2039-LB: Insulin Sensitivity Is Impaired Independent of Changes in Body Weight in Liver-Specific GDF15 Knockout Mice

Introduction & Objective: Growth differentiation factor 15 (GDF15), a stress-induced protein, constrains body weight gain in models of obesity by reducing feeding and potentially increasing energy expenditure, leading to improved insulin sensitivity. Whether GDF15 affects insulin sensitivity independent of changes in body weight remains an open question. Methods: To address this question directly, we generated liver-specific GDF15 knockout mice (Gdf15fl/fl x Albcre-/+ to yield Gdf15fl/fl/Albcre-/+ LKO or Gdf15fl/fl/Albcre-/- WT mice). GDF15 LKO mice were fed either standard chow or high-fat diet (HFD) for 4 and 12 weeks. After the dietary challenge, we performed comprehensive metabolic phenotyping. Results: Chow-fed GDF15 LKO mice were similar to WT mice and there were no differences in body weight, feeding, circulating GDF15 levels or glucose homeostasis. After 12 weeks HFD, circulating GDF15 was 50% less in LKO mice, which was associated with a modest increase in body weight and significantly increased plasma insulin levels during glucose tolerance tests, indicative of insulin resistance. To avoid the confounding influence of body weight on comparisons of insulin resistance, we fed LKO mice HFD for 4 weeks. Circulating GDF15 was 20% less in LKO mice and there were no differences in body weight or feeding compared to WT. Hyperinsulinemic euglycemic clamps demonstrated impaired whole-body insulin sensitivity in LKO mice that was due primarily to impaired suppression of hepatic glucose output by insulin, indicative of liver insulin resistance. Conclusion: These data demonstrate body weight-independent effects of hepatocyte GDF15 on insulin sensitivity and suggest the potential for local, GFRAL-independent effects of hepatocyte-derived GDF15 on liver insulin signaling. Disclosure J. Kastroll: None. M.J. Jurczak: None. J. Alder: None. A. Vandevender: None. N. Dedousis: None. I.J. Sipula: None.