Metabolomic alteration in adipose specific monocyte chemotactic protein-1 deficient mice fed a high-fat diet

Authors: Yan, Lin; RUST, BRET - Indiana University; SUNDARAM, SNEHA - Former ARS Employee; NIELSEN, FORREST - Retired ARS Employee

Submitted to: Nutrition and Metabolic Insights
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/19/2024
Publication Date: 9/28/2024
Citation: Yan, L., Rust, B., Sundaram, S., Nielsen, F.H. 2024. Metabolomic alteration in adipose specific monocyte chemotactic protein-1 deficient mice fed a high-fat diet. Nutrition and Metabolic Insights. 17:1-13. https://doi.org/10.1177/11786388241280859.
DOI: https://doi.org/10.1177/11786388241280859

Interpretive Summary: Obesity affects 42% (108.5 million) of the adult population in the U.S. Obesity is a metabolic disorder with excess accumulation of body fat mass, which is a risk factor for chronic diseases including diabetes, heart disease, stroke, and certain types of cancer. Fat tissue is not inert but an active organ in the body that produces biologically active chemicals. These chemicals play important roles in body fat buildup and metabolic disturbance in obesity. Monocyte chemotactic protein-1 (MCP1) is a fat-derived chemical. Increases in MCP1 are positively correlated with body mass index and metabolic disturbance (for example, increased insulin resistance and higher blood sugar) in humans with obesity. To understand the role of fat-derived MCP1 in metabolism, we conducted untargeted metabolomic analysis of primary metabolism using liver samples from wild-type control mice in comparison to transgenic mice with MCP1 specifically removed from fat tissue. We found that the expression of 15 metabolites differed significantly between wild-type and transgenic mice. These metabolites were involved in protein, energy, and lipid metabolism. Most importantly, two metabolic pathways that are related to amino acid metabolism (the aminoacyl-tRNA biosynthesis and the phenylalanine, tyrosine, and tryptophan biosynthesis pathways) were altered significantly between the two mouse types, indicating that fat-derived MCP1 may impact protein metabolism considerably. Findings from this study suggest that maintaining a healthy body weight without excess body fat mass can prevent the production of unwanted bioactive chemicals from fat, including MCP1, which can be beneficial to metabolic health and reduce the risk of obesity.

Technical Abstract: Monocyte chemotactic protein-1 (MCP-1) is a small inducible cytokine that is involved in obesity-related chronic disorders. Adipocytes produce MCP-1 that is elevated in obese humans and in rodent models of obesity. The objective of this study was to determine the hepatic metabolomic alterations caused by adipose-specific MCP-1 deficiency in a rodent model of obesity. Wide-type (WT) and adipose-specific Mcp-1 knockdown mice (Mcp-1-/-) were each assigned randomly to two groups and fed the AIN93G standard diet or a HFD for 12 weeks. Compared to the AIN93G diet, the HFD increased body weight, body fat mass, and plasma concentrations of insulin and leptin, regardless of genotype. There were no differences in these variables between WT and Mcp-1-/- mice when they were fed the same diet. Eighty-seven of 172 identified metabolites met the criteria for metabolomic comparisons among the four groups. Thirty-nine metabolites differed significantly between the two dietary treatments and 15 differed when Mcp-1-/- mice were compared to WT mice. The metabolites that significantly differed in both comparisons included those involved in amino acid, energy, lipid, nucleotide, and vitamin metabolism. Network analysis found that both HFD and adipose Mcp-1 knockdown may considerably impact amino acid metabolism as evidenced by alteration in the aminoacyl-tRNA biosynthesis pathways, in addition to alteration in the phenylalanine, tyrosine, and tryptophan biosynthesis pathway in Mcp-1-/- mice. However, decreased signals of amino acid metabolites in mice fed the HFD and increased signals of amino acid metabolites in Mcp-1-/- mice indicate that HFD may have down-regulated and adipose Mcp-1 knockdown may have up-regulated amino acid metabolism.