Currently about 2 billion people in the world are overweight; about one half billion are clinically obese. These individuals are at increased risk of cardiovascular disease, heart infarct, diabetes, and many forms of cancer. The last decades have taught us that obesity is not a disease of choice, and that highly conserved neuro-regulatory circuitry exists that controls appetite, satiety, energy expenditure and even peripheral endocrine sensitivity. Interestingly, since neurons are not self-sufficient metabolically, this circuitry by default requires energetic processing of neuronal support cells such as astrocytes and microglia. Recent data have implicated microglial activation as a potential causal element in the etiology of obesity associated metabolic disease. The energetic and regulatory mechanisms underlying such disease exacerbation remain a black box. Here we propose to combine the power of conditional mouse genetics and high-throughput NGS tools to i.) characterize, at the single cell and population levels, the acute and chronic hypothalamic inflammatory processes that accompany obesity; ii.) define the energetic requirements of microglial activation and their role in modulating disease outcome; and iii.) delineate the signaling constraints for microglial activation induced metabolic disease in vivo. Thus, we will genetically dissect some of the first definitive microglial metabolic and signaling machinery for obesity and diabetes.