Nescient helix-loop-helix 2 (Nhlh2) is a basic helix-loop-helix transcription factor that functions to communicate signals of energy availability. Based on the expression pattern of Nhlh2 in cold-sensitive areas of the hypothalamus, we hypothesized that mice containing a targeted deletion of Nhlh2 would be unable to maintain body temperature and that Nhlh2 gene expression would vary with cold exposure. Following cold exposure, Nhlh2 mRNA levels are significantly reduced throughout the hypothalamus. Furthermore, mice with a targeted deletion of Nhlh2 (N2KO mice) are unable to maintain body weight at 4°C. This paper attempts to describe these new results as they relate to the ongoing gene regulation that occurs in the hypothalamus following changes in energy availability brought about by food intake or cold exposure.