Vital functions of corticotropin-releasing factor (CRF) pathways in maintenance and regulation of energy homeostasis

Regulation of energy homeostasis is a vital function of the CNS requiring adaptive responses to maintain and support life after stress perturbations. The mechanisms whereby these processes occur are, however, only partially understood. A major determinate of these responses is corticotropin-releasing factor (CRF). Receptors for CRF, CRFR1 and CRFR2, have been hypothesized to play distinct roles in the alterations necessary for homeostatic maintenance. The function of CRFR2, in particular, has remained elusive despite its presence in both the CNS and periphery. In this work, we have used complimentary gene deletion and pharmacological approaches to elucidate the crucial role CRFR2 plays in the regulation of regional tissue thermogenesis and adaptive physiology. Analyses of interscapular brown adipose tissue (IBAT) thermogenesis by thermal signature analysis and the concordant biochemical changes in key sympathetic components in mice deficient for CRFR2 revealed significantly elevated basal IBAT thermogenesis and prolonged adrenergic responsivity of IBAT in older mice. Measurement of metabolic rates by indirect calorimetry after chronic high-fat diet challenge and treatment with the CRFR1 antagonist NBI-27914 revealed a decreased respiratory exchange ratio of these mice that was normalized with NBI-27914. Further, as a definitive measure for physiological pathology, mice examined in a behavioral model of differential temperature selection showed a predilection for warmer external temperatures, supporting a loss of body heat in these mice. These studies provide physiological, biochemical, and behavioral evidence for the critical participation of CRF pathways in the maintenance and adaptive responses necessary for regulation of energy homeostasis.