue (BAT). Therefore, we determine the effects of its receptor, guanylate cyclase C (GC-C), on mouse interscapular BAT (iBAT) activity during diet-induced thermogenesis (DIT). The activation of iBAT after a meal is diminished in GC-C KO mice, decreased in female wild type (WT) mice, and abolished in old WT animals. The activation of iBAT after a meal is the highest in male WT animals which leads to an increase in GC-C expression in the hypothalamus, an increase in iBAT volume by aging, and induction of iBAT markers of thermogenesis. In contrast to iBAT activation after a meal, iBAT activation after a cold exposure could still exist in GC-C KO mice and it is significantly higher in female WT mice. The expression of GC-C in the proopiomelanocortin neurons of the arcuate nucleus of the hypothalamus but not in iBAT suggests central regulation of iBAT function. The iBAT activity during DIT has significantly reduced in old mice but an intranasal application of UGN leads to an increase in iBAT activity in a dose-dependent manner which is in strong negative correlation to glucose concentration in blood. This activation was not present in GC-C KO mice. Our results suggest the physiological role of GC-C on the BAT regulation and its importance in the regulation of glucose homeostasis and the development of new therapy for obesity and insulin resistance.
KeywordsUroguanylin Hypothalamus Male vs female PET-CT MRI Infrared thermography
We would like to thank Petar Škavić, MD, Department of Forensic Medicine and Criminology, University of Zagreb, School of Medicine, Zagreb, Croatia for obtaining written consent from the families and collecting human samples, Danica Budinščak for technical support, Josip Dugandžić for expertise in graphic presentation and figure preparation, and Dr. Kris A. Steinbrecher, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA for a donation of GC-C KO animals.
Nikola Habek designed research; performed oxygen consumption, locomotor activity, RT-PCR, qPCR, intranasal application of UGN, and immunohistochemistry; analyzed data; performed statistical analysis; and contributed to the writing of the manuscript.
Marina Dobrivojević Radmilović designed and performed MRI experiments and analyzed data.
Milan Kordić designed and performed infrared thermography experiments and analyzed data.
Katarina Ilić designed and performed western blot analysis.
Sandra Grgić performed genotyping of WT and GC-C KO littermates.
Vladimir Farkaš, Robert Bagarić, and Alfred Švarc designed and performed PET-CT experiments and analyzed data.
Siniša Škokić designed and performed MRI experiments and analyzed data.
Aleksandra Dugandžić designed research, analyzed data, and wrote and revised the manuscript.
All authors read and approved the final manuscript.
This study was funded by a grant from the Croatian Science Foundation (FURNACE: 2018-01-7416).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
All applicable international, national, and institutional guidelines for the care and use of animals were followed. The experiments were performed in accordance with the ARRIVE guidelines. All procedures performed in studies involving animals were in accordance with the ethical standards of the University of Zagreb, School of Medicine, approved by Ethics Committee (EP 185/2018), and in accordance with the Ethical Codex of Croatian Society for Laboratory Animal Science. All efforts were made to minimize animal suffering and to reduce the number of animals used.
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