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Endocrine Abstracts (2021) 73 OC7.2 | DOI: 10.1530/endoabs.73.OC7.2

ECE2021 Oral Communications Oral Communications 7: Diabetes, Obesity, Metabolism and Nutrition (6 abstracts)

Hepatocyte GH signaling regulates carbohydrate processing in a STAT5b-independent manner

Mari C. Vázquez-Borrego1, 2, Mercedes Del Rio-Moreno1, 2, André Sarmento-Cabral1, 2, Mariyah Mahmood1, 2, Jose Cordoba-Chacon1, 2, Michelle Puchowicz3 & Rhonda Kineman1, 2



In the healthy liver, GH signals through multiple pathways to modulate hepatic function, with JAK2/STAT5b required to maintain circulating IGF1 levels. It has been previously reported that mice with developmental knockout of hepatocyte GHR, JAK2 or STAT5 develop steatosis associated with glucose intolerance, systemic insulin resistance and white adipose tissue (WAT) lipolysis. These changes are thought to be secondary to increased circulating GH, due to loss of IGF1 negative feedback. However, we have previously reported that mice with adult-onset hepatocyte-specific GHR knockdown (aHepGHRkd), that present with reduced IGF1 and elevated GH in the circulation, develop steatosis associated with enhanced de novo lipogenesis (DNL), without major alterations in systemic metabolic function. Importantly, steatosis and enhanced DNL are still evident in aHepGHRkd mice after normalization of GH by IGF1 treatment, indicating GH acts directly on the hepatocyte to control fat accumulation. We have extended our investigations to determine if loss of GHR-mediated STAT5b is the primary cause of sustained steatosis/DNL in the aHepGHRkd model. Specifically, male aHepGHRkd mice were treated with a hepatocyte-specific vector expressing constitutively active mouse STAT5b (AAV8-TBGp-STAT5bCA) and compared to GHR-intact mice [treated with control vector (Null)] 0010 h after 0700 h food withdrawal (post-absorptive state). STAT5b normalized IGF1 and GH levels in aHepGHRkd mice to that observed in GHR-intact controls and reduced, but did not completely normalize hepatic lipid content and DNL. Hepatic protein levels of glucokinase (GCK), fructokinase (KHK) and carbohydrate response element binding protein (ChREBP) were increased in aHepGHRkd mice with or without STAT5b reconstitution, suggesting the GHR signals independent of STAT5b, to control early events in hepatocyte carbohydrate processing. RNAseq analysis revealed 1278 hepatic genes were altered by aHepGHRkd. Of those genes, 942 were STAT5b-independent and included Gck and Khk, as well as liver pyruvate kinase (Pklr) and the glycogen branching enzyme (Gbe1). Taken together, these suggest GH acts directly on the hepatocyte, in a STAT5b-independent manner, to suppress carbohydrate processing. These actions may limit substrates for DNL and prevent steatosis. Additional studies in fed conditions are underway to test this hypothesis.

Volume 73

European Congress of Endocrinology 2021

Online
22 May 2021 - 26 May 2021

European Society of Endocrinology 

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