Macrophages React to Postprandial Signals and Regulate the Response to Feeding through Akt-mTOR–Dependent Production of IL-10

Abstract

We explored the role of the serine/threonine protein kinase Akt in macrophages, using conditional knockout models. Myeloid specific Akt1 Akt2 double knockout mice (MAktDKO mice), fed a normal chow diet, showed higher plasma glucose levels in the fed state. Among the various responses to feeding, the liver of MAktDKO mice did not show the repressed gluconeogenic gene expression in response to feeding. As this was also mimicked in mice treated with multiple antibiotics to eradicate the intestinal flora, lipopolysaccharide (LPS), which increases in the blood after feeding may play a role in this context. Among genes Akt dependently induced by LPS, IL-10 was induced in 72 hours when stimulated by LPS alone, but this induction was markedly shortened to 3 hours when also stimulated by insulin. Elevations of plasma concentrations of IL-10 could be detected in the portal vein after feeding, and such concentrations of IL-10 augmented suppression of gluconeogenic gene expression in primary hepatocytes by physiologically detected levels of insulin. Deficient suppression of gluconeogenic gene expression in these mice was rescued when mTOR signaling was strengthened by deletion of TSC2, implicating an important role of Akt-mTOR signaling in the feeding response. Moreover, mice injected with adenovirus expressing short hairpin RNA targeting the IL-10 receptor showed deficient suppression of post prandial gluconeogenic gene expression, in support of a model in which macrophages respond to postprandial signals, regulating glucose homeostasis in the liver by expressing IL-10 in an Akt-mTOR dependent process. Disclosure G. Toda: None. N. Kamei: None. K. Soeda: None. Y. Masuda: None. Y. Izumida: None. N. Kobayashi: None. T. Sasako: None. K. Tobe: Research Support; Self; Bristol-Myers Squibb Company, Takeda Pharmaceutical Company, Teijin Pharma Limited, Japan Diabetes Society, Eli Lilly and Company, MSD K.K., Kyowa Hakko Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Pfizer Inc., Astellas Parma Inc, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Company, Limited, Novo Nordisk Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Tsumura Co., Ono Pharmaceutical Co., Ltd., Novartis Pharma K.K., Sumitomo Dainippon Pharma Co. M.J. Birnbaum: None. T. Kadowaki: Consultant; Self; Novo Nordisk A/S, AstraZeneca, Merck Sharp Dohme Corp.. Research Support; Self; Kissei Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Sanofi, Kyowa Hakko Kirin Co., Ltd., Novo Nordisk A/S, Astellas Pharma, Daiichi Sankyo Company, Limited, Takeda, Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Merck Sharp Dohme Corp., Nippon Boehringer Ingelheim Co. Ltd.. Speaker's Bureau; Self; Astellas Pharma, AstraZeneca, Merck Sharp Dohme Corp., Ono Pharmaceutical Co., Ltd., Takeda, Eli Lilly and Company, Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk A/S. K. Ueki: Speaker's Bureau; Self; Daiichi Sankyo Company, Limited, Eli Lilly and Company, Boehringer Ingelheim Pharmaceuticals, Inc., MSD K.K., Novo Nordisk Inc., Mitsubishi Tanabe Pharma Corporation, Kyowa Hakko Kirin Co., Ltd., Takeda. Research Support; Self; Takeda, Astellas, Novo Nordisk Inc..