Taking KLF9 to "Cort" for crimes against metabolism

Abstract

Glucocorticoids (GCs) are essential for proper glycemic control, but in excess, can lead to hyperglycemia and diabetes. In this issue of the JCI, Cui et al. elucidate a mechanism by which GCs regulate gluconeogenesis utilizing the transcription factor Krüppel-like factor 9 (KLF9) in physiology and disease settings. They report that KLF9 is a GC-inducible factor that ultimately increases the transcription of proliferator-activated receptor γ coactivator 1 α (PGC1α), resulting in gluconeogenesis. Given the high incidence of GC-induced diabetes, identification of this signaling axis provides, not only critical scientific insight, but also a foundation for preventative therapies for patients receiving chronic GC treatment.

Figure 1. KLF9 participates in a KLF metabolic network.

Upper panel: Proposed model by which fasting or GC release concurrently increases expression of skeletal muscle KLF15 and hepatic KLF9 to coordinate gluconeogenesis. KLF15 facilitates BCAA catabolism to provide carbon substrates (alanine) for gluconeogenesis via induction of BCAT2 and BCKDh, while KLF9 increases transcription of the gluconeogenic coactivator Pgc1a. Lower panel: Redundancy in hepatic KLF function preserves glycemic control during fasting. KLF9, KLF10, and KLF14 increase transcription of Pgc1a, while KLF15 serves as a cofactor to increase transcription of the rate-limiting enzyme Pepck. Conversely, KLF11 represses Pepck transcription, thereby inhibiting gluconeogenesis in fed states.