We started the project based on previous evidence that disrupted hypothalamic functioning acts as a major player in hypercaloric diet-induced obesity and associated metabolic disorders. We initially observed that exposure to a hypercaloric diet leads to reactive changes in microglia and astrocytes (gliosis) and promotes hypervascularization within the hypothalamus. Interestingly, most of these observations precede neuronal dysfunction and substantial body weight gain, suggesting their role in promoting obesity. Intrigued by these findings, we continued our work and revealed that non-neural cells including microglia, astrocytes, and T-cells directly influence the activity of hunger-sensing circuits for controlling brain feeding centers. Specifically, we uncovered that the effectiveness of hypothalamic neurons in the control of feeding relies on non-neuronal cells like microglia, astrocytes and presence of T cells. Firstly, we observed that the combination of dietary fat and sugars, but not fat or obesity per se, is determinant for the induction of microglial activity and hypothalamic angiopathy, which are associated with the development of obesity. Besides microglia, we uncovered that hypothalamic astrocytes are key elements in the regulation of hypothalamic neovascularization previously observed in obese and diabetic mice. Importantly, we uncovered that a hypercaloric diet triggers the release of soluble factors like VEGF from hypothalamic astrocytes to elevate blood pressure promoting hypertension in obesity.
Regarding our studies related to immunosuppressive T cells, we found that they play a functional role in glial crosstalk with local immune activation in the brain regions participating in the regulation of systemic metabolism. Specifically, we discovered that Fox3+ Tregs depletion critically limits immune activation in the hypothalamus when challenged with a hypercaloric diet.
Finally, we tested the hypothesis that selective hypothalamic delivery of anti-inflammatory agents may reverse hypercaloric diet-induced hypothalamic inflammation. In a series of preclinical studies, the GLP-1/dexamethasone conjugate demonstrated GLP-1 receptor dependent glucocorticoid action in the brain and the ability to ameliorate obesity associated hypothalamic inflammation, improve high-fat diet induced glucose intolerance, and decrease body weight. Furthermore, we discovered the therapeutic value of a novel combination of the transient receptor potential cation channel subfamily M member 8 (TRPM8) agonist, icilin, with dimethylphenylpiperazinium (DMPP), a specific agonist at the nicotinic acetylcholine receptor subtype α3β4. Likewise, we continued our studies and expanded our approach of using specific brain-targeted polypharmacotherapy to improve body weight and glucose control in selected rodent models of obesity via GLP1 targets, which led to decreased hypothalamic inflammation and significant improvements in metabolic health.
The scientific results generated were disseminated via publications in high quality peer-reviewed journals with significant visibility and impact, not restricted to a minor community, and open to multidisciplinary research. Moreover, the new knowledge derived from this funding was presented at international and national conferences important in the field of neuroendocrinology, metabolism, and immunobiology, and endowed with a high-level audience as well as in workshops in and outside of the EU. Of note, the PI has received numerous awards and recognitions for his outstanding achievements in the field of obesity and diabetes. In recent years, Matthias Tschöp’s scientific contributions have greatly enriched the diabetes, obesity, and metabolism research landscape in Germany and worldwide thereby helping to significantly increase international visibility and create scientific networks. As Alexander-von-Humboldt Professor at the Technical University Munich and as scientific director at Helmholtz Munich, Matthias Tschöp will continue to build on the results generated with HypoFlam. Specifically he will use the generated insights to further invest in next generation strategies to improve our understanding of the complex interplay between health and the environment and to speed up the translation of basic research into practical applications for the tangible benefit of society.
