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

2022; American Association for the Advancement of Science; Volume: 8; Issue: 30 Linguagem: Inglês

10.1126/sciadv.abm7355

2375-2548

Carlos K. Katashima, Thayana de Oliveira Micheletti, Renata Rosseto Braga, Rodrigo S. Gaspar, Ludger J.E. Goeminne, Alexandre Moura‐Assis, Bárbara Crisol, Rafael S. Brícola, Vagner Ramon Rodrigues Silva, Camila de Oliveira Ramos, Alisson L. da Rocha, Mariana Tavares, Fernando Moreira Simabuco, Valquíria Aparecida Matheus, Lucas I Buscaratti, Henrique Marques‐Souza, Patricia Pazos, David González-Touceda, Sulay Tovar, María del Carmen Garcia, José Cesar Rosa Neto, Rui Curi, Sandro Massao Hirabara, Patrı́cia C. Brum, Patrícia O. Prada, Leandro Pereira de Moura, José Rodrigo Pauli, Adelino Sánchez Ramos da Silva, Dennys E. Cintra, Lı́cio A. Velloso, Eduardo R. Ropelle,

Regulation of Appetite and Obesity

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.