Obesity is a global health problem, and an effective treatment is lacking. Weight loss can be obtained by reducing food intake, but increasing energy expenditure may also be a good strategy to obtain sustained weight loss. In the ENAMEP project we aimed to stimulate energy expenditure by delivery of energy-regulating proteins to specific neurons in the ventromedial hypothalamus (VMH) that control thermogenesis in a rodent model. An important milestone in the project was to establish a mouse model of olanzapine-induced weight gain, like we have previously done for rats. However, the response in mice is quite different from rats, and we have spent quite some time to optimize the drug-delivery protocol and to obtain stable weigh gain in mice. E.g. an intramuscular depot injected was very effective in rats, but did not work in mice. But the mouse model is now working (olanzapine in food), which is an important milestone. Treatment of these animals with exosomes (for targeted delivery of plasmid DNA encoding the dominant negative form of the protein AMPK to the VMH neurons) reduced the olanzapine-induced body weight gain, but only moderately and not all experiments. The effect on thermogenic markers in the brown adipose tissue have also been investigated, but also here the results are inconclusive.
The lack of clear effects by the exosomes may be explained by how olanzapine affect energy expenditure. Despite the fact that olanzapine induces weight gain in both patients and in rodents, we have previously demonstrated that this drug also increases energy expenditure via UCP1 activation in brown adipose tissue. Thus, our attempts to further stimulate this process with exosomes may not be the most effective strategy. In light of these observations, the next logical step would be to target appetite regulation. Olanzapine clearly increases food intake in mice (similar to what is observed in patients), and we have earlier shown in rats that olanzapine stimulates appetite-inducing AgRP neurons in the hypothalamus. Thus, targeting exosomes to AgRP neurons with the aim to regulate food intake in the mouse model seems like a feasible approach. However, due to the labor-intensive process and the time it takes to produce exosomes, this strategy need to be funded in a separate project. The current project has given valuable insight into the olanzapine-induced weight gain, and the fact that we have now established a robust mouse model opens up for more targeted approaches with genetically modified mice and novel exosome strategies.
This program has shown the potential of an exosome-based nanomedicine approach for the treatment of obesity by targeting the hypothalamus to increase energy expenditure and thus to obesity-related diseases. This approach was demonstrated to successfully reduce body weight gain in two mice models (diet-induced obesity and genetic obesity). The aim of the current work package was to investigate whether the same approach could be used in a mice model of antipsychotic drug-induced obesity. First, we needed to establish this mice model (we could not use the available rat model for antipsychotic drug-induced weight gain due to limitations to produce sufficient amount of exosomes). During the project period, we have now managed to generate a robust mice model that is available to the community. This opens for the use of genetic mice models in the field of antipsychotic drug-induced obesity, which is a major addition of the pre-clinical tools available to study this phenomenon. Interestingly, the exosomes did not significantly reduce the body weight in this model and the findings were thus not analogous to what we observed in the diet- and genetic mice models for obesity. Our data show that the cause of weight gain matters for choice of treatment, which should be adjusted accordingly. More specifically, our data suggest that targeting the energy expenditure may be less effective to treat antipsychotic-induced weight gain than e.g. targeting food intake. The use of exosomes that target specific hypothalamic areas involved in appetite regulation should be the scope of future experiments.
The network aims to develop a “nanobiomedicine” approach to harness the biology of nanoscaled exosomes as an innovative strategy to assess suitable tools for specific targeting of the hypothalamic areas modulating energy balance. We aim to deliver DNA in specific neuronal hypothalamic populations to open a new avenue in pharmacological treatment of metabolic complications. Our hypothesis is that changes in pathways that mediate increased brown adipose tissue (BAT) thermogenesis can be obtained via specific inhibition of the therapeutic targets AMPK, GRP78 and NLRP3 in the ventromedial nucleus of the hypothalamus by the use of peripherally administered engineered exosomes.
Fernø is responsible for work package 4, were we explore the effect of SF1 exosomes on energy metabolism and body weight in an animal model of OLZ-induced weight gain. Administration of intramuscular OLZ depot injection ensures stable serum concentrations for weeks and leads to rapid weight gain in female rodent models. OLZ-induced weight gain is associated with hypothalamic AMPK activation, ER stress and inflammation and thus represents a clinically relevant pharmacological model to investigate the effect of exosomes that modulate hypothalamic AMPK and GRP78 pathways. The SF1 exosomes will be injected in the tail vein of rats 7 days after the OLZ depot injection, when the elevated body weight phenotype has emerged, with follow-up daily measurements of body weight and food intake to evaluate the effect of the exosome treatment. The effect of exosome treatment on BAT thermogenesis will also be evaluated in this model. Interestingly, the effect of OLZ on energy expenditure is ambiguous as it has been shown that OLZ exposure leads to elevated energy expenditure despite elevated body weight. It will thus be highly interesting to see whether the SF1 exosomes can provide further stimulation of energy expenditure and whether this will curb the body weight gain caused by OLZ-induced hyperphagia.