Anti-ghrelin therapeutic vaccine: A novel approach for obesity treatment

Abstract

Obesity is currently a major public health problem, due to the worldwide increasing rates of the disease and burden of the associated co-morbilities, such as, type 2 diabetes, cardiovascular disease and cancer. Despite its increasing clinical relevance, there are still very few tools to treat obesity. The cornerstones for obesity treatment are still diet and exercise; anti-obesity drugs, which cause anorexia or malabsorption of nutrients, can be used as adjuvant therapy, however achieve only a modest weight loss and often short-term due to weight regain. For severe obesity the only proven effective therapy is bariatric surgery, an invasive procedure that carries inherent risks and is only recommended for selected patients. Ghrelin is the only known hormone that stimulates food intake. In physiological conditions, ghrelin levels rise with fasting and decrease after meals. Most obese individuals have low fasting ghrelin levels that rise after food restriction and weigh loss, an explanation for the difficulty of weight loss maintenance. In contrast, in spite of major weight loss, the increase in ghrelin levels is prevented by some bariatric surgery techniques, which could contribute to sustain weight loss. As ghrelin is the only known orexigenic hormone, it has been hypothesized that blocking reactive ghrelin increase could induce a sustained weight control. Previous attempts to neutralize ghrelin orexigenic effects included passive immunizations by the inoculation of monoclonal anti-ghrelin antibodies and mixtures of monoclonal antibodies targeting different ghrelin haptens, which were able to decrease ghrelin-mediated and deprivation-induced food intake, while promoted an increase in energy expenditure, but had the limitation of having only acute effects; use of ghrelin receptor antagonists that demonstrated to improve glucose tolerance, suppress appetite and promote weight loss; and active immunization against ghrelin using keyhole limpet hemocyanin and bovine serum albumin as carrier proteins, which required the use of adjuvants that may be responsible for inflammatory responses and have limited use in humans. A novel molecular approach is the use of an anti-ghrelin vaccine using Virus-like Particles as immunogenic carrier, which appears to be well-tolerated, decrease food intake and increase energy expenditure in both normal weight and diet-induced obese (DIO) mice. Vaccinated DIO mice also display a significant decrease of NPY gene expression in the basal hypothalamus reflecting a decrease in central orexigenic drive. All together, data suggests that this novel therapeutic anti-ghrelin vaccine is safe, has a positive impact on energy homeostasis and may be a useful tool for obesity treatment.