Rogue one: Liver immune cells turn to dark side in the face of obesity

By Will Chu

- Last updated on GMT

Multiple factors contribute to obesity-induced insulin resistance, but low-grade chronic inflammation of metabolic tissues of the liver is one central factor in its development. ©iStock
Multiple factors contribute to obesity-induced insulin resistance, but low-grade chronic inflammation of metabolic tissues of the liver is one central factor in its development. ©iStock

Related tags: Obesity, Insulin

Being overweight and following a high-fat diet appears to reprogram virus-fighting immune cells into disease-promotors in a discovery that sheds light as to why the liver produces an excess of glucose in diabetics.

Experimenting on human livers and mice cells, the scientists found that obesity can cause specific white blood cells (liver CD8+ T cells) to turn from removing viral infections into inflammatory cells that increase blood sugar and worsen insulin resistance.

The discovery also adds further insights into why the liver overproduces glucose in diabetic patients.

It is thought a pro-inflammatory response interferes with normal metabolism in the liver, jamming up or blocking insulin signalling to the liver cells.

This causes the organ to continue producing sugar that floods the bloodstream.

"This response never manifested itself until humans started to eat high-sugar, high-fat, high-calorie diets,"​ said Magar Ghazarian, lead author previously from the Department of Immunology, University of Toronto.

According to fellow study author Dr. Shawn Winer the findings move diabetic research from a nutritional and hormonal condition to one that has a heavy immune system and inflammation influence.

“That's the developing link,​ he commented.  “Inflammation is emerging to be a major mediator of insulin resistance."

Type 2 diabetes is one of the fastest growing diseases in Europe with about 60 million people currently afflicted.

The World health Organization (WHO) projects diabetes deaths will double between 2005 and 2030.

Being overweight or obese is an important risk factor for diabetes. It is estimated that about 10.3% of men and 9.6% of women aged 25 years and over in the European Region have the condition.

Study details 

mice animal experiment research science iStock.com MarquesPhotography
Mice were fed with either a normal chow diet (NCD - 15% kcal fat) or a high-fat diet (HFD - 60% kcal fat). ©iStock/Marques Photography

Researchers from the University of Toronto fed mice with either a normal chow diet (NCD - 15% kilocalories (kcal) fat) or a high-fat diet (HFD - 60% kcal fat) starting at 6 weeks of age for 16 to 32 weeks.

Compared with NCD–fed mice, HFD-fed mice showed worsened glucose tolerance test (GTT), insulin tolerance test (ITT), and increased triglycerides in the blood.

In addition, there was a substantial increase in the numbers of CD8+ T immune cells in the liver, indicating an altered immune response.

Instead, these cells launch an inflammatory response to fat and to bacteria that travel to the liver from the gut through the blood.

The cells then produce increased numbers of cytokine proteins – part of the pro-inflammatory response that interferes with normal metabolism in the liver, blocking insulin signalling to the liver.

In further work using human liver cells, higher levels of CD8+ T cells were linked with higher levels of blood sugar or more advanced fatty liver disease. 

“We found that under conditions of obesity and a high-fat diet, the cells that typically strengthen our immune system by killing viruses and pathogens instead increase blood sugar. They become pathogenic and worsen insulin resistance,"​ said Dr Daniel Winer, assistant professor at the Department of Laboratory Medicine and Pathobiology and Immunology, University of Toronto.

"The immune system in the liver represents a key missing link in our understanding of how the liver malfunctions in obesity to dysregulate sugar levels,"​ added Dr Xavier Revelo, a post-doctoral fellow also based at the University’s Department of Laboratory Medicine and Pathobiology and Immunology.

The liver is an organ that is particularly affected by the effects of obesity and a high-fat diet.

Nonalcoholic fatty liver disease (NAFLD), which can progress to nonalcoholic steatohepatitis (NASH) are manifestations of metabolic syndrome in the liver.

While the underlying mechanisms linking fatty liver, inflammation, and insulin resistance (IR) are largely unknown, NAFLD has been associated with enhanced proinflammatory cytokine​ markers.

The team thought that CD8 + T cells could potentially be used as markers for the progression of fatty liver disease.

Current estimates​ place the number of people suffering from a chronic liver condition in the European Union at 29 million.

Source: Science Immunology

Published online ahead of print: doi: 10.1126/sciimmunol.aai7616

“Type I interferon responses drive intrahepatic T cells to promote metabolic syndrome.”

Authors: Magar Ghazarian, Xavier Revelo, Daniel Winer, Shawn Winer, Daniel Winer

Related topics: Science, Reformulation, Diet and health

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