Gene Impacted by High Fat Diets Identified

It has long been known that genes determine the characteristics of an organism and today it is known that they can even influence the type of diseases an individual is likely to develop. Watson and Crick discovered that genes are segments of DNA that are codes for the synthesis of specific proteins that have a structural or functional role within the body. Gene expression occurs through the processes of transcription and translation.

Interest in genes linked to obesity

Obesity is an increasing problem in the developed world and much research is being conducted on the condition. Genes linked to obesity have been of particular interest. In 2007 scientists claimed to have found a gene that was linked to obesity. Research showed that individuals with two copies of the gene had a 70 percent greater risk of becoming obese than those with none and on average weighed 3kg more. Half of white Europeans had one copy of the gene and one in six had two copies. The gene could explain why certain individuals find it hard to lose weight. It was hoped that further understanding of how the gene influenced the development of obesity would lead to treatments for the condition. Obesity is the main cause of cancer, heart disease and type 2 diabetes and presents a greater danger to an individual than alcohol, smoking or poverty.

Deletion of gene prevents obesity in mice

Now researchers at the University of Michigan have identified a gene that controls obesity in mice. If the gene was switched off the mice remained thin even on a high fat diet. The gene is also associated with inflammatory processes. Alan Saltiel, director of the U-M Life Sciences Institute said that researchers have long been looking for genes associated with obesity, known as obesogenes, but this is the first time that the deletion of a particular gene has been shown to stop weight gain in an animal.

IKKE

It is known that obesity and type 2 diabetes are associated with chronic inflammation. The association is studied by deleting genes that are part of the signaling pathway in mice. The mutant mice are known as knockout mice. Recent studies have examined the effects of deleting the gene IkappaB kinase epsilon (IKKE), which is known to be an activator of a major inflammation-signaling pathway.

Inflammation is the body’s response to infection, irritation or injury and is a complex process. Many different processes are mobilized to destroy damaged tissues, fight off invaders and prepare the body for healing. Cells have to undergo large changes in their gene expression programs. Master regulators control large groups of genes. The master regulators, otherwise known as transcription factors, bind to DNA sequences in the regulatory regions of genes. When this binding occurs, the transcription of DNA into messenger RNA is activated and in turn the mRNA is translated into proteins. A small number of master regulator proteins can completely change a cell’s functions. NF-kappa B is one of these master regulators. If NF-kappa B was always active the body would be in a constant state of inflammation, but this is prevented by the inhibitor I kappa B. A complex of IKKE proteins gives the signal to release NF-kappa B and these proteins are under the control of the gene IKKE.

Deleting the IKKE gene protects mice against conditions that would in humans lead to type 2 diabetes. This condition is associated with obesity and its incidence is on the rise in America, in children and adolescents, as well as the adult population.

Mice with the IKKE gene gained weight when fed a high-fat diet and also showed a loss of insulin sensitivity, which is a precursor to the development of type 2 diabetes.

The study is of interest because if it could be shown that the same gene is linked to obesity in humans then it would provide a target for potential drugs to treat obesity, diabetes and other complications associated with the condition.

The high-fat diet mice were fed a substance similar to lard in which 45 percent of its calories came from fat. Control mice were fed a standard feed with 4.5 percent of its calories derived from fat. The mice were started on their dietary regimen at 8 weeks of age and were maintained on the diet for 14 or 16 weeks.

The IKKE gene produces a protein kinase of the same name. Protein kinases are enzymes with the ability to turn other proteins off or on. IKKE protein kinase appears to target proteins that control genes that regulate the metabolism of the mouse.

When normal mice were fed a high-fat diet their IKKE protein kinase levels rose and their metabolic rate slowed. As a result the mice gained weight. This shows that in normal mice IKKE protein kinase acts as a brake on metabolism. Fat cells and liver cells in both obese mice and humans produce greater amounts of IKKE protein.

When knockout mice were fed a high-fat diet they did not gain as much weight. In addition there was no hepatic inflammation or insulin insensitivity and leptin levels were lower. Serum cholesterol levels were also lower than those in the control group. Whilst the control group of mice developed steatosis (fatty liver) and insulin resistance as well as general inflammation in liver and fat tissue the knockout mice remained healthy. This is apparently due to the fact that IKKE protein kinase is no longer produced and so cannot act as a brake on the metabolism. The metabolic rate thus rises, burning more calories and leading to less fat being stored. Even when the knockout mice were fed a normal diet their metabolism differed from that of the normal mice. Their body weight was similar but insulin levels were 50 percent higher and triglyceride levels were reduced by 20 percent.

The knockout mice did not exercise more than the control mice thus the difference must have been due to the burning of extra calories. This was reflected in the raised body temperature of the mice and increased oxygen consumption, which was double that of the control mice. Compared to the control mice the rectal temperature of the knockout mice was 0.5 degrees higher on the normal diet and 1.4 degrees higher on the high-fat diet.

Earlier findings have shown that mice without the IKKE gene are more susceptible to lethal viral infections, which may be because the same pathway is involved in immune function.

Previous research has indicated that IKKE and its protein kinase play a role in metabolism and weight regulation. The IKKE gene is primarily associated with immune and inflammatory processes, but as obesity typically causes low-level inflammation throughout the body it is not surprising that IKKE is linked to obesity.

Action of IKKE and the search for drugs

IKKE’s action is still not fully understood, including the substrates that it acts upon. It may be that the targets are repressors or transcriptional activators that regulate metabolic genes. Members of the interferon regulatory factor family in certain fat cells are of particular interest. The researchers suggest that IKKE directly regulates the multiple pathways that activate marcophages and adipocytes in the liver and other parts of the body. However, its role could be more limited so that deletion of the gene simply prevents the initial inflammatory response to a fatty diet leading to metabolic resistance to diet.

The search is now on to find a molecule that would block the action of IKKE protein kinase which would create the same effect without having to knock out the gene. If such inhibitors could be found they would be good candidates for drugs to treat obesity.

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