Insulin- and Lipopolysaccharide-Mediated Signaling in Adipose Tissue Macrophages Regulates Postprandial Glycemia through Akt-mTOR Activation.

Abstract

The physiological role of immune cells in the regulation of postprandial glucose metabolism has not been fully elucidated. We have found that adipose tissue macrophages produce interleukin-10 (IL-10) upon feeding, which suppresses hepatic glucose production in cooperation with insulin. Both elevated insulin and gut-microbiome-derived lipopolysaccharide in response to feeding are required for IL-10 production via the Akt/mammalian target of rapamycin (mTOR) pathway. Indeed, myeloid-specific knockout of the insulin receptor or bone marrow transplantation of mutant TLR4 marrow cells results in increased expression of gluconeogenic genes and impaired glucose tolerance. Furthermore, myeloid-specific Akt1 and Akt2 knockout results in similar phenotypes that are rescued by additional knockout of TSC2, an inhibitor of mTOR. In obesity, IL-10 production is impaired due to insulin resistance in macrophages, whereas adenovirus-mediated expression of IL-10 ameliorates postprandial hyperglycemia. Thus, the orchestrated response of the endogenous hormone and gut environment to feeding is a key regulator of postprandial glycemia.

• Authors: Gotaro Toda, Kotaro Soeda, Yukiko Okazaki, Naoki Kobayashi, Yukari Masuda, Naoko Arakawa, Hirotsugu Suwanai, Yosuke Masamoto, Yoshihiko Izumida, Nozomu Kamei, Takayoshi Sasako, Ryo Suzuki, Tetsuya Kubota, Naoto Kubota, Mineo Kurokawa, Kazuyuki Tobe, Tetsuo Noda, Kenya Honda, Domenico Accili, Toshimasa Yamauchi, Takashi Kadowaki, Kohjiro Ueki
• Journal: Molecular cell (Mol Cell) Vol. 79 Issue 1 Pg. 43-53.e4 (07 02 2020) ISSN: 1097-4164 [Electronic] United States
• PMID: 32464093 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Blood Glucose
• Hypoglycemic Agents
• IL10 protein, mouse
• Insulin
• Lipopolysaccharides
• Tsc2 protein, mouse
• Tuberous Sclerosis Complex 2 Protein
• Interleukin-10
• mTOR protein, mouse
• Akt1 protein, mouse
• Akt2 protein, mouse
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases

Topics

• Adipose Tissue (drug effects, metabolism)
• Animals
• Blood Glucose (analysis)
• Gluconeogenesis (genetics)
• Hyperglycemia (etiology, metabolism, pathology)
• Hypoglycemic Agents (pharmacology)
• Insulin (pharmacology)
• Insulin Resistance
• Interleukin-10 (physiology)
• Lipopolysaccharides (pharmacology)
• Macrophages (drug effects, metabolism)
• Male
• Mice
• Mice, Inbred C3H
• Mice, Knockout
• Postprandial Period
• Proto-Oncogene Proteins c-akt (physiology)
• Signal Transduction
• TOR Serine-Threonine Kinases (genetics, metabolism)
• Tuberous Sclerosis Complex 2 Protein (physiology)