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Kisspeptin 1 (Kiss1) was defined as a novel hormone target for CREBH to explain these FGF21-independent effects of CREBH. Knockdown of Kiss1 in HFHS-fed CREBH-Tg Fgf21-/- mice showed partially canceled improvement of glucose metabolism. Taken collectively, we propose that hepatic CREBH pleiotropically improves diet-induced obesity-mediated dysfunctions in peripheral cells by improving systemic energy kcalorie burning in FGF21-dependent and FGF21-indep