The FGF21-CCL11 Axis Mediates Beiging of White Adipose Tissues by Coupling Sympathetic Nervous System to Type 2 Immunity

Huang, Zengshu; Zhong, Ling; Lee, Jimmy Tsz Hang; Zhang, Jialiang; Wu, Donghai; Geng, Leiluo; Wang, Yudong; Wong, Chi Ming; Xu, Aimin

doi:10.1016/j.cmet.2017.08.003

Cited by 120 publications

(133 citation statements)

References 51 publications

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“…During the long‐term fasting, hepatokine FGF21 is upregulated to directly target adipose tissue to facilitate fat utilization and activate the ketogenesis signaling (Badman et al , ; BonDurant et al , ; Fisher et al , ; Huang et al , ). In addition, FGF21 overexpression results in a variety of abnormalities including female infertility, circadian behavior disruption and bone loss (Bookout et al , ; Owen et al , ; Wei et al , b).…”

Section: Discussionmentioning

confidence: 99%

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HRD1‐ERAD controls production of the hepatokine FGF21 through CREBH polyubiquitination

Wei

Chen

et al. 2018

The EMBO Journal

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The endoplasmic reticulum‐associated protein degradation (ERAD) is responsible for recognizing and retro‐translocating protein substrates, misfolded or not, from the ER for cytosolic proteasomal degradation. HMG‐CoA Reductase (HMGCR) Degradation protein—HRD1—was initially identified as an E3 ligase critical for ERAD. However, its physiological functions remain largely undefined. Herein, we discovered that hepatic HRD1 expression is induced in the postprandial condition upon mouse refeeding. Mice with liver‐specific HRD1 deletion failed to repress FGF21 production in serum and liver even in the refeeding condition and phenocopy the FGF21 gain‐of‐function mice showing growth retardation, female infertility, and diurnal circadian behavior disruption. HRD1‐ERAD facilitates the degradation of the liver‐specific ER‐tethered transcription factor CREBH to downregulate FGF21 expression. HRD1‐ERAD catalyzes polyubiquitin conjugation onto CREBH at lysine 294 for its proteasomal degradation, bridging a multi‐organ crosstalk in regulating growth, circadian behavior, and female fertility through regulating the CREBH‐FGF21 regulatory axis.

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Section: Discussionmentioning

confidence: 99%

“…*P < 0.05 and **P < 0.01 by unpaired Student's t-test. the ketogenesis signaling (Badman et al, 2009;BonDurant et al, 2017;Fisher et al, 2012;Huang et al, 2017). In addition, FGF21 overexpression results in a variety of abnormalities including female infertility, circadian behavior disruption and bone loss Owen et al, 2013;Wei et al, 2012b).…”

Section: Discussionmentioning

confidence: 99%

HRD1‐ERAD controls production of the hepatokine FGF21 through CREBH polyubiquitination

Wei

Chen

et al. 2018

The EMBO Journal

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“…However, despite of the fact that transcription of adiponectin was remarkably induced within white adipose tissue upon cold challenge [67], such a change was not abolished adipose-specific deletion of FGF21 or its co-receptor β Klotho [75], indicating that cold-evoked upregulation of adiponectin in adipose tissue was not controlled under FGF21. Moreover, although adiponectin deficient mice were also less sensitive to white adipose browning stimulated by cold [67,76], it seems that it activates browning remodeling in distinct ways as FGF21.…”

Section: Fgf21-adiponectin Axis In Cold Adaptationmentioning

confidence: 91%

“…Recently it is found that FGF21 expression was also strongly upregulated in white adipocytes under cold-acclimated conditions [75]. By using the adipocyte-specific FGF21 knockout mice, it was further revealed that adipocytederived FGF21 acts in an autocrine manner to promote the expression and secretion of CCL11 via activation of ERK1/2 [75]. This event then drives recruitment of eosinophils into subcutaneous WAT, leading to increases in accumulation of M2 macrophages, and proliferation/commitment of adipocyte precursors into beige adipocytes.…”

Section: Fgf21-adiponectin Axis In Cold Adaptationmentioning

confidence: 99%

Adipose Tissue as an Endocrine Organ

Hui¹,

Feng²

2018

Adipose Tissue

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As one of the largest endocrine organs in the body, adipose tissue secrets a number of bioactive hormones, called adipokines. The expression and secretion of adipokines are tightly controlled and coordinated by physiological and pathophysiological conditions. In multiple physiological conditions, such as obesity, cold adaptation, exercise training, expression and secretion of adipokines are altered accordingly, which in turn modulate the metabolism of the whole body in endocrine, paracrine and autocrine manners. The varied changes in adipose tissues are pivotal mediators that aid the body to adapt to various physiological and pathological conditions, whereas almost all obesity-associated diseases are attributable to dysregulation of adipokines.

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“…This route of action has been proposed as a major endocrine axis of FGF21 for insulin sensitization; lowering of systemic glucose, triacylglycerol, and LDL; fighting against obesity, diabetes, fatty liver diseases, hyperlipidemia, and associated comorbidities; and achieving metabolic health [2,73,74,107]. Some of these effects are likely mediated by adipokines, such as CCL11 and adiponectin, as shown in mice [108,109]. In cold-induced nonshivering thermogenesis or exercise stress condition, BAT also becomes a source of endocrine FGF21 in a β-adrenergicand cAMPdependent manner, which in turn facilitates mitochondrial genesis, oxidative capacity, uncoupling, and heat generation, leading to adaptation to cold conditions and core body temperature maintenance [110][111][112].…”

Section: Fgf21 Metabolic Axismentioning

confidence: 99%

The FGF metabolic axis

2019

Front. Med.

112

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Members of the fibroblast growth factor (FGF) family play pleiotropic roles in cellular and metabolic homeostasis. During evolution, the ancestor FGF expands into multiple members by acquiring divergent structural elements that enable functional divergence and specification. Heparan sulfate-binding FGFs, which play critical roles in embryonic development and adult tissue remodeling homeostasis, adapt to an autocrine/paracrine mode of action to promote cell proliferation and population growth. By contrast, FGF19, 21, and 23 coevolve through losing binding affinity for extracellular matrix heparan sulfate while acquiring affinity for transmembrane α-Klotho (KL) or β-KL as a coreceptor, thereby adapting to an endocrine mode of action to drive interorgan crosstalk that regulates a broad spectrum of metabolic homeostasis. FGF19 metabolic axis from the ileum to liver negatively controls diurnal bile acid biosynthesis. FGF21 metabolic axes play multifaceted roles in controlling the homeostasis of lipid, glucose, and energy metabolism. FGF23 axes from the bone to kidney and parathyroid regulate metabolic homeostasis of phosphate, calcium, vitamin D, and parathyroid hormone that are important for bone health and systemic mineral balance. The significant divergence in structural elements and multiple functional specifications of FGF19, 21, and 23 in cellular and organismal metabolism instead of cell proliferation and growth sufficiently necessitate a new unified and specific term for these three endocrine FGFs. Thus, the term "FGF Metabolic Axis," which distinguishes the unique pathways and functions of endocrine FGFs from other autocrine/paracrine mitogenic FGFs, is coined.

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The FGF21-CCL11 Axis Mediates Beiging of White Adipose Tissues by Coupling Sympathetic Nervous System to Type 2 Immunity

Cited by 120 publications

References 51 publications

HRD1‐ERAD controls production of the hepatokine FGF21 through CREBH polyubiquitination

HRD1‐ERAD controls production of the hepatokine FGF21 through CREBH polyubiquitination

Adipose Tissue as an Endocrine Organ

The FGF metabolic axis

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