THU047 Growth Hormone (GH) Signaling In Hepatocytes Controls Hepatic Insulin Sensitivity And Nutrient Disposition
Authors: del Rio-Moreno Mercedes , del Carmen Vazquez-Borrego Maria , Cordoba-Chacon Jose , McGuinness Owen P , Kineman Rhonda D 
Published: October 2023

Disclosure: M. del Rio-Moreno: None. M. Vazquez-Borrego: None. J. Cordoba-Chacon: None. O.P. McGuinness: None. R.D. Kineman: None.

It is commonly accepted that GH reduces the actions of insulin. However, we reported plasma GH levels within a physiological range are negatively associated with insulin-mediated glucose uptake, but positively associated with insulin-mediated suppression of hepatic glucose production (HGP) [Cordoba-Chacon J. et al. 2014. AJP Endocrinol Metab]. These findings suggest that GH may promote insulin’s actions on the liver. To determine the direct contribution of GH signaling on hepatic insulin sensitivity, hyperinsulinemic-euglycemic clamps were performed with stable isotope tracers in chow-fed adult-onset, hepatocyte-specific GHR knockdown (aHepGHRkd) mice. aHepGHRkd mice show reduced IGF1 and increased GH levels [Cordoba-Chacon J. et al 2015, Diabetes] which indirectly impacts systemic insulin sensitivity and substrate flux to the liver. To normalize plasma IGF1 and GH levels, aHepGHRkd mice were co-treated with adeno-associated virus (AAV) that express IGF1 or a constitutively active form of STAT5b (STAT5bCA). These AAVs have a thyroxin binding globulin promoter, leading to hepatocyte-specific expression. Under both basal and clamped conditions, aHepGHRkd mice exhibited hyperinsulinemia, that was normalized by AAV-mediated IGF1 and STAT5bCA expression. Interestingly, glucose disappearance (Rd), tissue-specific glucose uptake, or HGP (gluconeogenesis and glycogenolysis) did not differ across all groups. However, higher insulin tone in aHepGHRkd mice was required to achieve the same level of Rd and suppression of HGP in the steady-state, which was indicative of systemic and hepatic insulin resistance. These observations are consistent with our previous findings that GH reduces tissue-specific glucose uptake but promotes insulin-mediated control of HGP. In contrast, aHepGHRkd mice exhibited an increased rate of hepatic de novo lipogenesis, and an increase in plasma levels of newly formed triglyceride and triglyceride-bound palmitate, that was normalized by IGF1 and STAT5bCA expression. Taken together, these results indicate loss of hepatocyte GH signaling leads to pathway selective hepatic insulin resistance. This pathway selective hepatic insulin resistance has also been reported in mouse models due to altered substrate delivery to the liver as consequence of excess dietary intake and/or increased adipose tissue lipolysis. However, chow-fed aHepGHRkd mice show hyperinsulinemia that was sufficient to normalize systemic glucose uptake and suppress WAT lipolysis, as noted by normal plasma NEFA levels under both basal and clamped conditions. Therefore, changes in substrate delivery to the liver cannot readily explain the changes observed, suggesting hepatocyte GHR-signaling plays a direct role in partitioning of hepatic nutrients in response to insulin.

Presentation: Thursday, June 15, 2023