Thelivers of obese mice respond to sugar many times slower than those in healthy mice because they must rely on a less-efficient form of metabolism, according to a study published in Science Signaling, demonstrating fundamental differences in how their bodies manage food.
The Japanese scientists behind the paper revealed that healthy mice employ fast-acting enzyme regulation when they eat the simple sugar glucose, a system unavailable to the obese mice, which also had Type 2 diabetes and high blood sugar. Instead, the unhealthy mice had to rely on the relatively slow and imprecise process of activating genes to make use of the sugar.
Their findings could be used to understand the roles of genetics and other factors in the metabolism of humans with similar conditions.
The researchers studied dozens of obese, diabetic mice to learn how their livers processed glucose, a simple sugar. (The mice had been bred not to produce the hunger-inhibiting hormone leptin; they developed clear symptoms of Type 2 diabetes, which reduces the quantity and efficacy of insulin and impairs glucose tolerance.) They used “wildtype” mice as a healthy control group and took several liver and blood samples from both kinds of mice during the four hours after feeding them glucose.
The samples were analyzed to see how consuming sugar affected a range of biological systems — insulin signaling, gene expression, metabolic reactions, metabolic enzymes and metabolites, which are molecules produced when the body processes food and other essential compounds during metabolism.
The researchers then plugged the data into a network that interconnected these different layers to paint a comprehensive picture of what the liver is doing to metabolize the sugars.
“Using the constructed network, we can comprehensively identify the mechanism of multi-factorial complex diseases, such as metabolic syndrome” in the obese rats, Shinya Kuroda and Toshiya Kokaji, two authors of the paper from the University of Tokyo, said in an email. Metabolic syndrome involves a cluster of conditions that can cause Type 2 diabetes and heart disease, such as high blood pressure, high blood sugar and excess belly fat.
The wildtype mice used many metabolites in their livers to quickly respond to the glucose, including some crucial to many reactions such as the energy-carrying ATP. The metabolites also drove enzymes that catalyze metabolic reactions involved in breaking down sugar.
Their metabolite-driven response was much faster than those found in obese mice, which responded with many fewer metabolites. Instead, they relied on expressing genes to create new enzymes, carbohydrates and lipids to use metabolic reactions for the sugar, a much slower process.
“We revealed that rapid changes in metabolites widely regulated metabolism in the liver of healthy mice after glucose injection, while obese mice lost most of the rapid regulations and activated relatively slower transcriptional regulations,” said Kuroda and Kokaji, who are respectively a professor and a graduate student in their university’s department of biological sciences.
They said fast-acting metabolic regulation found in the wildtype mice may lessen post-meal spikes in blood sugar, which are commonly experienced by diabetics.
The slow response in obese mice may have been because their metabolites were already overburdened. The research team observed that concentrations of ATP and some other metabolites were highest in obese mice despite their concentrations being the same as before consuming sugar, having risen only in the healthy mice.
It suggested that the obese mice were already maxed out on metabolites when producing energy during the 16 hours of fasting the mice underwent before eating sugar, the researchers wrote. This could explain why they couldn’t tap that quick system to handle the newly consumed glucose.
Kuroda and Kokaji said they are currently comparing their findings to genes in humans with Type 2 diabetes to understand how genetics cause it and other conditions. They also plan to use a similar analysis to other analyze organs that are connected to metabolic processes and disrupted by obesity and Type 2 diabetes, such as body fat and muscle tissues.
The article, “Transomics analysis reveals allosteric and gene regulation axes for altered hepatic glucose-responsive metabolism in obesity” was published Dec. 1 in Science Signaling. The authors of the study were Toshiya Kokaji, Atsushi Hatano, Miki Eto, Keigo Morita, Satoshi Ohno, Ken-ichi Hironaka, Riku Egami, Akira Terakawa, Yutaka Suzuki, Shinya Kuroda, University of Tokyo; Yuki Ito, University of Tokyo and Kyushu University; Katsuyuki Yugi, University of Tokyo and Keio University; Masashi Fujii, University of Tokyo and Hiroshima University; Takaho Tsuchiya, Haruka Ozaki, University of Tsukuba; Hiroshi Inoue; Shinsuke Uda Hiroyuki Kubota, Keiichi Nakayama, Kyushu University; Kazutaka Ikeda, Yokohama City University; Makoto Arita, Yokohama City University and Keio University; Masaki Matsumoto, Niigata University; Akiyoshi Hirayama, Tomoyoshi Soga, Keio University. The lead authors were Toshiya Kokaji, Atsushi Hatano and Yuki Ito.