Unraveling corticotropin-releasing factor family-orchestrated signaling and function in both sexes.

Stress responses to physical, psychological, environmental, or cellular stressors, has two arms: initiation and recovery. Corticotropin-releasing factor (CRF) is primarily responsible for regulating and/or initiating stress responses via, whereas urocortins (UCNs) are involved in the recovery response to stress via feedback inhibition. Stress is a loaded, polysemous word and is experienced in a myriad of ways. Some stressors are good for an individual, in fact essential, whereas other stressors are associated with bad outcomes. Perceived stress, like beauty, lies in the eye of the beholder, and hence the same stressor can result in individual-specific outcomes. In mammals, there are two main biological sexes with reproduction as primary function. Reproduction and nutrition can also be viewed as stressors; based on a body of work from my laboratory, we propose that the functions of all other organs have co-evolved to optimize and facilitate an individual's nutritional and reproductive functions. Hence, sex differences in physiologically relevant outcomes are innate and occur at all levels- molecular, endocrine, immune, and (patho)physiological. CRF and three UCNs are peptide hormones that mediate their physiological effects by binding to two known G protein-coupled receptors (GPCRs), CRF₁ and CRF₂. Expression and function of CRF family of hormones and their receptors is likely to be sexually dimorphic in all organs. In this chapter, based on the large body of work from others and my laboratory, an overview of the CRF family with special emphasis on sex-specific actions of peripherally expressed CRF₂ receptor in health and disease is provided.