Endocrinology. 2014 Dec;155(12):4706-19.

Hepatic CREB3L3 controls whole-body energy homeostasis and improves obesity and diabetes.

Nakagawa Y1, Satoh A, Yabe S, Furusawa M, Tokushige N, Tezuka H, Mikami M, Iwata W, Shingyouchi A, Matsuzaka T, Kiwata S, Fujimoto Y, Shimizu H, Danno H, Yamamoto T, Ishii K, Karasawa T, Takeuchi Y, Iwasaki H, Shimada M, Kawakami Y, Urayama O, Sone H, Takekoshi K, Kobayashi K, Yatoh S, Takahashi A, Yahagi N, Suzuki H, Yamada N, Shimano H.
  • 1Department 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.



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.

PMID: 25233440



During fasting, several transcription factors co-ordinate to regulate energy homeostasis. CREB3L3 (cAMP response element binding protein 3 like-3), which is a member of CREB/ATF family, is a membrane-bound transcription factor and is restrictively expressed in liver and intestine. Previous reports showed that CREB3L3 is induced in response to endoplasmic reticulum stress, activates transcription of the genes encoding acute phase proteins such as serum amyloid P-component (Apcs) and C-reactive protein (Crp)1. Meanwhile, Creb3l3 is involved in nutrition and its gene expression is upregulated at fasting and primarily by fatty acids2. However, its fasting response is not happened in db/db mice, a diabetic obese mouse model3.


In this study, we identified the novel functions of CREB3L3 as a global metabolic regulator of starvation. The main direct target of CREB3L3 is Fgf21, an emerging anti-metabolic syndrome hepatokine, which has been thought to be regulated by PPARα, another fasting regulator4,5. We also found that CREB3L3 governs PPARα activation at both the transcriptional regulation and protein-protein interaction. Creb3l3 is down-regulated in Ppara−/− mice, conversely, Ppara is down-regulated in Creb3l3−/− mice. Promoter analysis revealed that PPARα binds to Creb3l3 promoter and CREB3L3 activates Ppara promoter2,3. This mutual activation between CREB3L3 and PPARα works in an autoloop fashion3. CREB3L3 forms the complex with PPARα and recruits PPARα co-activator such as PGC-1α to PPARα, resulting in activation of PPARα transcriptional activity (Fig. 1)3. Taken together, CREB3L3 as well as PPARα bind to the promoter region of Fgf21, resulting in direct and indirect activation of Fgf21 expression6,7.


We also determined HNF4α as the upstream factor for Creb3l3. In liver from HNF4α knock-down mice, both Creb3l3 and Ppara expression are blunted3. Therefore, during fasting, HNF4α is a central molecule to regulate CREB3L3 and PPARα. We propose new fasting transcription network paradigm including HNF4α, PPARα, and CREB3L3, which governs fasting-response gene expression such as Fgf21 (Fig. 2).


CREB3L3 should be added to the list of crucial transcription factors mediating starvation responses, and the mutual amplification mechanism with PPARα provides a new concept in coordinated regulation of energy metabolism factors at starvation. These involve induction of systemic lipolysis, hepatic ketogenesis, and insulin sensitivity with increased energy expenditure, leading to ameliorate metabolic syndrome (Fig. 3). We propose that CREB3L3 could be a new therapeutic target for metabolic disorders including obesity and diabetes.



1          Zhang, K. et al. Endoplasmic reticulum stress activates cleavage of CREBH to induce a systemic inflammatory response. Cell 124, 587-599, doi:S0092-8674(06)00004-3 [pii]10.1016/j.cell.2005.11.040 (2006).

2          Danno, H. et al. The liver-enriched transcription factor CREBH is nutritionally regulated and activated by fatty acids and PPARalpha. Biochem Biophys Res Commun 391, 1222-1227, doi:S0006-291X(09)02419-X [pii]10.1016/j.bbrc.2009.12.046 (2010).

3          Nakagawa, Y. et al. Hepatic CREB3L3 Controls Whole-Body Energy Homeostasis and Improves Obesity and Diabetes. Endocrinology 155, 4706-4719, doi:10.1210/en.2014-1113 (2014).

4          Inagaki, T. et al. Endocrine regulation of the fasting response by PPARalpha-mediated induction of fibroblast growth factor 21. Cell metabolism 5, 415-425, doi:S1550-4131(07)00130-1 [pii]10.1016/j.cmet.2007.05.003 (2007).

5          Badman, M. K. et al. Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states. Cell metabolism 5, 426-437, doi:S1550-4131(07)00129-5 [pii]10.1016/j.cmet.2007.05.002 (2007).

6          Kim, H. et al. Liver-enriched transcription factor CREBH interacts with peroxisome proliferator-activated receptor alpha to regulate metabolic hormone FGF21. Endocrinology 155, 769-782, doi:10.1210/en.2013-1490 (2014).

7          Bae, K. H., Min, A. K., Kim, J. G., Lee, I. K. & Park, K. G. Alpha lipoic acid induces hepatic fibroblast growth factor 21 expression via up-regulation of CREBH. Biochem Biophys Res Commun 455, 212-217, doi:10.1016/j.bbrc.2014.10.147 (2014).




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