Sci. Aging Knowl. Environ., 17 March 2004
Vol. 2004, Issue 11, p. nf27
[DOI: 10.1126/sageke.2004.11.nf27]

NEWS FOCUS

Throwing Fat on the Fire

Mice lacking supposed insulin enabler are surprisingly lean

R. John Davenport

http://sageke.sciencemag.org/cgi/content/full/2004/11/nf27

BANFF, CANADA--A molecule that purportedly spurs cells to absorb glucose might do something completely different, according to work presented here on 7 March 2004 at the Diabetes Mellitus Keystone Symposium. Mice that lack the molecule unexpectedly carry less fat and balance blood sugar as well as normal animals do. The results refute the idea that the protein spurs glucose transport and reveal that the molecule trims fat metabolism.

Type II diabetes develops when cells stop responding to insulin, which normally prods them to soak up blood-borne sugar. To understand the disease's origins and find ways to prevent or treat it, researchers want to illuminate the molecular relays through which insulin prompts glucose transport and identify what steps go awry. Many studies have suggested that insulin acts through a particular chain of molecules, the so-called classical insulin pathway. But some research suggests that insulin also uses another set of proteins, which includes one called c-Cbl. That idea stems from the observation that insulin's receptor protein gloms onto and modifies proteins in the c-Cbl pathway, which influences movement of glucose-importing proteins to a cell's surface. But researchers weren't certain whether c-Cbl affects an animal's metabolism through these activities.

To clarify this protein's role in insulin signaling, Molero and colleagues studied mice that lack the Cblc gene. If c-Cbl abets insulin signaling, such mice would soak up glucose poorly. Instead, the animals absorbed blood glucose at a normal rate, the team found. The creatures carried less fat than unaltered animals did, despite gobbling 30% more calories. This observation suggests that energy consumption soars when c-Cbl is missing. Supporting this idea, the animals consumed one-third more oxygen--a measure of metabolism--than did normal animals, had warmer bodies, and switched into a fat-burning mode. Additional studies revealed that the animals' muscles took up more sugar than normal, but their fat and liver did not, so the team investigated whether the engineered rodents' muscles were responsible for ramping up metabolism. Mitochondria--cells' energy-producing structures--were twice as large as those in normal mice, suggesting enhanced fuel-burning capacity. In addition, a gene called Ucp3 was unusually active in muscle of c-Cbl-deficient mice. This gene encodes a protein that short-circuits ATP production and instead creates heat (see "Greasing Aging's Downward Slide").

The research suggests that c-Cbl doesn't influence insulin signaling but instead blocks fat-burning signals, says biochemist Michael Czech of the University of Massachusetts Medical Center in Worcester. His group also presented data revealing that blocking several components of the c-Cbl pathway did not blunt glucose uptake in fat cells, supporting the results of Molero and colleagues. The results contradict the model that c-Cbl relays insulin's signal, but they don't disprove it, says diabetes researcher Morris Birnbaum of the University of Pennsylvania in Philadelphia. The findings also "tell us that [c-Cbl] has an unexpected role in energy metabolism," he adds. Further work should address where in the body the protein acts, says Birnbaum. For instance, the molecule might influence brain centers that control appetite and metabolism. If c-Cbl's unexpected role holds up, the protein's activity might promote--rather than prevent--diabetes.


March 17, 2004
  1. P. Mitra, X. Zheng, M. P. Czech, RNAi-mediated gene silencing of c-Cbl plus Cbl-b or CrkII fails to attenuate insulin stimulation of hexose transport in 3T3L1 adipocytes. Diabetes Mellitus Keystone Symposium, 4-10 March 2004, Banff, Canada. [Meeting Web Site]
  2. J. C. Molero, G. Cooney, T. Jensen, H. Herzog, D. E. James, c-Cbl deficient mice show reduced adiposity, higher energy expenditure and improved peripheral insulin sensitivity. Diabetes Mellitus Keystone Symposium, 4-10 March 2004, Banff, Canada. [Meeting Web Site]
Citation: R. J. Davenport, Throwing Fat on the Fire. Sci. Aging Knowl. Environ. 2004 (11), nf27 (2004).








Science of Aging Knowledge Environment. ISSN 1539-6150