Uroguanylin Action in the Brain Reduces Weight Gain in Obese Mice via Different Efferent Autonomic Pathways

• DOI: 10.2337/db15-0889
• Publication Date: 2015-11-14T02:43:37Z
• Authors: Cintia Folgueira; Daniel Beiroa; Aurelie Callon; Omar Al-Massadi; Silvia Barja-Fern...; Ana Senra; Johan Fernø; Miguel López; Carlos Dieguez; Felipe F. Casanueva; Françoise Rohner-...; Luisa M. Seoane; Ruben Nogueiras
• Keywords: Male; 0301 basic medicine; Sympathetic Nervous System; Adipose Tissue, White; Efferent Pathways; Eating; Mice; 03 medical and health sciences; Adipose Tissue, Brown; Animals; Homeostasis; info:eu-repo/classification/ddc/612; Autonomic Pathways; Obesity; Intestinal Mucosa; ddc:612; Defecation; Natriuretic Peptides; Adiposity; Mice, Knockout; 2. Zero hunger; Brain; Thermogenesis; Vagus Nerve; Energy Metabolism

The gut-brain axis is of great importance in the control of energy homeostasis. The identification of uroguanylin (UGN), a peptide released in the intestines that is regulated by nutritional status and anorectic actions, as the endogenous ligand for the guanylyl cyclase 2C receptor has revealed a new system in the regulation of energy balance. We show that chronic central infusion of UGN reduces weight gain and adiposity in diet-induced obese mice. These effects were independent of food intake and involved specific efferent autonomic pathways. On one hand, brain UGN induces brown adipose tissue thermogenesis, as well as browning and lipid mobilization in white adipose tissue through stimulation of the sympathetic nervous system. On the other hand, brain UGN augments fecal output through the vagus nerve. These findings are of relevance as they suggest that the beneficial metabolic actions of UGN through the sympathetic nervous system do not involve nondesirable gastrointestinal adverse effects, such as diarrhea. The present work provides mechanistic insights into how UGN influences energy homeostasis and suggests that UGN action in the brain represents a feasible pharmacological target in the treatment of obesity.