The
bile acid receptor, TGR5, is a key regulator of
glucose homeostasis, but the mechanisms by which TGR5 signaling improves
glucose regulation are incompletely defined. In particular, TGR5 has an increasingly appreciated role in liver physiology and pathobiology; however, whether TGR5 signaling within the liver contributes to its glucoregulatory effects is unknown. Therefore, we investigated the role of hepatocyte TGR5 signaling on
glucose regulation using a hepatocyte-specific TGR5 knockout mouse model. Hepatocyte-specific Tgr5Hep+/+ and Tgr5Hep-/- mice were fed a high fat diet (HFD) for 7 weeks and then orally gavaged with three doses of a highly potent, TGR5-specific agonist,
Compound 18 (10 mg/kg), or vehicle, over 72 h and underwent an oral
glucose tolerance test (OGTT) after the last dose. Herein, we report that TGR5
mRNA and
protein is present in mouse hepatocytes. Cumulative food intake,
body weight, and adiposity do not differ between Tgr5Hep+/+ and Tgr5Hep-/- mice with or without treatment with
Compound 18. However, administration of
Compound 18 improves
glucose tolerance in Tgr5HEP+/+ mice, but not in Tgr5Hep-/- mice. Further, this effect occurred independent of
body weight and
GLP-1 secretion. Together, these data demonstrate that TGR5 is expressed in hepatocytes, where it functions as a key regulator of whole-body
glucose homeostasis.