title: Hepatic CREB3L3 controls whole-body energy homeostasis and improves obesity and diabetes.
abstract: Transcriptional regulation of metabolic genes in the liver is the key to maintaining systemic energy homeostasis during starvation. The membrane-bound transcription factor cAMP-responsive element-binding protein 3-like 3 (CREB3L3) has been reported to be activated during fasting and to regulate triglyceride metabolism. Here, we show that CREB3L3 confers a wide spectrum of metabolic responses to starvation in vivo. Adenoviral and transgenic overexpression of nuclear CREB3L3 induced systemic lipolysis, hepatic ketogenesis, and insulin sensitivity with increased energy expenditure, leading to marked reduction in body weight, plasma lipid levels, and glucose levels. CREB3L3 overexpression activated gene expression levels and plasma levels of antidiabetic hormones, including fibroblast growth factor 21 and IGF-binding protein 2. Amelioration of diabetes by hepatic activation of CREB3L3 was also observed in several types of diabetic obese mice. Nuclear CREB3L3 mutually activates the peroxisome proliferator-activated receptor (PPAR) α promoter in an autoloop fashion and is crucial for the ligand transactivation of PPARα by interacting with its transcriptional regulator, peroxisome proliferator-activated receptor gamma coactivator-1α. CREB3L3 directly and indirectly controls fibroblast growth factor 21 expression and its plasma level, which contributes at least partially to the catabolic effects of CREB3L3 on systemic energy homeostasis in the entire body. Therefore, CREB3L3 is a therapeutic target for obesity and diabetes.
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism) (Y.N., A.Sa., S.Yab., M.F., N.T., H.T., M.M., W.I., A.Sh., T.M., S.K., Y.F., H.Shimi., H.D., T.Y., K.I., T.K., Y.T., H.I., M.S., Y.K., O.U., H.So., K.T., K.K., S.Yat., A.T., N.Yah., H.Su., N.Yam., H.Shima.), Division of Clinical Medicine, Faculty of Medicine, and 2International Institute for Integrative Sleep Medicine (WPI-IIIS) (Y.N., H.Shima.), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Nakagawa
authors.forename: Aoi
authors.initials: A
authors.lastname: Satoh
authors.forename: Sachiko
authors.initials: S
authors.lastname: Yabe
authors.forename: Mika
authors.initials: M
authors.lastname: Furusawa
authors.forename: Naoko
authors.initials: N
authors.lastname: Tokushige
authors.forename: Hitomi
authors.initials: H
authors.lastname: Tezuka
authors.forename: Motoki
authors.initials: M
authors.lastname: Mikami
authors.forename: Wakiko
authors.initials: W
authors.lastname: Iwata
authors.forename: Akiko
authors.initials: A
authors.lastname: Shingyouchi
authors.forename: Takashi
authors.initials: T
authors.lastname: Matsuzaka
authors.forename: Shiori
authors.initials: S
authors.lastname: Kiwata
authors.forename: Yuri
authors.initials: Y
authors.lastname: Fujimoto
authors.forename: Hidehisa
authors.initials: H
authors.lastname: Shimizu
authors.forename: Hirosuke
authors.initials: H
authors.lastname: Danno
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Kiyoaki
authors.initials: K
authors.lastname: Ishii
authors.forename: Tadayoshi
authors.initials: T
authors.lastname: Karasawa
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Takeuchi
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Iwasaki
authors.forename: Masako
authors.initials: M
authors.lastname: Shimada
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kawakami
authors.forename: Osamu
authors.initials: O
authors.lastname: Urayama
authors.forename: Hirohito
authors.initials: H
authors.lastname: Sone
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Takekoshi
authors.forename: Kazuto
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Shigeru
authors.initials: S
authors.lastname: Yatoh
authors.forename: Akimitsu
authors.initials: A
authors.lastname: Takahashi
authors.forename: Naoya
authors.initials: N
authors.lastname: Yahagi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Suzuki
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Yamada
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Shimano
mesh_terms: D000818:Animals; D001835:Body Weight; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D004435:Eating; D004734:Energy Metabolism; D005215:Fasting / Q000378:metabolism*; D005346:Fibroblast Growth Factors / Q000378:metabolism; D005508:Food Deprivation / Q000502:physiology; D015870:Gene Expression; D006706:Homeostasis; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009765:Obesity / Q000209:etiology / Q000378:metabolism; D047493:PPAR alpha / Q000378:metabolism; D013217:Starvation / Q000378:metabolism
chemical_list: C500051:Creb3l3 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D047493:PPAR alpha; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors