Abstract 1904 Deficient hypothalamic leptin signaling alters visceral adipose tissue immunometabolism in adult Wistar rat

It is known that the increased circulating levels of leptin in obesity stimulate the inflammatory response by macrophages. However, whether deficient central leptin signaling can modify visceral adipose tissue (vAT) immunometabolism remains to be elucidated. In this work, we reduced the central leptin signaling in normoleptinemic adult Wistar rats by chronically administering the superactive leptin receptor antagonist (SLA) (D23L/L39A/D40A/F41A) intracerebroventricularly for 21 days and investigated its impact on vAT immunoregulation. SLA infusion decreased hypothalamic phosphorylation of STAT3. This hypothalamic leptin signaling deficiency mediated by SLA resulted in augmented body weight and food intake, increased visceral adiposity, and adipocyte hypertrophy, without affecting serum leptin levels. Moreover, flow cytometry analysis revealed a phenotypic switch in macrophage polarization in the stromal vascular fraction from vAT in SLA-infused rats. Hypothalamic leptin signaling deficiency did not alter the anti-inflammatory M2 macrophages, while the pro-inflammatory M1 macrophages and dendritic cells increased 2.8- and 1.7-fold, respectively. Additionally, serum levels of pro-inflammatory cytokines IL-6, IL-1beta, and MCP-1 were increased, parallel to decreased levels of the anti-inflammatory cytokine IL-10. Finally, although there was a trend to increase the protein levels of TLR4 and NF-kappa B in vAT, basal phosphorylation of JNK increased markedly 2.5-fold in this tissue. Our results suggest that before the development of hyperleptinemia, decreasing central leptin signaling in normoleptinemic rats reproduces systemic low-grade inflammation associated with obesity, highlighting the important role of central leptin signaling in adipose tissue remodeling and immunometabolism regulation. This work was supported by Ministerio de Ciencia, Innovación y Universidades under project grants RTI2018-098643-B-I00. Ministerio de Ciencia e Innovación under project grants PID2021-128243OB-I00. University of Castilla-La Mancha and the European Regional Development Fund (FEDER) under project grants 2021 GRIN-30987.