Roles for Cell-Cell Adhesion and Contact in Obesity-Induced Hepatic Myeloid Cell Accumulation and Glucose Intolerance

Publication date: 14 March 2017
Source:Cell Reports, Volume 18, Issue 11
Author(s): Yasutaka Miyachi, Kyoichiro Tsuchiya, Chikara Komiya, Kumiko Shiba, Noriko Shimazu, Shinobu Yamaguchi, Michiyo Deushi, Mizuko Osaka, Kouji Inoue, Yuta Sato, Sayaka Matsumoto, Junichi Kikuta, Kenjiro Wake, Masayuki Yoshida, Masaru Ishii, Yoshihiro Ogawa
Obesity promotes infiltration of inflammatory cells into various tissues, leading to parenchymal and stromal cell interaction and development of cellular and organ dysfunction. Liver sinusoidal endothelial cells (LSECs) are the first cells that contact portal blood cells and substances in the liver, but their functions in the development of obesity-associated glucose metabolism remain unclear. Here, we find that LSECs are involved in obesity-associated accumulation of myeloid cells via VLA-4-dependent cell-cell adhesion. VLA-4 blockade in mice fed a high-fat diet attenuated myeloid cell accumulation in the liver to improve hepatic inflammation and systemic glucose intolerance. Ex vivo studies further show that cell-cell contact between intrahepatic leukocytes and parenchymal hepatocytes induces gluconeogenesis via a Notch-dependent pathway. These findings suggest that cell-cell interaction between parenchymal and stromal cells regulates hepatic glucose metabolism and offers potential strategies for treatment or prevention of obesity-associated glucose intolerance.

Graphical abstract

Teaser

Obesity promotes myeloid cell accumulation in the liver, increasing hepatic inflammation and glucose intolerance. Miyachi et al. find that liver sinusoidal endothelial cells play an important role in hepatic myeloid cell accumulation via VLA-4-dependent cell-cell adhesion. Accumulating myeloid cells activate Notch signaling and gluconeogenesis in hepatocytes through cell-cell contact.


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