Fat-Fighting Feedback

Science Signaling  21 Apr 2009:
Vol. 2, Issue 67, pp. ec136
DOI: 10.1126/scisignal.267ec136

A gene therapy approach to treating obesity has obvious beneficial potential, but how could such a strategy be implemented without risk of excessive weight loss or cachexia? To avoid this, Cao et al. devised a therapy aimed at mimicking normal physiological feedback to treat obesity and diabetes in a mouse model. They allowed db/db mice, which have a phenotype like that of humans with type 2 diabetes, to become obese and show strong symptoms of diabetes. They then treated such animals by inducing increased expression of brain-derived neurotrophic factor (BDNF) after injection of a recombinant adeno-associated virus vector in the hypothalamus. Such treatment caused dramatic weight loss. To create a situation in which a stable, more normal body weight could be maintained, the authors created a modified vector in which the promoter from a gene whose transcription is strongly increased in response to BDNF was used to drive expression of microRNA that would inhibit BDNF expression. The authors expected that inclusion of this construct in the same vector that encoded BDNF under control of a constitutive promoter would confer animals with a regulatory system in which strong expression of BDNF would activate expression of its own inhibitor in the form of the microRNA. Indeed, animals expressing the modified vector achieved a stable body weight 3 to 4 weeks after injection that was maintained throughout the 11-week experiment. They also had improved insulin sensitivity and metabolic status. Thus, the authors suggest that such a strategy might allow establishment of a new healthier and stable set point for metabolic regulation in the brain that would alleviate the numerous health risks associated with obesity.

L. Cao, E.-J. D. Lin, M. C. Cahill, C. Wang, X. Liu, M. J. During, Molecular therapy of obesity and diabetes by a physiological autoregulatory approach. Nat. Med. 15, 447–454 (2009). [PubMed]