Mouse model may provide link between metabolism, disease

A gene called c-Cbl ('see sybil') has emerged as a hot -- literally -- new lead into the genetic maze linking differences in energy metabolism to obesity and type 2 diabetes.

Dr David James' diabetes and obesity research group at Sydney's Garvan Medical Research Institute have shown that transgenic 'knockout' mice lacking a functional c-Cbl gene run 'hot' and burn energy at a rate that allows them to eat much more than their normal littermates without gaining weight.

The c-Cbl knockout mouse has a basal metabolic rate 30 per cent higher than its normal littermates, reflected in a core temperature that averages 1 degree higher.

The Garvan team published its findings this week in the Journal of Clinical Investigation. They reported that, at a similar bodyweight to their littermates, the knockout mice are leaner and more muscular, with lower levels of triglycerides and free fatty acids in their serum.

They also have lower levels of leptin, the appetite-regulating hormone secreted by fat-storing adipocytes. They also have enhanced insulin action that allows them to make more efficient use of blood glucose, and reduces their risk of type 2 diabetes.

James said the discovery was made by chance, and came as a big surprise -- there had been no indication that c-Cbl might play a role in obesity and diabetes.

His team didn't create the c-Cbl knockout mouse -- it was developed by Prof David Bowtell's research team of the Peter MacCallum Cancer Research Institute in Melbourne, which was investigating the gene's role in mediating the immune system's response to mutant proteins expressed by tumours. "I'd love to say we had a vision, but the result was completely unexpected," he said.

James said the mouse represented a new avenue for investigating the genetic mechanisms involved in diabetes -- and possibly, to develop new drug therapies to treat obesity and diabetes. The discovery could lead to new drugs to treat obesity and diabetes, by allowing people to over-eat and then burn off surplus food energy into heat, instead of storing it as fat.

James says the gene may not have a direct role in obesity and energy metabolism. However, it may act to control the levels of another factor that may be part of the elusive internal thermostat that regulates basal metabolic rate.

Shutting down the gene appears to set the thermostat on high, so the body rapidly burns off excess biochemical energy instead of transferring it to long-term storage, as fat.

One reason the c-Cbl gene's role in energy metabolism was unsuspected is that it codes for a ubiquitin ligase -- an enzyme that 'tags' unwanted proteins, marking them for destruction by the body's cellular waste-disposal systems.

The challenge now is to identify which of the proteins it is marking for disposal to modulate energy metabolism -- James' suspicion is that its target is a receptor tyrosine kinase, a cellular 'switch' that activates the body thermostat. If this is the case, silencing c-Cbl would up-regulate the expression of the receptor tyrosine kinase, setting the thermostat on high to burn fat.

While there are early indications that c-Cbl main effect is to switch muscle metabolism into thermogenesis, James says there is an exciting possibility that the muscles are merely the downstream target for a signal originating in the brain - in the hypothalamus, the centre of basic drives, including appetite.

"A lot of the emphasis in metabolic research is now switching to the brain," he said. "We're focusing on skeletal muscle, but we're cognizant of the possibility that the effect may originate in the brain.

"There's a lot more going on in the hypothalamus than appetite regulation -- it could be that thermogenesis is centrally programmed, in the brain. An interesting way of thinking about the significance of this discovery is to ask whether overeating turns on the pathways that normally control weight, or does it switch them off?"

Asked if the c-Cbl knockout mouse might have a parallel in some variant of a human gene that allows a lucky few people to eat as much as they like without gaining weight, James said, "Why would we doubt it? We know such people exist, and that there must be a molecular basis to their high metabolic rate."