Researchers from the University of Wisconsin-Madison report that the too much food or energy consumption leads to a problem called metabolic inflammation, according to findings from the mice studies.
"Metabolic inflammation is a chronic, low-grade condition consisting of inflammatory-like responses at the molecular level. It has many downstream consequences," said researcher Dongsheng Cai. "It causes cellular dysfunction, which can decrease the regulation of several physiological processes, including metabolism."
Metabolic inflammation may also be at the core of many chronic, obesity-related metabolic disorders that are so common today, he added.
The new research, published in the journal Cell, highlights the complex nature of obesity and the possible underlying mechanisms.
The food industry has come under increasing pressure to help tackle the rise of obesity. Over 300m adults are obese worldwide, according to latest statistics from the WHO and the International Obesity Task Force. About one-quarter of the US adult population is said to be obese, with rates in Western Europe on the rise although not yet at similar levels.
Study details
The researchers looked at the hypothalamus – the brain structure responsible for maintaining a energy balance in the body – of mice, and focused on a protein complex called NF-kappaB/ IKKbeta.
According to the researchers this pathway is much more abundant in the hypothalamus than in peripheral tissue, but it normally remains inactive in the brain.
However, a high-fat diet that led to over-nutrition was found to activate IKKbeta/NF-kappaB, specifically in neurons in the hypothalamus. This stimulation of the pathway led the animals to increase their energy consumption, while suppressing it helped them maintain normal food intake and body weight.
"When we knocked out the IKKbeta gene to suppress NF-kappaB activity in these neurons, the animals were significantly protected from energy over-consumption and obesity development," said Cai.
Looking inside the cells in order to understand the mechanism, the researchers found that a cell component called the endoplasmic reticulum (ER) underwent stress under conditions of over-nutrition. This stress was the source of the activation of IKKbeta/NF-kappaB.
Suppression of the ER stress led to a preservation of the normal regulation of food intake and prevented obesity, said the researchers.
While a lot of work still needs to be done, building on these very preliminary findings, Cai said that he is maintaining a view of the bigger picture.
The key questions left to be answered are: "How does the environment connect to the genetics that seem to underlie the obesity epidemic? What are the key steps that have led to the dramatic rise of diabetes in the past three decades? Why can't the body adjust to changes that have occurred in the way people eat and what they eat?" he said.
Source: CellVolume 135, Pages 61-73 “Hypothalamic IKKβ/NF-κB and ER Stress Link Overnutrition to Energy Imbalance and Obesity”
Authors: X. Zhang, G. Zhang, H. Zhang, M. Karin, H. Bai, D. Cai