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

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Katashima, Carlos Kiyoshi ; Micheletti, Thayana de Oliveira ; Braga, Renata Rosseto ; Gaspar, Rodrigo Stellzer ; Goeminne, Ludger J. E. ; Moura-Assis, Alexandre ; Crisol, Barbara Moreira ; Bricola, Rafael S. ; Silva, Vagner Ramon R. ; Ramos, Camila de Oliveira ; 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 ; Garcia, Maria del Carmen ; Rosa Neto, Jose Cesar ; Curi, Rui ; Hirabara, Sandro Massao ; Brum, Patricia Chakur ; Prada, Patricia Oliveira ; de Moura, Leandro P. ; Pauli, Jose Rodrigo ; da Silva, Adelino S. R. ; Cintra, Dennys Esper ; Velloso, Licio A. ; Ropelle, Eduardo Rochete

• Document type: Journal article
• Source: SCIENCE ADVANCES; v. 8, n. 30, p. 14-pg., 2022-07-29.

Abstract

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 alpha 2-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. (AU)

• FAPESP's process: 12/23006-1 - Effect of IL-6 on the hypothalamic activation of AMPK / ACC in skeletal muscle of mice: The role of physical exercise.
• Grantee: Thayana de Oliveira Micheletti
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 19/21709-4 - Implications of mitonuclear imbalance and UPRmt in hypothalamic neurons in the genesis of Obesity
• Grantee: Eduardo Rochete Ropelle
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 13/26053-3 - Effect of IL-6 on the hypothalamic activation of AMPK/ACC in skeletal muscle of mice: the role of physical exercise
• Grantee: Thayana de Oliveira Micheletti
• Support Opportunities: Scholarships abroad - Research Internship - Master's degree
• FAPESP's process: 18/04192-5 - Evaluation of the Parilation and the Mitonuclear Imbalance and the UPRmt in the Skeletal Musculature of Mice in Overtraining.
• Grantee: Barbara Moreira Crisol
• Support Opportunities: Scholarships in Brazil - Doctorate