Inhibition of Crif1 protects fatty acid-induced POMC neuron-like cell-line damage by increasing CPT-1 function

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Regina-Ferreira, Lara ; Valdivieso-Rivera, Fernando ; Angelim, Monara K. S. C. ; Menezes dos Reis, Larissa ; Furino, Vanessa O. ; Morari, Joseane ; Maia de Sousa, Lizandra ; Consonni, Silvio Roberto ; Sponton, Carlos H. ; Moraes-Vieira, Pedro M. ; Velloso, Licio A.

• Document type: Journal article
• Source: AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM; v. 326, n. 5, p. 15-pg., 2024-05-10.

Abstract

Hypothalamic proopiomelanocortin (POMC) neurons are sensors of signals that reflect the energy stored in the body. Inducing mild stress in proopiomelanocortin neurons protects them from the damage promoted by the consumption of a high-fat diet, mitigating the development of obesity; however, the cellular mechanisms behind these effects are unknown. Here, we induced mild stress in a proopiomelanocortin neuron cell line by inhibiting Crif1. In proopiomelanocortin neurons exposed to high levels of palmitate, the partial inhibition of Crif1 reverted the defects in mitochondrial respiration and ATP production; this was accompanied by improved mitochondrial fusion/fission cycling. Furthermore, the partial inhibition of Crif1 resulted in increased reactive oxygen species production, increased fatty acid oxidation, and reduced dependency on glucose for mitochondrial respiration. These changes were dependent on the activity of CPT-1. Thus, we identified a CPT-1-dependent metabolic shift toward greater utilization of fatty acids as substrates for respiration as the mechanism behind the protective effect of mild stress against palmitate-induced damage of proopiomelanocortin neurons. (AU)

• FAPESP's process: 13/07607-8 - OCRC - Obesity and Comorbidities Research Center
• Grantee: Licio Augusto Velloso
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 21/06461-6 - Integrated mitochondrial stress response and the regulation of pro-opiomelanocortin processing in hypothalamic neuronal cell lines
• Grantee: Lara Regina Ferreira
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 22/04576-3 - EMU awarded in process 2020/16030-0: 96-well metabolic analyzer seahorse XFe96
• Grantee: Pedro Manoel Mendes de Moraes Vieira
• Support Opportunities: Multi-user Equipment Program