Harnessing the Integrated Stress Response to Counteract Metabolic Disease
Authors: Anne S. Henkel
Journal: Hepatology (2018)

SEE ARTICLE ON PAGE 2167 Over a decade ago, fibroblast growth factor 21 (FGF21) was identified as a novel regulator of metabolism.1 Since that time, accumulating data have substantiated the therapeutic potential of this hormone in counteracting metabolic disease. Increasing levels of FGF21 in mice, either through transgenic overexpression or exogenous administration, has consistently produced favorable effects on obesity and its sequelae. Mechanistically, FGF21 has been shown to promote browning of adipose tissue, increase thermogenesis, and enhance energy expenditure. Although the limited experience using exogenous FGF21 in human trials is encouraging,2 boosting endogenous FGF21 production by manipulating its physiological regulatory mechanisms is viewed as an exciting alternative, yet unproven, therapeutic strategy. Given the purported therapeutic potential of FGF21 in treating metabolic disease, the regulation of this hormone has been an area of intense scrutiny in recent years. Although initially characterized as a fasting‐induced hormone, FGF21 is clearly regulated by numerous types of physiological and pathophysiological stress. Moreover, FGF21 has become an established target of an adaptive cellular response, termed integrated stress response (ISR). ISR is mediated by four stress‐responsive kinases that converge on a common target, termed eukaryotic initiation factor 2α (eIF2α; Fig. 1). Activated eIF2α functions to counteract stress, in part, by suppressing global protein translation. Despite halting translation of most proteins, eIF2α selectively increases the translation of activating transcription factor 4 (ATF4), considered a master regulator of ISR. Importantly, numerous studies have now shown that ATF4 transcriptionally activates FGF21, providing a crucial mechanistic link between ISR and metabolic function.3 A key checkpoint in regulation of ISR is dephosphorylation of eIF2α by growth arrest and damage inducible protein 34 (GADD34) and constitutive repressor of eIF2α phosphorylation (CReP).Figure 1: Diverse metabolic consequences of targeting the ISR. In response to diverse stress stimuli, ISR kinases (GCN2, PERK, PKR, and HRI) phosphorylate eIF2α, which activates ATF4, the master regulator of ISR. ATF4, in turn, activates FGF21. CReP, and GADD34 function to dephosphorylate and thereby inactivate eIF2α. Targeting these core elements of ISR through pharmacological or genetic manipulation produces highly variable and contradictory metabolic phenotypes. Abbreviations: GCN2, general control nonderepressible 2; HRI, heme‐regulated inhibitor kinase; PERK, PKR‐like endoplasmic reticulum kinase; PKR, protein kinase R.In this issue of Hepatology, Xu et al. report on the role of CReP in mediating metabolic disease in mice.4 Using mice bearing a hepatocyte‐specific deletion of CReP (CRePLKO mice), the investigators examined the function of hepatic CReP in the development of diet‐induced obesity (DIO), insulin resistance (IR), and hepatic steatosis (HS). The investigators found that deletion of hepatic CReP resulted in constitutive phosphorylation of eIF2α, resulting in induction of FGF21 through ATF4 activation. Enhanced FGF21 expression among CRePLKO mice promoted browning of white adipose tissue and enhanced energy expenditure. Importantly, CRePLKO mice showed reduced body weight at baseline and attenuated weight gain when challenged with a high‐fat diet. CRePLKO mice also showed remarkable protection from IR and HS in response to high‐fat feeding. Whether the improvement in HS was entirely secondary to reduced adiposity remains unclear, and additional studies are warranted to determine whether CReP modifies fatty liver disease independently of body weight. These exciting findings raise the question of whether ISR may be harnessed therapeutically to reverse metabolic disease. To shed light on this important question, the investigators acutely suppressed hepatic CReP expression using adenoviral‐mediated introduction of Cre‐recombinase in adult mice with DIO. Acute suppression of CReP resulted in a 20% reduction in body weight over the ensuing 2 weeks associated with improvement in both HS and IR. To prove a mechanistic role for FGF21 in mediating the metabolic benefits of CReP‐deletion, the investigators generated liver‐specific CReP and FGF21 double‐knockout mice. Browning of adipose tissue observed among CRePLKO mice was completely abolished by loss of FGF21. Similarly, enhanced energy expenditure, protection from obesity, and improvement in IR observed among CRePLKO mice were lost in the absence of FGF21. In summary, Xu et al. uncover a novel function of CReP in regulating metabolic disease in mice by modulation of the ISR target, FGF21. Of broader significance, this work provides new insight into the complex interplay between cellular stress responses and development of metabolic disease. This work supports the hypothesis that enhancing endogenous FGF21 levels by boosting ISR may serve as a novel strategy to treat metabolic diseases. Caution must be taken, however, in extrapolating these findings to human disease. Moreover, the striking effects of FGF21 in ameliorating murine metabolic disease have not fully translated to humans. In contrast to the profound effects of FGF21 on glucose metabolism in mice, for example, the glucose‐lowering effects of FGF21 in humans are arguably minimal.2 Perhaps of greater significance is the observation that circulating FGF21 levels are actually elevated in obesity, raising speculation that obesity represents an FGF21‐resistant state. As such, eliciting the beneficial effects of FGF21 among obese patients may require increasing FGF21 to supraphysiological levels. It remains to be seen whether augmenting endogenous FGF21 levels by modulation of ISR could generate the circulating levels required to produce a physiologically significant effect in humans. When considering the therapeutic implications of augmenting ISR, perhaps of greater concern is that manipulation of core elements of ISR has been shown to produce highly variable metabolic phenotypes (Fig. 1). Consistent with the conclusion of Xu et al., that enhancing eIF2α activation protects against metabolic disease, others have shown that genetic ablation of eIF2α exacerbates HS in mice subjected to endoplasmic reticulum (ER) stress, a known trigger of ISR.5 In contrast, however, other studies have found that deactivating eIF2α protects against metabolic disease. GADD34, like CReP, functions to dephosphorylate, and thereby inactivate, eIF2α. Transgenic mice overexpressing GADD34 are protected from high‐fat‐diet–induced HS, indicating that GADD34 and CReP may have opposing effects on metabolic disease.6 Furthermore, Xu et al. show that the beneficial metabolic effects of CReP deletion are associated with induction of ATF4, yet disruption of Atf4 in mice has previously been shown to ameliorate metabolic disease.7 Salubrinal and nelfinavir are agents that function, in part, by inhibiting CReP, thereby promoting eIF2α phosphorylation.8 Although these agents have not been rigorously studied in metabolic disease, it is discouraging that treating genetically obese mice with salubrinal was reported to have no effect on body weight.10 Furthermore, it is well established that long‐term use of human immunodeficiency virus protease inhibitors, such as nelfinavir, promotes hyperlipidemia, type 2 diabetes, and lipodystrophy. Collectively, these data suggest that phosphorylated eIF2α and ATF4 exert highly variable effects on metabolism depending on the experimental conditions. Furthermore, the stress response induced by CReP deletion appears to be distinct from that elicited by other triggers of eIF2α phosphorylation. Future studies are warranted to fully characterize the interplay between eIF2α phosphorylation and metabolic pathways. In particular, it will be important to define the molecular mechanisms that underlie the seemingly opposing effects of CReP and GADD34 on metabolic disease. These discrepant metabolic phenotypes highlight a broader concern about manipulating core elements of a highly evolutionarily conserved signaling cascade such as ISR. ISR regulates fundamental physiological processes that are critical to maintaining cellular homeostasis. ATF4 alone regulates hundreds of genes with diverse, and at times opposing, physiological effects. Before ISR may be targeted therapeutically in metabolic disease, we need a clearer understanding of the molecular signals governing the diverse consequences of ISR activation. The article by Xu et al. brings us one step closer to fully understanding the complex mechanisms by which fundamental cellular stress responses contribute to metabolic disorders. Potential conflict of interest Nothing to report.