'Metabolic surgery restores nutrient sensing and gut-brain signaling pathways towards metabolic health: perspective towards a microbiome-based metabolite treatment of obesity and related diseases'

• Applicant: Professorin Dr. Wiebke Kristin Fenske
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 445384662

Obesity and excess weight concerns more than half of the Germanpopulation today, making obesity to a major public health issue,mainly due to its association with life-limiting health issues includingtype 2 diabetes, hepatic steatosis, pulmonary and cardiovasculardiseases, neurodegenerative disorders, and different cancers.Nutritional environments, with high abundance of saturated fatty acidsand lack of physical activity contribute to the obesity epidemic bypromoting a state of chronic low-grade inflammation, which leads tosystemic metabolic dysfunction. More recent evidence indicates thatdiet-induced conditions of hypothalamic gliosis and inflammation,which modulate hypothalamic gene expression towards overeating,independently serve as critical mediators of weight gain and metabolicdistress. Despite important advances in our understanding of the gutbrainaxis as a central player in energy balance and metabolic control,little progress has been made for anti-obesity pharmacotherapy,leaving metabolic surgical procedures as the only strategy enablingsustained weight loss and metabolic health benefits today. However,given the highly invasive character of these surgeries and theirlimitation as a last therapeutic resort to only morbidly obese patients,deciphering their mechanisms of action is an important challenge toidentify critical targets for possibly novel less invasive therapeuticinterventions and builds a main scientific interest of my lab. The factthat the gastrointestinal (GI) tract is the prime target of metabolicsurgery makes it a key player. Notably, surgical reconfiguration of theGI tract critically changes the composition and diversity of the gutmicrobiome and its metabolite products, which has emerged as animportant regulator of the host immunity, metabolism and appetitecontrol. However, the functional role of the reshaped gut microbiomein the reinstatement of metabolic health after surgery has not yet beencharacterized, and its potential to exert metabolite signaling-basedtreatment strategies against obesity remains to be elucidated. Thisproject aims to characterize the deleterious effects of energetic dietand gut dysbiosis on hypothalamic gliosis and neuronal injury as adriver for obesity and metabolic disease. Moreover, using in vivo, exvivo and in vitro approaches, it will test the hypothesis that modulationof the microbial-host interaction after RYGB surgery integratesimmunologic, metabolic, and environmental cues to reprogramhypothalamic energy and metabolic control towards restoredmetabolic health.

• DFG Programme: Research Grants