, physiological, and molecular differences in response to dietary restriction in three inbred mouse strains. Am J Physiol Endocrinol Metab 291: E574 -E581, 2006. First published May 2, 2006; doi:10.1152/ajpendo.00068.2006.-Food restriction paradigms are widely used in animal studies to investigate systems involved in energy regulation. We have observed behavioral, physiological, and molecular differences in response to food restriction in three inbred mouse strains, C57BL/6J, A/J, and DBA/2J. These are the progenitors of chromosome substitution and recombinant inbred mouse strains used for mapping complex traits. DBA/2J and A/J mice increased their locomotor activity during food restriction, and both displayed a decrease in body temperature, but the decrease was significantly larger in DBA/2J compared with A/J mice. C57BL/6J mice did not increase their locomotor activity and displayed a large decrease in their body temperature. The large decline in body temperature during food restriction in DBA/2J and C57BL/6J strains was associated with a robust reduction in plasma leptin levels. DBA/2J mice showed a marked decrease in white and brown adipose tissue masses and an upregulation of the antithermogenic hypothalamic neuropeptide Y Y1 receptor. In contrast, A/J mice showed a reduction in body temperature to a lesser extent that may be explained by downregulation of the thermogenic melanocortin 3 receptor and by behavioral thermoregulation as a consequence of their increased locomotor activity. These data indicate that genetic background is an important parameter in controlling an animal's adaptation strategy in response to food restriction. Therefore, mouse genetic mapping populations based on these progenitor lines are highly valuable for investigating mechanisms underlying strain-dependent differences in behavioral physiology that are seen during reduced food availability. locomotor activity; body temperature; food intake; neuropeptide Y; melanocortin ENERGY BALANCE is regulated by processes that influence food intake and energy expenditure. The main components of energy expenditure are metabolism and thermogenesis induced by exercise, cold, and diet, and these are regulated by the interaction of behavioral, physiological, and molecular mechanisms. Imbalances in energy state can result in health problems, such as malnutrition, eating disorders, or obesity Food restriction paradigms are widely used in animal studies to investigate mechanisms involved in the regulation of energy balance Behavioral thermoregulation is one of the mechanisms by which endothermic animals achieve and maintain a stable body temperature during times of food shortage In addition to behavioral thermogenesis, endothermic animals use autonomic mechanisms to regulate their core temperature (47). For example, brown adipose tissue (BAT)-mediated nonshivering thermogenesis is involved in heat production when animals are exposed to cold. Mitochondrial uncoupling proteins (UCPs) in the BAT generate heat by uncoupling oxidative phosphorylation, and, in mice, targeted inactivation of the gene coding for UCP1 leads to cold sensitivity (13). Leptin increases the thermogenesis in BAT by increasing UCP1 expression (48); therefore, decreased heat production resulting from hypoleptinemia could be associated with the increased locomotor activity seen in some inbred mice strains and rats in response to restricted feeding. Leptin's effects on the hypothalamic neuropeptide Y (NPY) and melanocortin systems have been implicated in the regulation of energy balance (56, 59). For example, selective NPY Y 1 and Y 5 receptor agonists increase food consumption and decrease circulating levels of thyroid hormones, showing that both receptors mediate the stimulatory effects of NPY on foo
