Hepatic follistatin increases basal metabolic rate and attenuates diet-induced obesity during hepatic insulin resistance
Insulin resistance not compensated by secretion reduces energy storage, but little is known about its effect upon energy expenditure (EE). Insulin receptor substrates Irs1 and Irs2 mediate signaling in all tissues, resulting in the inhibition of FoxO transcription factors. We found that hepatic disruption of Irs1 and Irs2 (LDKO mice) attenuated high-fat diet (HFD)-induced obesity and increased whole-body EE in a FoxO1-dependent manner. Hepatic disruption of Fst (follistatin), a FoxO1-regulated hepatokine, normalized EE in LDKO mice and restored adipose mass during HFD consumption. Moreover, hepatic Fst disruption alone increased fat mass accumulation, whereas hepatic overexpression of Fst attenuated high HFD-induced obesity. Excess circulating Fst in overexpressing mice neutralized Mstn (myostatin), activating mTORC1-promoted pathways of nutrient uptake and EE in skeletal muscle. Similar to Fst overexpression, direct activation of muscle mTORC1 also reduced adipose mass. We conclude that Fst-promoted EE in muscle attenuates obesity during hepatic insulin resistance. Overall design: We generated the LDKO (Irs1L/L:Irs2L/L:CreAlb)  as previously described. We obtained FstL/L mice from Dr. Martin Matzuk (Baylor College of Medicine, Houston, TX). FstL/L mice were designed with loxP sites inserted before exon 2 and after exon 5 of the Fst gene. We generated LTKOFstKO mice by crossing FstL/L mice with LDKO mice.Expression of selected genes by RNAseq in skeletal muscle from Cntr, LDKO and LTKOFstL/L mice fed chow between 5 and 16 weeks.