In addition to playing a central role in energy homeostasis, leptin is also an important player in the inflammatory response. Systemic inflammation is accompanied by fever (less severe cases) or hypothermia (more severe cases). In leptin-irresponsive mutants, the hypothermia of systemic inflammation is exaggerated, presumably due to the enhanced production and cryogenic action of tumor necrosis factor (TNF)-alpha. Mechanisms that exaggerate hypothermia can also attenuate fever, particularly in a cool environment. Another common manifestation of systemic inflammation is behavioral depression. Along with the production of interleukin (IL)-1beta, this manifestation is exaggerated in leptin-irresponsive mutants. The enhanced production of TNF-alpha and IL-1beta may be due, at least in part, to insufficient activation of the anti-inflammatory hypothalamo-pituitary-adrenal axis by immune stimuli in the absence of leptin signaling. In experimental animals and humans that are responsive to leptin, suppression of leptin production under conditions of negative energy balance (e.g., fasting) can exaggerate both hypothermia and behavioral depression. Since these manifestations aid energy conservation, exaggeration of these manifestations under conditions of negative energy balance is likely to be beneficial.