1594-P: Interorgan Insulin-Leptin Signal Cross Talk Originating in the Liver Enhances Survival under Food-Shortage Conditions

Abstract

The liver can store energy and distribute it to other tissues/organs, according to the energy states involving hepatic insulin action. In addition, we and others have shown that the liver transmits metabolic information to other organs, via neuronal and humoral mechanisms. Herein, we demonstrate a novel form of inter-organ crosstalk originating in the liver, which links hepatic insulin action with hypothalamic leptin signaling and promotes survival during food shortage. We first observed that tamoxifen-inducible liver insulin receptor (IR) knockout (iLIRKO) mice ate more and consumed less oxygen with decreased hypothalamic leptin action, thereby gaining body weight. Circulating soluble leptin receptor (sLepR) levels were elevated in iLIRKO mice. We then produced tamoxifen-inducible liver leptin receptor (LepR) and IR double-knockout (iLLepRIRKO) mice. In iLLepRIRKO mice, sLepR elevations were not seen. Moreover, increased body weights, hyperphagia and decreased whole-body oxygen consumption seen in iLIRKO mice were reversed, indicating the importance of hepatic sLepR production in the liver-hypothalamus crosstalk. Human hepatic lepr and circulating sLepR levels also correlated negatively with hepatic insulin action indices. Additionally, we restricted food intake in wild type mice. Food restriction decreased hepatic insulin action and whole-body oxygen consumption with increased circulating sLepR. We furthermore performed food restriction in tamoxifen-inducible liver LepR knockout (iLLepRKO) mice. Notably, in iLLepRKO mice, the decreases in basal metabolic rates were blunted and mortality was markedly increased during food restriction. Collectively, the liver translates metabolic cues regarding energy-deficient status, which is reflected by decreased hepatic insulin action, into sLepR, thereby suppressing energy dissipation. This novel inter-organ crosstalk may assure survival of individuals facing food shortages in nature. Disclosure K.Takahashi: Speaker's Bureau; Taisho Pharmaceutical Holdings Co., Ltd. T.Yamada: Speaker's Bureau; MSD, Mitsubishi Tanabe Pharma Corporation, Eli Lilly Japan K.K., Boehringer Ingelheim Japan, Inc., Novo Nordisk, Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Abbott Japan Co., Ltd. H.Katagiri: None. Funding Japan Society for the Promotion of Science (21K08522, 22H03126, 20H05694); Japan Science and Technology Agency (JPMJPS2023)