OR33-1 Increased Activin Bioavailability Enhances Hepatic Insulin Sensitivity While Inducing Hepatic Steatosis

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR33-Insulin Signaling & Inflammation
Monday, June 17, 2013: 11:15 AM-12:45 PM
Presentation Start Time: 11:15 AM
Room 303 (Moscone Center)
Nathan Ungerleider1, Lara Bonomi2, Melissa Brown1 and Alan Schneyer*3
1UMass-Amherst, Springfield, MA, 2Pioneer Valley Life Science Institute, Springfield, MA, 3UMass-Amherst, Amherst, MA
Fatty liver is frequently associated with obesity, insulin resistance and diabetes yet it remains unclear whether fatty liver is a contributing factor or a consequence of reduced insulin responsiveness.  Excessive lipids or their metabolites can reduce responsiveness of liver and/or muscle cells to insulin.  On the other hand, insulin resistance can reduce lipid uptake by adipocytes leading to fatty deposits in hepatocytes, and/or, when restricted to the glucose storage pathway, lead to hyperinsulinemia and increased hepatic triglycerides (TG).   A number of mouse models have identified fatty liver in the absence of insulin resistance suggesting that fatty liver and insulin resistance may be independent defects in some cases.  To determine the physiological roles of follistatin like-3 (FSTL3), a secreted antagonist of activin, myostatin and GDF11, we created FSTL3 KO mice. In addition to the “enhanced” metabolic phenotype of these mice which included enlarged islets, β-cell hyperplasia, reduced visceral fat, and enhanced glucose tolerance and whole body insulin sensitivity, these mice uniformly develop fatty liver by 6 months.  To investigate possible mechanisms for the development of hepatic steatosis in a setting of enhanced whole body insulin sensitivity, we found that FSTL3 KO livers had significantly elevated TG content compared to WT littermates.  To determine hepatic insulin sensitivity, phosphorylated AKT/total AKT was assessed in liver samples 10 min after insulin treatment.  Surprisingly, insulin signaling was significantly elevated in FSTL3 KO mouse liver despite the excessive TG storage.  To determine possible mechanisms for this enhanced insulin response, HepG2 hepatoma cells were pre-treated with 2 nM activin A for 4 hrs followed by insulin exposure for 10 min.  Phospho-AKT was significantly increased in activin treated HepG2 cells indicating that activin can enhance hepatocyte insulin responsiveness.  Gene expression analysis suggested that increased lipid uptake, enhanced de novo lipid synthesis, decreased lipolysis and/or enhanced glucose uptake contribute to increased hepatic TG content in FSTL3 KO mice.  Our results indicate that activin enhances hepatocyte insulin response which ultimately leads to hepatic steatosis in the absence of insulin resistance.  Thus, regulation of activin bioactivity is critical for maintaining normal liver lipid homeostasis while FSTL3 antagonists may be useful for increasing liver insulin sensitivity.

Nothing to Disclose: NU, LB, MB, AS

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: NIH/NIDDK R01 DK075058
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