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Matthias Tschöp successfully completed the ERC Project “Targeting Hypothalamic inFlammation in obesity and diabetes (HypoFlam)”

IDO,

The key objective of this proposal was to further dissect and characterize the cell-specific neuroendocrine signaling mechanisms that underlie the development of obesity, diabetes, and their co-morbidities, with a special emphasis on hypothalamic inflammation and cellular degeneration. A related focus was to develop and preclinically assess the efficacy of novel drugs targeting the CNS to better treat obesity, diabetes, and their associated co-morbidities with the ultimate goal to bring novel drug candidates into clinical development.

Helmholtz Munich / © Matthias Tschöp

Control of excess body fat is one of the greatest healthcare challenges of our time. The global obesity prevalence has nearly tripled since 1975 and excess body weight afflicts more than two thirds of the European population. Obesity thereby promotes the incidence of conditions such as type 2 diabetes and cardiovascular diseases, and increases the risk of death due to cancer of the esophagus, colon and rectum, liver, gallbladder, pancreas, and kidney. It complicates the management of multiple diseases, enhancing the prospect for unfavorable outcomes, as prominently noted in the current COVID-19 pandemic. Obesity is associated with decreased life expectancy of 5–20 years depending upon its duration, the magnitude of excess weight, and the emergence of associated comorbid diseases.Also, in light of the socioeconomic burden that resides in the need to counteract excess body fat mass, the development of safe and efficient pharmacotherapies to combat the obesity pandemic is of utmost importance. Development of novel anti-obesity therapeutics requires a deep understanding and characterization of disease-related pathomechanisms, including the neuroendocrine disturbances in the central nervous system that leads to perturbed sensation to hunger and satiety. In this proposal, we significantly expanded current knowledge in understanding, characterizing, and targeting of obesity and diabetes-linked pathomechanisms and report the design and evaluation of novel drugs specifically designed to overcome current limitations in drug efficacy and safety.

The vision of this proposal was to identify previously undescribed neuroendocrine aspects of diabetes-relevant pathomechanisms and provide the subsequent insights to further enable the development of novel personalized therapeutic and preventive strategies for the benefit of patients. The studies were designed with the main goal of combining research strengths and technological expertise toward strategies which contribute to personalizing medicine in the disease context of obesity and diabetes so as to tackle important questions and fully exploit a common strategy for understanding metabolic diseases.

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.

pubWe strongly believe that our studies are accelerating the understanding of the pathogenesis of diet-induced obesity and type 2 diabetes through answering important questions regarding the CNS control of systemic metabolism with relevance for obesity and diabetes field using state-of-art methods in rodents and humans.