Sleep disorders and obesity are common diseases that can reduce the length or quality of life for millions of people. These diseases result in part from the dysfunction of cell populations in the hypothalamus that regulate the sleep/wake cycle and energy balance, respectively. There has been increased knowledge in recent decades regarding the cellular and molecular basis of sleep disorders and obesity, but much remains to be discovered to convert current understanding into effective therapies. This work details efforts to identify molecular mechanisms of two diseases. The first project explored whether mutations in the DNMT1 gene that cause autosomal dominant neurodegenerative disease in humans, which preferentially affects the hypocretin neurons that regulate sleep, also induce neuronal loss when introduced into mice. No evidence was found for the loss of sleep-regulatory hypocretin neurons in Dnmt1 mutant mice. The second project used proximity proteomic methods to identify proteins that regulate human leptin receptor (LEPR) signalling, since leptin signalling is essential for normal body weight regulation. Several candidate proteins were identified that may negatively regulate signalling through LEPR and are of potential therapeutic relevance for obesity.