Gap junctions regulate the activity of AgRP neurons and diet-induced obesity in male mice

Author(s)

de Souza, Gabriel O. ; Chaves, Fernanda M. ; Silva, Josiane N. ; Pedroso, Joao A. B. ; Metzger, Martin ; Frazao, Renata ; Donato Jr, Jose

• Document type: Journal article
• Source: Journal of Endocrinology; v. 255, n. 2, p. 16-pg., 2022-11-01.

Abstract

Recent studies indicated an important role of connexins, gap junction proteins, in the regulation of metabolism. However, most of these studies focused on the glial expression of connexins, whereas the actions of connexins in neurons are still poorly investigated. Thus, the present study had the objective to investigate the possible involvement of gap junctions, and in particular connexin 43 (CX43), for the central regulation of energy homeostasis. Initially, we demonstrated that hypothalamic CX43 expression was suppressed in fasted mice. Using whole-cell patch-clamp recordings, we showed that pharmacological blockade of gap junctions induced hyperpolarization and decreased the frequency of action potentials in 50-70% of agouti-related protein (AgRP)-expressing neurons, depending on the blocker used (carbenoxolone disodium, TAT-Gap19 or Gap 26). When recordings were performed with a biocytin-filled pipette, this intercellular tracer was detected in surrounding cells. Then, an AgRP-specific CX43 knockout (AgRP & UDelta;CX43) mouse was generated. AgRP & UDelta;CX43 mice exhibited no differences in body weight, adiposity, food intake, energy expenditure and glucose homeostasis. Metabolic responses to 24 h fasting or during refeeding were also not altered in AgRP & UDelta;CX43 mice. However, AgRP & UDelta;CX43 male, but not female mice, exhibited a partial protection against high-fat diet-induced obesity, even though no significant changes in energy intake or expenditure were detected. In summary, our findings indicate that gap junctions regulate the activity of AgRP neurons, and AgRP-specific CX43 ablation is sufficient to mildly prevent diet-induced obesity specifically in males. (AU)

• FAPESP's process: 21/11551-4 - Study of hypothalamic circuits that regulate metabolism and the endocrine system
• Grantee: Josiane do Nascimento Silva
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 19/21707-1 - Food deprivation effects in kisspeptin neurons excitability
• Grantee: Renata Frazão
• Support Opportunities: Regular Research Grants
• FAPESP's process: 17/21854-9 - Investigation of pro- and anti-inflamatory cytokines in biophysical properties of POMC and AgRP neurons of the arcuate nucleus of the hypothalamus
• Grantee: Fernanda Machado Chaves
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 20/01318-8 - Central nervous system as a target of growth hormone for the regulation of multiple biological functions
• Grantee: Jose Donato Junior
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 17/16473-6 - Processing of aversive stimuli: circuitry between the laterodorsal tegmental nucleus, the habenula, and dorsal and median raphe nuclei
• Grantee: Martin Andreas Metzger
• Support Opportunities: Regular Research Grants