SAT-647 - Adult Onset, Hepatocyte-Specific GHR-Knockdown (Ahepghrkd) Prevents Diet-Induced Obesity That Is Reversed by Restoration of Hepatocyte IGF1 Production.

Our recent work used aHepGHRkd mice (GHRfl/fl mice treated with AAV8-TBGp-Cre) to study the impact on liver metabolism and progression of metabolic dysfunction associated steatohepatitis (MASH). Since hepatic GHR signals through STAT5 to sustain circulating IGF1, aHepGHRkd reduces IGF1, thereby removing negative feedback to the pituitary, resulting in a rise in GH levels. In order to tease apart the global effects of this reciprocal IGF1/GH shift on metabolic function, from the direct STAT5-dependent and independent actions of GHR signaling on hepatocyte function, subsets of aHepGHRkd are treated with AAV8-TBGp-rIGF1 or an AAV8-TBGp expressing constitutively active STAT5 (STAT5CA), where both normalize IGF1 and GH in aHepGHRkd mice. Prior work demonstrates aHepGHRkd leads to a MASH-like phenotype in chow-fed male mice that is exacerbated by feeding a diet high in fat and carbohydrate (fast-food diet, FFD), associated with increased hepatic de novo lipogenesis (DNL), inflammation, fibrosis and ductular reaction (DR). Restoration of hepatocyte STAT5 activity, but not IGF1 alone, reduces fibrosis and DR, but does not normalize liver DNL or inflammation. These results demonstrate GH acts directly on the hepatocyte through STAT5-dependent and independent mechanisms to limit MASH progression. Herein we report that, despite the liver injury observed in FFD-fed aHepGHRkd male mice, adipose tissue mass is < 50% of GHR-intact controls after 3.5 and 6 months of FFD feeding, with greatest impact to the subcutaneous and mesenteric depots. These changes were associated with a reduction in circulating insulin after 6 months of diet, without alterations in response to glucose or insulin tolerance tests or changes in circulating non-esterified fatty acids. Both AAV8-TBGp-IGF1 and STAT5CA increased adipose tissue mass towards that observed in GHR-intact controls. An additional study was conducted to compare the impact of aHepGHRkd and 3.5 months of FFD-feeding in both male and female mice. As previously reported, aHepGHRkd reduced circulating IGF1 and this was reversed by AAV8-TBGp-rIGF1 replacement and STAT5CA in both male and female mice. Consistent with the initial studies, male FFD-fed aHepGHRkd mice gain less weight attributed to less adipose tissue mass compared to GHR-intact controls, which was partially reversed by restoration of hepatocyte IGF1 and STAT5CA. FFD-fed aHepGHRkd female mice also gained less body weight, compared to GHR-intact controls, however this was not reflected by significant changes in whole body composition or specific fat-depot weights. We hypothesize that circulating IGF1 directly or indirectly influences adipose tissue metabolic and inflammatory endpoints in males and that additional factors in females, such as estrogen, override the actions of IGF1 to maintain adipose steady state. Studies are ongoing to test these hypotheses.

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