Body weight is usually tightly maintained by brain circuits that regulate appetite and energy expenditure. These circuits tend to favour weight gain, as for most of our evolution starvation was a bigger hazard than obesity-related disease. As such, weight loss from body weight set point is well-protected against by the brain, both in the context of starvation and dieting. However, involuntary weight loss is a common comorbidity of chronic diseases such as cancer. This weight loss is termed cachexia, or anorexia-cachexia syndrome, and results from loss of both fat and muscle mass. Cachexia onset increases surgical risk, reduces tolerance to radio- and chemotherapy, and increases frailty. One outstanding question is how does the usually robust brain control of appetite and metabolism break down so completely in cachexia? To investigate this, we have been using a mouse model of pancreatic cancer cachexia, and using genetic neuroscience techniques to probe how appetite-regulating hypothalamic circuits are changed during cancer. We have shown that a population of metabolic sensory neurons in the hypothalamus, the NPY/AgRP neurons, are less responsive to metabolic cues during cancer, but when artificially activated using chemogenetics, they are able to promote eating and retention of fat and muscle mass. This has implications for current and future therapeutic strategies for cachexia.