Project description: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.
Project description:Elucidation of the mechanisms controlling glucose homeostasis may deepen our understanding of the pathogenesis of T2DM and provide new therapeutic strategies for T2DM in the future. As reported, Dyrk1b is a pleiotropic protein and its genetic mutations are associated with blood glucose levels. However, the role of Dyrk1b in glucose metabolism is not well understood. Herein, we find that hepatic Dyrk1b overexpression in mice impairs the glucose tolerance and insulin resistance, whereas global Dyrk1b deficiency improves glucose metabolism of mcie. Dyrk1b overexpression in vitro blunts insulin signalling and glucose uptake. Collectively, our study uncovers a novel link between hepatic Dyrk1b and whole body glucose homeostasis.