摘要：SummaryMice overexpressing the nuclear form of CREBH mainly in the liver (CREBH-Tg) showed suppression of high-fat high-sucrose (HFHS) diet-induced obesity accompanied by an increase in plasma fibroblast growth factor 21 (FGF21) levels. CREBH overexpression induced browning in inguinal white adipose tissue (WAT) and whole-body energy expenditure, which was canceled inFgf21−/−mice. Deficiency of FGF21 in CREBH-Tg mice mostly canceled the improvement of obesity, but the suppression of inflammation of epidermal WAT, amelioration of insulin resistance, and improvement of glucose metabolism still sustained. Kisspeptin 1 (Kiss1) was identified as a novel hormone target for CREBH to explain these FGF21-independent effects of CREBH. Knockdown of Kiss1 in HFHS-fed CREBH-TgFgf21−/−mice showed partially canceled improvement of glucose metabolism. Taken together, we propose that hepatic CREBH pleiotropically improves diet-induced obesity-mediated dysfunctions in peripheral tissues by improving systemic energy metabolism in FGF21-dependent and FGF21-independent mechanisms.Graphical AbstractDisplay OmittedHighlights•Deficiency of FGF21 in CREBH-Tg mice mostly cancels the improvement of obesity•CREBH induces browning in iWAT•CREBH suppresses inflammation of eWAT•CREBH-induced Kiss1 contributes to improvement of glucose metabolismObesity Medicine; Molecular Genetics
