Metabolic Dysfunction within Brown Adipose Tissue and Skeletal Muscle Caused by Complete Hepatic Insulin Resistance Is Reversible by FGF-21 Treatment

Hepatic Irs1/Irs2 double knockout mice (LDKO) developed severe systemic insulin resistance, glucose intolerance, and dysregulated gluconeogenesis and hyperinsulinemia—which was largely normalized upon deletion of FoxO1. Although hepatic insulin resistance was established genetically in the LDKO mice, altered hepatokine secretion can dysregulate the metabolism of other tissues—including white (WAT) and brown (BAT) adipose tissues, and skeletal muscle. Compared against control mice, glucose uptake into BAT and various skeletal muscles of LDKO-mice was reduced strongly before and during insulin stimulation. Moreover, BAT exhibited higher gene expression levels of muscle and white adipose tissue markers, whereas expression of BAT and thermogenesis markers were decreased. This indicated immature BAT development, and consequently LDKO-mice failed to maintain body core temperature when exposed to a 4°C environment. Among the dysregulated hepatokines in LDKO-mice, FGF-21 (fibroblast growth factor 21) was reduced significantly. As circulating FGF-21 is produced almost entirely in the liver, LDKO-mice treated by hepatic infection with FGF-21^AdV (adenoviral FFG-21) displayed better glucose tolerance, insulin sensitivity, and glucose uptake into BAT and skeletal muscle. FGF-21 also restored normal cold sensitivity. On a high fat diet (HFD) LDKO mice developed severe hyperglycemia; however LDKO•FGF-21^AdV-mice lost weight and glucose tolerance improved. These results suggest that reduced FGF-21 contributed to BAT and skeletal muscle dysfunction in LDKO-mice, which can dysregulate systemic glucose homeostasis during hepatic insulin resistance. Expression of FGF-21 can restore and improve glucose metabolism despite the persistent hepatic insulin resistance and uncontrolled gluconeogenesis in these mice.