Evidence for a neuromuscular circuit involving hypothalamic interleukin-6 in the control of skeletal muscle metabolism

• Published in: Science advances Vol. 8; no. 30; p. eabm7355
• Main Authors: Katashima, Carlos Kiyoshi, de Oliveira Micheletti, Thayana, Braga, Renata Rosseto, Gaspar, Rodrigo Stellzer, Goeminne, Ludger J. E., Moura-Assis, Alexandre, Crisol, Barbara Moreira, Brícola, Rafael S., Silva, Vagner Ramon R., de Oliveira Ramos, Camila, da Rocha, Alisson L., Tavares, Mariana Rosolen, Simabuco, Fernando Moreira, Matheus, Valquiria Aparecida, Buscaratti, Lucas, Marques-Souza, Henrique, Pazos, Patricia, Gonzalez-Touceda, David, Tovar, Sulay, del Carmen García, María, Neto, Jose Cesar Rosa, Curi, Rui, Hirabara, Sandro Massao, Brum, Patrícia Chakur, Prada, Patrícia Oliveira, de Moura, Leandro P., Pauli, José Rodrigo, da Silva, Adelino S. R., Cintra, Dennys Esper, Velloso, Licio A., Ropelle, Eduardo Rochete
• Format: Journal Article
• Language: English
• Published: American Association for the Advancement of Science 29.07.2022
• Subjects: Biomedicine and Life Sciences; Neuroscience; Physiology; SciAdv r-articles
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.abm7355

Hypothalamic interleukin-6 (IL6) exerts a broad metabolic control. Here, we demonstrated that IL6 activates the ERK1/2 pathway in the ventromedial hypothalamus (VMH), stimulating AMPK/ACC signaling and fatty acid oxidation in mouse skeletal muscle. Bioinformatics analysis revealed that the hypothalamic IL6/ERK1/2 axis is closely associated with fatty acid oxidation– and mitochondrial-related genes in the skeletal muscle of isogenic BXD mouse strains and humans. We showed that the hypothalamic IL6/ERK1/2 pathway requires the α2-adrenergic pathway to modify fatty acid skeletal muscle metabolism. To address the physiological relevance of these findings, we demonstrated that this neuromuscular circuit is required to underpin AMPK/ACC signaling activation and fatty acid oxidation after exercise. Last, the selective down-regulation of IL6 receptor in VMH abolished the effects of exercise to sustain AMPK and ACC phosphorylation and fatty acid oxidation in the muscle after exercise. Together, these data demonstrated that the IL6/ERK axis in VMH controls fatty acid metabolism in the skeletal muscle. Neuromuscular circuit drives fatty acid oxidation in muscle fibers.