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Mapping connections between liver, muscle and metabolism in obesity Mouse study finds obesity disrupts metabolism both within and between organs

March 11, 2021

Graphical abstract of the research project showing a healthy and obese mouse in the top left corner, blood test in the center, and liver and muscle at the bottom.

Researchers revealed obesity-induced dysfunction of inter-organ metabolic cycles by constructing a trans-omic network by integrating blood metabolites data with data about the altered metabolism in liver and muscle of healthy and obese mice. © Shinya Kuroda CC BY-SA 3.0

Researchers have identified changes in the metabolism of liver and skeletal muscle cells in live mice that are likely connected to obesity-associated metabolic disorders. This study was led by Professor Shinya Kuroda, head of the Systems Biology Lab at the University of Tokyo and an expert in trans-omics research, which combines the different "omics" scientific specialties — transcriptomics (gene activity), proteomics (proteins), and metabolomics (metabolites) — to map the molecular interactions inside cells in a highly detailed way.

“We are interested in elucidating the whole picture of how obesity disrupts healthy control of metabolic processes in our body through an unbiased and comprehensive analysis of metabolic molecules,” said Kuroda.

Metabolism is regulated both within individual organs and by interactions between organs through the blood. According to current scientific understanding, obesity is linked to Type 2 diabetes because obesity disrupts the healthy metabolic cycle between organs.

“The inter-organ metabolic cycles are large and complex. To reveal the dysfunction of regulatory mechanisms associated with obesity, we constructed large-scale regulatory networks of the differences in liver and muscle metabolism between healthy and obese mice,” Kuroda explained.

Researchers collected blood, muscle and liver samples from adult (10-week-old) mice that had fasted for 16 hours. Researchers tested both healthy (wild-type) mice and mice genetically predisposed to obesity. The samples were put through a range of different analyses to identify and quantify genetic material, proteins and substances produced by metabolism called metabolites.

In total, researchers examined the expression of 13,795 genes in the liver and 14,301 genes in skeletal muscle, 2,373 proteins in liver and 1,078 proteins in skeletal muscle, plus phosphorylation (chemical modification of adding a phosphate group) of an additional 14 proteins involved in insulin signaling, and 167 metabolites in liver and 102 polar metabolites in skeletal muscle.

After identifying any molecules that existed in different amounts in healthy and obese mice, researchers used databases to identify the cell signaling pathways that involve those molecules. By connecting the different networks, researchers built a map of the likely cellular signaling networks controlling metabolism in the liver and muscle of healthy and obese mice.

“It was surprising to discover that enhanced glucose production in the liver and reduced glucose utilization in muscles may lead to high fasting blood sugar levels in obese mice [blood sugar measured after 16 hours of not eating]. It was also an impressive experience to clarify the potential mechanisms of those dysfunctions in each organ,” Kuroda commented.

This research is a peer-reviewed experimental study in mice, published in iScience, a Cell Press journal. Collaborators at RIKEN Center for Integrative Medical Science, Niigata University, Keio University, University of Tsukuba, Kanazawa University and Kyushu University also contributed to this research.

Papers

Riku Egami, Toshiya Kokaji, Atsushi Hatano, Katsuyuki Yugi, Miki Eto, Keigo Morita, Satoshi Ohno, Masashi Fujii, Ken-ichi Hironaka, Saori Uematsu, Akira Terakawa, Yunfan Bai, Yifei Pan, Takaho Tsuchiya, Haruka Ozaki, Hiroshi Inoue, Shinsuke Uda, Hiroyuki Kubota, Yutaka Suzuki, Masaki Matsumoto, Keiichi I. Nakayama, Akiyoshi Hirayama, Tomoyoshi Soga, and Shinya Kuroda, "Trans-Omic Analysis Reveals Obesity-Associated Dysregulation of Inter-Organ Metabolic Cycles between the Liver and Skeletal Muscle," iScience: February 20, 2021, doi:10.1016/j.isci.2021.102217.
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