Contribution of thermogenic mechanisms by male and female mice lacking pituitary adenylate cyclase-activating polypeptide in response to cold acclimation.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide critical to the regulation of the stress response, including having a role in energy homeostasis. Mice lacking PACAP are cold-sensitive and have impaired adrenergic-induced thermogenesis. Interestingly, null mice can survive cold housing if acclimated slowly, similar to observations in uncoupling protein 1 (UCP1)-deficient mice. We hypothesized that null mice use alternate thermogenic pathways to compensate for impaired adaptive thermogenesis when acclimated to cold. Observations of behavior and assessment of fiber type in skeletal muscles did not show evidence of prolonged burst shivering or changes in oxidative metabolism in male or female mice during cold acclimation compared with mice. Despite previous work that has established impaired capacity for adaptive thermogenesis in null mice, adaptive thermogenesis can be induced in mice lacking PACAP to support survival with cold housing. Interestingly, sex-specific morphological and molecular differences in adipose tissue remodeling were observed in null mice compared with controls. Thus, sexual dimorphisms are highlighted in adipose tissue remodeling and thermogenesis with cold acclimation in the absence of PACAP. This manuscript adds to the literature of endocrine regulation of adaptive thermogenesis and energy balance. It specifically describes the role of pituitary adenylate cyclase-activating polypeptide on the regulation of brown adipose tissue via the sympathetic nervous system with a focus on compensatory mechanisms of thermogenesis. We highlight sex-specific differences in energy metabolism.