Methods for weight reduction
Autophagy is typically activated by starvation, allowing cells and organisms to mobilize their energy reserves. It is known that pharmacological modulation of autophagy represents a therapeutic potential. Here the inventors report that a protein that is released from cells in an unconventional, autophagy-dependent manner, namely, diazepam binding inhibitor (DBI), regulates autophagy. In particular, the inventors demonstrate that DBI inhibits autophagy and that the supply of recombinant DBI to mice enhanced glycolysis, enhanced lipogenesis, and inhibited fatty acid oxidation. The inventors show that neutralisation of DBI by a monoclonal antibody and an active immunization by means of an immunogenic DBI derivative eliciting autoantibodies induce autophagy and lead to metabolic changes that increase starvation-induced weight loss, reduce food intake upon refeeding, and reduce weight gain in response to hypercaloric diets. Accordingly, the present invention relates to methods and pharmaceutical compositions for modulating autophagy based on the modulation of the activity or expression of DBI.
1. A method of weight loss by inducing autophagy in a patient, the method comprising administering to the patient a weight loss medical treatment composition comprising an anti-diazepam binding inhibitor (DBI) antibody; wherein the anti-DBI antibody is a DBI neutralizing antibody, and wherein the administering results in reduction of DBI activity in the patient, thereby inducing autophagy and achieving weight loss in the patient.
2. The method of claim 1 , wherein the administering of the weight loss medical treatment composition results in decreased food intake, relative to prior to the administering of the weight loss medical treatment composition comprising the inhibitor of human diazepam binding inhibitor activity.
3. The method of claim 1 , wherein the administering of the weight loss medical treatment composition results in increased plasma glucose levels, as determined in an in vitro assay, relative to prior to the administering of the weight loss medical treatment composition.
4. The method of claim 3 , wherein the plasma glucose levels are increased in the patient by at least 50 mg/dL 30 minutes after the administering of the weight loss medical treatment composition, relative to plasma glucose levels prior to the administering of the weight loss medical treatment composition.
5. The method of claim 1 , wherein the administering of the weight loss medical treatment composition is sufficient to decrease plasma insulin levels in the patient, relative to prior to the administering of the weight loss medical treatment composition.
6. The method of claim 1 , wherein the administering of the weight loss medical treatment composition is sufficient to decrease C-peptide levels in the patient, relative to prior to the administering of the weight loss medical treatment composition.
7. The method of claim 1 , wherein the administering of the weight loss medical treatment composition is sufficient to decrease gastric inhibitory peptide in the patient, relative to prior to the administering of the weight loss medical treatment composition.
8. The method of claim 1 , wherein the patient is on a hypercaloric diet prior to the administering of the weight loss medical treatment composition.
9. The method of claim 1 , wherein the patient is overweight.
10. The method of claim 1 , wherein the patient is human.
11. The method of claim 1 , wherein the anti-DBI antibody is a monoclonal antibody.