1741-P: Immune Regulation of Postprandial Glycemia and Whole-Body Insulin Sensitivity through Myeloid Production of IL-10
Authors: TODA GOTARO , SOEDA KOTARO , ARAKAWA NAOKO , MASUDA YUKARI , KOBAYASHI NAOKI , SUWANAI HIROTSUGU , IZUMIDA YOSHIHIKO , YAMAUCHI TOSHIMASA , KADOWAKI TAKASHI , UEKI KOHJIRO 
Published: June 2020

As feeding increases signals that potently induce gene expression in immune cells, we aimed to elucidate the role of myeloid cells in normal postprandial metabolism. Feeding increased serum levels of LPS, which is known to induce multiple genes in immune cells. Notably, LPS together with insulin potently induced IL-10 in macrophages, which could also be detected in the postprandial portal vein in vivo. In cultured hepatocytes, physiological levels of insulin alone did not suppress gluconeogenic gene expression, although when added together with medium from macrophages stimulated with LPS and insulin, they were markedly suppressed. This suppression was not seen in medium from macrophages of IL-10 knockout mice, showing this to be an IL-10 dependent process. Plasma glucose concentration ad libitum was elevated in mice injected with adenovirus encoding shRNA targeting the IL-10 receptor, and the normal postprandial suppression of gluconeogenic genes in liver was compromised, showing the importance of the IL-10 signal in postprandial glucose metabolism. Furthermore, myeloid-specific knockout of Akt1 and Akt2 resulted in similar phenotypes that were rescued by incrementing mTOR signaling, pointing to an Akt-mTOR dependent mechanism. As whole-body deficiency of IL-10 has been reported to decrease body weight and increase insulin sensitivity, we assessed the effect of myeloid deficiency of IL-10 by conducting bone marrow transfer from IL-10 knockout mice to wild type mice. While these phenotypes were recapitulated, postprandial glucose production was not improved despite markedly increased whole-body insulin sensitivity. These results pointed to the differential actions of myeloid IL-10 where baseline production maintains normal body weight, while postprandial increases in the hepatic-portal system suppresses hepatic gluconeogenic gene expression, collectively showing the need for context-dependent administration of IL-10 based therapies.

Disclosure
G. Toda: None. K. Soeda: None. N. Arakawa: None. Y. Masuda: None. N. Kobayashi: None. H. Suwanai: None. Y. Izumida: None. T. Yamauchi: Research Support; Self; AeroSwitch, Asahi Mutual Life Insurance Company, Astellas Pharma Inc., AstraZeneca K.K., Boehringer Ingelheim International GmbH, Daiichi Sankyo Company, Limited, Kowa Pharmaceutical company,limited., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Corporation Life Sciences Limited, Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Novo Nordisk Inc., NTT Docomo Inc., Ono Pharmaceutical Co., Ltd., Sanofi K.K., Sanwa Kagaku Kenkyusho, Shionogi & Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, TOSOH CORPORATION. Other Relationship; Self; Covidien Japan Inc. (Medtronic Japan Co., Ltd.), Eli Lilly Japan K.K., Johnson & Johnson, Kissei Pharmaceutical Co., Ltd. T. Kadowaki: Research Support; Self; Astellas Pharma Inc., Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, MSD Corporation, Novartis Pharma K.K., Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited. Speaker’s Bureau; Self; Abbott, Astellas Pharma Inc., AstraZeneca K.K., Boehringer Ingelheim Pharmaceuticals, Inc., Cosmic Corporation, Daiichi Sankyo, Eli Lilly Japan K.K., FUJIFILM, Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Medscape Education, Medtronic, Mitsubishi Tanabe Pharma Corporation, MSD Corporation, NIPRO Medical Corporation, Novartis Pharma K.K., Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Terumo Medical Corporation. Other Relationship; Self; Asahi Mutual Life Insurance. K. Ueki: None.

Funding
Japan Society for the Promotion of Science (16K15488, 17K16141, 19K17954)