Hormones such as fibroblast growth factor 21 (FGF21) and glucocorticoids (GCs) play crucial roles in coordinating the adaptive starvation response. Here we examine the interplay between these hormones. It was previously shown that FGF21 induces corticosterone levels in mice by acting on the brain. We now show that this induces the expression of genes required for GC synthesis in the adrenal gland. FGF21 also increases corticosterone secretion from the adrenal in response to ACTH. We further show that the relationship between FGF21 and GCs is bidirectional. GCs induce Fgf21 expression in the liver by acting on the GC receptor (GR). The GR binds in a ligand-dependent manner to a noncanonical GR response element located approximately 4.4 kb upstream of the Fgf21 transcription start site. The GR cooperates with the nuclear fatty acid receptor, peroxisome proliferator-activated receptor-α, to stimulate Fgf21 transcription. GR and peroxisome proliferator-activated receptor-α ligands have additive effects on Fgf21 expression both in vivo and in primary cultures of mouse hepatocytes. We conclude that FGF21 and GCs regulate each other's production in a feed-forward loop and suggest that this provides a mechanism for bypassing negative feedback on the hypothalamic-pituitary-adrenal axis to allow sustained gluconeogenesis during starvation.

Use of the case-crossover design in pharmacoepidemiology has increased rapidly in the last decade. As the application of the case-crossover design continues to increase, it is important to develop standards of practice, especially for display of data.

Purpose: Consensus is needed on conceptual foundations, terminology and relationships among the various self-controlled "trigger" study designs that control for timeinvariant confounding factors and target the association between transient exposures (potential triggers) and abrupt outcomes. The International Society for Pharmacoepidemiology (ISPE) funded a working group of ISPE members to develop guidance material for the application and reporting of self-controlled study designs, similar to Standards of Reporting Observational Epidemiology (STROBE). This first paper focuses on navigation between the types of self-controlled designs to permit a foundational understanding with guiding principles.Methods: We leveraged a systematic review of applications of these designs, that we term Self-controlled Crossover Observational PharmacoEpidemiologic (SCOPE) studies. Starting from first principles and using case examples, we reviewed outcomeanchored (case-crossover [CCO], case-time control [CTC], case-case-time control [CCTC]) and exposure-anchored (self-controlled case-series [SCCS]) study designs.Results: Key methodological features related to exposure, outcome and time-related concerns were clarified, and a common language and worksheet to facilitate the design of SCOPE studies is introduced.Conclusions: Consensus on conceptual foundations, terminology and relationships among SCOPE designs will facilitate understanding and critical appraisal of published studies, as well as help in the design, analysis and review of new SCOPE studies. This

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