Leptin recruits Creb-regulated transcriptional coactivator 1 to improve hyperglycemia in insulin-deficient diabetes.
OBJECTIVE
Leptin alleviates hyperglycemia in rodent models of Type 1 diabetes by activating leptin receptors within the central nervous system. Here we delineate whether non-canonical leptin signaling through the Creb-regulated transcriptional coactivator 1 (Crtc1) contributes to leptin-dependent improvements in diabetic glucose metabolism.


METHODS
We employed mice with a targeted genetic disruption of Crtc1, tracer dilution techniques and neuroanatomical studies to interrogate whether Crtc1 enables leptin to improve glucose metabolism in streptozotocin-induced (STZ) diabetes.


RESULTS
Here we show that leptin improves diabetic glucose metabolism through Crtc1-dependent and independent mechanisms. We find that leptin reduces diabetic hyperglycemia, hepatic gluconeogenic gene expression and selectively increases glucose disposal to brown adipose tissue and heart, in STZ-diabetic Crtc1 (WT) mice but not Crtc1 (+/-) mice. By contrast, leptin decreases circulating glucagon levels in both STZ-diabetic Crtc1 (WT) and Crtc1 (+/-) mice. We also demonstrate that leptin promotes Crtc1 nuclear translocation in pro-opiomelanocortin (Pomc) and non-Pomc neurons within the hypothalamic arcuate nucleus (ARC). Accordingly, leptin's ability to induce Pomc gene expression in the ARC is blunted in STZ-diabetic Crtc1 (+/-) mice.


CONCLUSIONS
Our study reveals that Crtc1 functions as a conduit for leptin's glucoregulatory actions in insulin-dependent diabetes. This study also highlights a new role for Crtc1 in modulating peripheral glucose metabolism.
Metabolic Disease Program, Sanford-Burnham Medical Research Institute, 6400 Sanger Road, Orlando, FL 32827, United States.
Geun Hyang
GH
Kim
Metabolic Disease Program, Sanford-Burnham Medical Research Institute, 6400 Sanger Road, Orlando, FL 32827, United States.
Andras
A
Szabo
Cardiometabolic Phenotyping Core, Sanford-Burnham Medical Research Institute, 6400 Sanger Road, Orlando, FL 32827, United States.
Emily M
EM
King
Cardiometabolic Phenotyping Core, Sanford-Burnham Medical Research Institute, 6400 Sanger Road, Orlando, FL 32827, United States.
Jennifer
J
Ayala
Metabolic Disease Program, Sanford-Burnham Medical Research Institute, 6400 Sanger Road, Orlando, FL 32827, United States ; Cardiometabolic Phenotyping Core, Sanford-Burnham Medical Research Institute, 6400 Sanger Road, Orlando, FL 32827, United States.
Julio E
JE
Ayala
Metabolic Disease Program, Sanford-Burnham Medical Research Institute, 6400 Sanger Road, Orlando, FL 32827, United States.
Judith Y
JY
Altarejos
Creb-regulated transcriptional coactivator 1; Glucose; Hypothalamus; Leptin; Type 1 diabetes