Therapeutic Targeting of Stress Metabolism In Obesity and Metabolic Disease

Background: While sufficient acute stress responses are crucial for adaptation to the environments, severe acute and prolonged chronic stress drive maladaptive changes in an organism that drive the progression of several chronic diseases, including obesity and metabolic disease. Stress metabolism is largely governed by two cascades. Corticotropin-Releasing Factor (CRF), synthesized and released from several brain nuclei in response to stressful stimulus, signals directly to neuronal circuits that impact behavior, cognition, metabolism, and several other processes. In parallel, CRF synthesis and release is greatest in the Paraventricular Nucleus (PVN) of the hypothalamus, where it travels along descending neurons that stimulate Adrenocorticotropic Hormone (ACTH) release from the pituitary gland, which enters circulation to stimulate cortisol/ corticosterone synthesis and release from the adrenal cortex. While the relationship between stress and metabolic disease progression has been partially characterized, attempts to develop therapeutics that target the progressive contributions of stress to clinical disease have been underwhelming, potentially due to modest and transient impact basal stress metabolite levels and short drug half lives. Methods: We developed a picomolar-affinity monoclonal antibody against CRF that suppresses both basal and stress-induced glucocorticoid levels with a half life of 6-7 days. We used metabolic phenotyping, transcriptomics/proteomics, and body composition analysis to assess metabolic benefits of treatment in diet-induced, genetic, and aged murine models. Results: Longitudinal antibody treatment in animal models of dietinduced and mongenic obesity shows durable therapeutic effect in diet and age-induced metabolic dysfunction, resulting in a 30-50% reduction in body weight gain, 10-25% reduction in food intake, improved glucose tolerance, reduced fasting insulin levels, and improved body composition. Secondary effects include reduction in hepatic adipose content, reductions in visceral fat mass, and addition of skeletal muscle mass. Conclusions: These endpoints implicate blunting of stress metabolism as novel and multimodal approach to targeting several pathways in chronic metabolic disease and may represent primary or adjunctive therapies for several pervasive clinical diseases.