Brainstem-Immune Mechanisms Driving Metabolic Alterations in Cancer and Infection

Abstract

Weight loss and changes in fuel partitioning are features of infection and cancer. Yet, the neural and molecular mechanisms underlying these metabolic alterations remain insufficiently understood. Sustained weight loss can become maladaptive and thereby reduce life expectancy. This thesis investigated the role of GFRAL-expressing neurons as central triggers of systemic metabolic responses under conditions of stress including cancer and infection. Despite substantial evidence linking GFRAL⁺ neuron signaling to reduced food intake, its broader role in systemic metabolic regulation remained unclear. I found that acute activation of GFRAL⁺ neurons mimicked gluco-, endo-, and thermoregulatory adaptations characteristic of starvation and torpor, a hypometabolic state defined by reduced body temperature and energy expenditure (Paper I). This state was accompanied by impaired insulin sensitivity and reduced skeletal muscle glucose uptake. In addition, transcriptional and metabolomic analysis were consistent with augmented ketogenesis and altered substrate utilization. Whether infection-induced weight loss is mediated by shared or stimulus-specific neuronal mechanisms is unclear. To determine whether and how GFRAL⁺ neurons contribute to infection-induced weight loss, I examined their potential role during innate immune challenge (Paper II). Sensing of viral double-stranded RNA (dsRNA) via toll-like receptor 3 (TLR3) was found to elevate circulating GDF15, a hormone that reduces appetite via its dedicated GFRAL receptor, which in turn activated GFRAL⁺ neurons. This activation promoted a catabolic state characterized by increased lipid utilization and weight loss, independently of anorexia. Notably, this pathway is specific to viral dsRNA, supporting a high degree of functional organization of immune-to-brain signaling in metabolic control. Together, these findings identified a TLR3-GDF15-GFRAL pathway coupling immune sensing to central regulation of energy balance. Although GDF15 levels are elevated in certain cancers, it remained elusive whether GFRAL⁺ neurons causally contribute to weight loss and glucose dysregulation during pancreatic ductal adenocarcinoma (PDAC), one of the deadliest cancers in which weight loss and diabetes are hallmarks. In a mouse model of PDAC, elevated circulating GDF15 was associated with activation of GFRAL⁺ neurons and the development of weight loss and anorexia. Ablation of GFRAL⁺ neurons prevented the weight loss and attenuated the anorexia, while their activation bidirectionally altered macronutrient handling. In patients with pancreatic carcinoma, circulating GDF15 levels correlated with negative energy balance, increased lipid utilization, and reduced carbohydrate oxidation, indicating a shift in whole-body substrate utilization (Paper III). Together, these results establish GFRAL⁺ neurons as central coordinators of a metabolic program that promotes lipid utilization over carbohydrates and contributes to weight loss in distinct pathological contexts rather than acting as generic mediators of metabolic alterations in cancer and infection.