Dysregulated FGF21 Links Hepatic Insulin Resistance to Dysfunctional BAT

LDKO (hepatic Irs1/Irs2 double knockout) mice show a severe diabetic phenotype owing to the impaired communication of the insulin resistant liver throughout the body by the dysregulated production and secretion of hepatokines. Excess Fst (follistatin) secreted by the liver of LDKO-mice inhibits insulin action in WAT (white adipose tissue) and promotes hepatic glucose production; however, Fst does not dysregulate BAT (brown adipose tissue). Regardless, BAT in LDKO-mice lacked typical BAT characteristics on the anatomical and molecular level. Glucose uptake was severely impaired, which might contribute to the diabetic phenotype of LDKO-mice. Succinate stimulates BAT and protects control mice against obesity and hyperglycemia during HFD feeding; however, succinate has no beneficial effect in LDKO-mice revealing non-responsive/dysfunctional BAT in these mice. Transplantation of healthy BAT from wild type mice into LDKO-mice was unbeneficial, whereas transplantation of healthy BAT into control mice improved their whole-body glucose metabolism and glucose tolerance. Next, we investigated whether dysregulated hepatokines might impair BAT function in LDKO-mice. Among the dysregulated hepatokines in LDKO-mice FGF-21 (fibroblast growth factor 21) was reduced significantly. Re-expression of FGF-21 in the liver via adenoviral infection increased FGF-21 serum levels into the normal range and restored normal glucose uptake into BAT and improved glucose tolerance during chow or HFD feeding. These results suggest that reduced FGF-21 promotes BAT dysfunction during hepatic insulin resistance, whereas re-expression of FGF-21 restored glucose metabolism regardless of the persistent hepatic insulin resistance and uncontrolled gluconeogenesis owing to elevated hepatic Fst. Disclosure O. Stoehr: None. R. Tao: None. K.D. Copps: None. M.F. White: Advisory Panel; Self; Housey Pharmaceutical Research Laboratories.