Response to Leptin-deficient mice are not hypothermic, they are anapyrexic

To the Editor: The Comment by Fisher, Cannon and Nedergaard [1] on our recent paper [2] advocates use of the term ‘anapyrexia,’ which connotes a biologically defended decrease of body temperature; e.g., the opposite of a fever, to describe the subnormal core temperature of leptin-deficient ob/ob mice. Another option is the conjunction ‘regulated hypothermia’ [3], based on the Glossary of Terms for Thermal Physiology [4], which notes that “hypothermia may be regulated (e.g., Torpor, Hibernation) or may be forced if heat loss exceeds the capacity for total heat production.” Crucial to these deliberations is that while ob/ob mice maintain normothermia when housed in a thermoneutral environment, and prefer such an environment when provided the option, they maintain a reduced core temperature when housed at sub-thermoneutrality, and the threshold at which they mount autonomic defenses against body heat loss is similarly subnormal. Leptin deficiency, therefore, gives rise to an unusual phenotype in which the biological defense of core temperature varies with external temperature. ‘Pyrexia,’ by contrast, involves a coordinated suite of autonomic and behavioral effector shifts reflective of a true regulated state (e.g., ‘regulated hypothermia’) that is largely insensitive to environmental temperature. Such terms do not accurately capture the unusual phenotype of ob/ob mice. To better understand the biological underpinnings of what is observed, we propose that the ob/ob mouse brain responds to cold stress with a lowering of core temperature as part of an adaptive response to conserve energy, based on the widely accepted premise that lack of a leptin signal conveys a severe deficiency of stored fuel [5]. This “evolutionarily-based adaptive hypothermia model” proposes that when housed in a sub-thermoneutral environment, adaptive lowering of core temperature minimizes energy costs, thereby favoring survival, particularly given the increased susceptibility to heat loss of these mice. Given the opportunity to seek out a thermoneutral environment, however, they will do so [6]. This model is readily distinguished from ‘regulated hypothermia,’ which implies a coordinated set of effector responses to defend a sub-normal core temperature, including a preference for a sub-thermoneutral environment, which is not observed in ob/ob mice. Since leptin deficiency is ordinarily experienced only in the setting of severe food restriction, the ‘adaptive hypothermia’ model predicts that affected animals are motivated to achieve normal body temperature if this can be accomplished at minimal energy or predation