3-OR: Hepatocyte Gdf15 Is Sufficient for Increased Plasma GDF15 Levels and Body Weight Constraint during High-Fat–Diet Feeding and Restores Insulin Sensitivity in a Liver-Specific Manner

Growth and differentiation factor 15 (GDF15) is a stress-induced secreted protein whose plasma levels are increased in obese patients. Recombinant GDF15 reduces body weight (BW) and improves glycemia in obese models, which is largely attributed to central action of GDF15 to suppress feeding. Despite this, the tissue specific sites of GDF15 production during obesity are unknown and the potential for local action is understudied. To determine the hepatocyte specific contribution of Gdf15 to changes in circulating GDF15 and effects on obesity, we utilized a Gdf15 KO-first mouse strain where endogenous expression of Gdf15 can be restored in a tissue specific fashion via Flp recombinase (FLP) . Gdf15 KO-first mice received AAV8-TBG-Gfp (KO+GFP) or AAV8-TBG-Flp (liver specific Gdf15 expression; KO+FLP) and were fed HFD for 12 weeks, alongside age-matched C57BL6 mice (WT) . Plasma GDF15 levels were undetectable in KO+GFP and similar between KO+FLP and WT HFD. BW was reduced in KO+FLP compared with KO+GFP and was not different from HFD WT. Interestingly, differences in BW were due to greater changes in lean (LM) compared with fat mass (FM) . Feeding was reduced in KO+FLP when expressed per mouse but not when expressed per g BW or LM, nor when the relationship between BW/LM and feeding were assessed by ANCOVA. Plasma insulin levels were increased in KO+GFP compared with WT HFD and markedly lower in KO+FLP compared with KO+GFP and WT HFD. Hyperinsulinemic euglycemic clamps demonstrated improved insulin sensitivity in KO+FLP due solely to changes in liver insulin action. These data suggest that feeding alone did not account for the changes in BW or insulin resistance, which would favor loss of FM and a generalized improvement in whole-body insulin sensitivity. They also demonstrate that hepatocyte Gdf15 is sufficient for obesity-associated increases in circulating GDF15 and suggest the potential for local effects of GDF15.