PI3K signaling pathway in leptin receptor expressing cells is not required for endotoxemia‐induced hypophagia (LB764)

Abstract

Hypophagia and increased energy expenditure under inflammatory conditions, such as that observed after bacterial lipopolysaccharide (LPS) administration, are associated with leptin secretion and stimulation of JAK2‐STAT3 signaling in the CNS. Anorexic effect of leptin also depends on the activation of PI3K signaling pathway. However, the role of PI3K in the endotoxemia‐induced anorexia remains an open question. To investigate if PI3K in leptin receptor expressing cells has a role in the hypophagia and body weight (BW) loss induced by acute endotoxin treatment, mice expressing Cre‐recombinase driven by Lepr promoter were crossed with mice with loxP‐modified p110α allele (Pi3kca gene) and were treated with LPS (100ug/Kg, ip) (1 LPS). Since long term exposure to endotoxin induces desensitization of hypophagia and an inability of leptin to phosphorylate STAT3, we also tested PI3K role in feeding and BW gain in mice submitted to repeated LPS injections (6 LPS). Single LPS, but not 6 LPS control mice (p110α fl/fl), showed reduced food intake (1 LPS: 1.67 ± 0.18g, 6 LPS: 3.07 ± 0.34g), compared with saline injection (3.83 ± 0.25g). Acute LPS also reduced BW (‐0.97 ± 0.19g), compared with 6 LPS (0.49 ± 0.16g) and saline groups (0.31 ± 0.12g). The hypophagia and BW loss induced by 1 LPS were similar in p110α fl/fl‐LepR cre/cre mice; (1.72 ± 0.28g; ‐0.91 ± 0.14g BW), with no changes in 6 LPS (3.47 ± 0.12g; 0.92 ± 0.09g BW) and saline groups (3.25 ± 0.22g; 0.47 ± 0.18g BW). The data suggest that PI3K in leptin receptor expressing cells is not required for acute LPS induced anorexia and has no effect on food intake and BW gain during long term endotoxemia.Grant Funding Source: Supported by FAPESP and NIH: HD61539; HD 69702