Next Article in Journal
The Sensitization of Triple-Negative Breast Cancers to Poly ADP Ribose Polymerase Inhibition Independent of BRCA1/2 Mutation Status by Chemically Modified microRNA-489
Previous Article in Journal
Targeted Inhibitors of EGFR: Structure, Biology, Biomarkers, and Clinical Applications
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Cells
Volume 13
Issue 1
10.3390/cells13010048
cells-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

The Emerging Role of SIRT7 in Glucose and Lipid Metabolism

by
Kazuya Yamagata
1,2,*,
Tomoya Mizumoto
1 and
Tatsuya Yoshizawa
1
1
Department of Medical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan
2
Center for Metabolic Regulation of Healthy Aging, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan
*
Author to whom correspondence should be addressed.
Cells 2024, 13(1), 48; https://doi.org/10.3390/cells13010048
Submission received: 21 November 2023 / Revised: 13 December 2023 / Accepted: 24 December 2023 / Published: 25 December 2023
Browse Figures
Review Reports Versions Notes

Abstract

:
Sirtuins (SIRT1–7 in mammals) are a family of NAD+-dependent lysine deacetylases and deacylases that regulate diverse biological processes, including metabolism, stress responses, and aging. SIRT7 is the least well-studied member of the sirtuins, but accumulating evidence has shown that SIRT7 plays critical roles in the regulation of glucose and lipid metabolism by modulating many target proteins in white adipose tissue, brown adipose tissue, and liver tissue. This review focuses on the emerging roles of SIRT7 in glucose and lipid metabolism in comparison with SIRT1 and SIRT6. We also discuss the possible implications of SIRT7 inhibition in the treatment of metabolic diseases such as type 2 diabetes and obesity.

1. Introduction

Sirtuins (SIRT1–7 in mammals) are evolutionally conserved nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases and deacylases that regulate a wide variety of biological processes, including metabolism, stress responses, genomic stability, tumorigenesis, and aging. The seven SIRTs share a highly conserved NAD+-binding and catalytic core domain, while the N- and C- terminal regions vary structurally and contribute to differences in tissue expression, subcellular localization, and enzymatic activities [1,2,3]. SIRT1 and SIRT6 are located predominantly in the nucleus (nuclear sirtuin). SIRT7 is another nuclear sirtuin and is present in the nucleolus and nucleoplasm but also resides in the cytoplasm. SIRT2 is cytoplasmically localized, whereas SIRT3, SIRT4, and SIRT5 are located mainly in the mitochondria [4]. Regarding enzymatic activities, SIRT1, SIRT2, and SIRT3 have strong deacetylase activity, while SIRT4, SIRT5, and SIRT6 have either weak or undetectable deacetylase activity in various in vitro assays. SIRT4 has ADP-ribosyltransferase activity [5], and SIRT5 has demalonylase and desuccinylase activities [6]. SIRT6 preferentially catalyzes deacylation of long-chain fatty-acyl groups from target proteins [7,8].
SIRT7 is ubiquitously expressed in almost all tissues, with the exception of skeletal muscle [9]. The enzymatic activity of SIRT7 was unknown for a long time, but Baber et al. reported that SIRT7 possesses histone H3K18 selective deacetylation activity [10]. Since this breakthrough, a number of target proteins and physiological functions of SIRT7 have been identified (Table 1) [10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44] and it is now clear that SIRT7 plays critical roles in many biological processes, including gene expression, genome stability, stress response, and metabolism. Recent studies have also revealed that in addition to deacetylase activity, SIRT7 has both deacylase and ADP-ribosyltransferase activities [39,40,41,42,43,44]. SIRT1 and SIRT6 are crucial regulators of fat and glucose metabolism, but the metabolic roles of SIRT7 received little research attention until recently [2,45,46,47]. However, accumulating evidence indicates that SIRT7 also plays a critical role in the regulation of metabolism. This review focuses on the recent progress in elucidating the role of SIRT7 in lipid and glucose metabolism in comparison with SIRT1 and SIRT6. Other cellular and biological roles of SIRT7, such as stress response, are covered in several recent reviews [48,49,50,51]. A better understanding of the metabolic roles of SIRT7 might be useful in the development of new strategies for treating metabolic diseases such as obesity and type 2 diabetes.

2. The Role of Nuclear Sirtuins in Lipid Metabolism

White adipose tissue (WAT) is the predominant type of fat in humans, and white adipocytes serve as a storage depot for excess energy as triacylglycerol. During fasting, triacylglycerol stored in adipocytes is hydrolyzed to produce fatty acids. These fatty acids are then oxidized in the liver, muscles, and so on to generate ATP. Fatty acids are also used for heat production in brown adipose tissue (BAT). Recent studies have clarified that SIRT7 influences diverse aspects of lipid homeostasis in these organs.

2.1. Adipogenesis

Adipogenesis is a well-orchestrated multistage differentiation process in which fibroblast-like preadipocytes mature into lipid-laden, insulin-responsive adipocytes. This process is regulated by a cascade of transcriptional factors, among which nuclear receptor peroxisome proliferator-activated γ (PPARγ) functions as a master regulator [52,53,54]. SIRT1 represses the activity of PPARγ by promoting the docking of co-repressors such as nuclear receptor co-repressor (NCoR) and silencing mediator of retinoid and thyroid hormone receptors (SMRT) on the promoters of PPARγ target genes [55]. Thus, SIRT1 acts as a negative regulator of adipogenesis.
Mitotic clonal expansion is an event that occurs early in the process of adipogenesis [52,53]. Kinesin family member 5C (KIF5C) is a negative regulator of mitotic clonal expansion, and SIRT6 negatively regulates KIF5C expression through deacetylation of H3K9 and H3K56 at the promoter. Thus, SIRT6 is essential for adipogenesis because it regulates mitotic clonal expansion [56]. However, it has also been reported that SIRT6 inhibits preadipocyte differentiation by activating the AMP-activated protein kinase (AMPK) pathway [57].
SIRT7 is also implicated in the regulation of adipogenesis [58,59]. Mechanistically, SIRT7 restricts SIRT1 activity by inhibiting SIRT1 autodeacetylation activity [59]. As described above, SIRT1 suppresses adipogenesis [55]. Thus, SIRT7 promotes adipogenesis by inhibiting SIRT1 activity and enhancing PPARγ activity (Figure 1A). These findings clearly indicate that SIRT7 and SIRT1 play opposite roles in adipogenesis.

2.2. Lipolysis and Lipogenesis

White adipocytes are the main storage compartment of triacylglycerol in the body, and the storage mechanism is regulated by the balance of lipid synthesis and hydrolyzation (lipolysis). In the fasting state, the rate of lipolysis increases, and free fatty acids (FFAs) are released into the blood, while the outflow of FFAs from adipocytes decreases in the fed state. In addition to its role in adipogenesis, PPARγ also plays a crucial role in increasing the uptake and trapping of FFAs in mature adipocytes by regulating the expression of lipoprotein lipase (LPL), fatty acid transport protein (FATP), and CD36 [54,60]. SIRT1 represses PPARγ activity as described above and enhances lipolysis in differentiated mature adipocytes [55]. Consistently, the release of FFAs from white adipocytes upon fasting was compromised in Sirt1+/− mice [55].
Adipose triglyceride lipase (ATGL) is a rate-limiting enzyme that catalyzes the initial step of lipolysis and converts triacylglycerol to diacylglycerol [61,62]. The expression of ATGL is controlled by Forkhead Box O1 (FOXO1) in adipocytes, and SIRT6 deficiency represses the transcription of Atgl by increasing the acetylation of FOXO1, thereby promoting its nuclear exclusion [63,64]. Therefore, both SIRT1 and SIRT6 promote lipolysis in white adipocytes.
PPARγ exists as two isoforms, PPARγ1 and PPARγ2, as a result of alternative splicing and different promoter usage [54]. PPARγ1 is expressed in many tissues, but the expression of PPARγ2, which contains 30 additional amino acids at the N-terminus, is restricted to adipose tissue. SIRT7 binds to PPARγ2 and deacetylates it at K382 [20]. C3H10T1/2-derived adipocytes expressing PPARγ2K382Q (a mimic of acetylated K) accumulate much less fat compared with adipocytes expressing PPARγ2K382R (a mimic of deacetylated K).
Intriguingly, the expression of lipogenic genes, including Fasn (encoding fatty acid synthase), Acaca (encoding acetyl CoA carboxylase α), Scd1 (encoding stearoyl CoA desaturase), and Srebp1c (encoding sterol regulatory element binding protein 1c), were selectively decreased in both the PPARγ2K382Q cells and WAT of Sirt7 knockout (KO) mice. These findings indicate that SIRT7-dependent PPARγ2 deacetylation at K382 preferentially promotes lipogenesis in white adipocytes (Figure 1B) [20]. SIRT7 is also reported to promote lipogenesis by inducing the methylation of SREBP1a in tumors [40].

2.3. Thermogenesis

In addition to WAT, mammals also possess BAT, which plays a crucial role in whole-body energy expenditure through non-shivering thermogenesis. Uncoupling protein 1 (UCP1) is a brown adipocyte-specific protein located within mitochondria that catalyzes a protein leak across the inner mitochondrial membrane. Brown adipocytes dissipate energy as heat through the activation of UCP1 by uncoupling fuel oxidation from ATP synthesis [65,66]. β3-adrenergic receptors are abundantly expressed in brown adipocytes, and β-adrenergic receptor stimulation (e.g., cold exposure) increases the generation of cAMP and leads to protein kinase A (PKA) activation. PKA-dependent phosphorylation of p38α map kinase phosphorylates activating transcription factor 2 (ATF2) to induce Ppargc1a (encoding peroxisome proliferator-activated receptor gamma coactivator 1alpha; PGC1α) transcription. PGC1α co-activates transcription factors (e.g., PPARγ) assembled on the Ucp1 enhancer, thereby increasing Ucp1 gene expression [67,68]. Transgenic mice overexpressing SIRT1 display enhanced BAT function with increased thermogenesis and energy expenditure [69], whereas SIRT1-deficient mice exhibit decreased thermogenesis and energy expenditure when fed a high-fat diet (HFD) [70]. Thus, SIRT1 functions as a positive regulator of BAT activity. Beige adipocytes are an inducible form of UCP1+ thermogenic adipocytes that sporadically reside within subcutaneous WAT [66]. SIRT1 also promotes the induction of beige adipocytes in WAT (i.e., browning) by deacetylating PPARγ on K268 and K293 [71]. SIRT1-dependent PPARγ deacetylation enhances the browning of WAT by regulating ligand-dependent coactivator/corepressor exchange at the PPARγ transcriptional complex.
SIRT6 also positively regulates thermogenesis in brown adipocytes and promotes the induction of beige adipocytes [72]. SIRT6 increases the transcription of Ppargc1a by enhancing the binding of phosphorylated ATF2 to its promoter region. Adipocyte-specific SIRT6-deficient mice exhibited impaired thermogenesis and reduced whole-body energy expenditure [72]. SIRT6 also regulates lipid catabolism and thermogenesis in BAT by promoting the deacetylation of FOXO1 [73].
In contrast to SIRT1 and SIRT6, SIRT7 suppresses thermogenesis and energy expenditure by regulating the function of brown adipocytes [21]. Whole-body and BAT-specific Sirt7 KO mice showed higher body temperature and energy expenditure with increased UCP1 protein expression in BAT. Mechanistically, SIRT7 deacetylates insulin-like growth factor 2 mRNA-binding protein 2 (IMP2/IGF2BP2), an RNA-binding protein that inhibits the translation of Ucp1 mRNA [74], thereby enhancing its inhibitory action on Ucp1 (Figure 1C). SIRT7 deficiency also enhances the browning of inguinal WAT [21], although the detailed mechanisms are not known. These findings indicate that SIRT7 suppresses not only thermogenesis in BAT but also the induction of beige adipocytes.

2.4. Adipose Tissue Inflammation

Excess energy intake is associated with the accumulation of lipids in adipocytes and the expansion of adipose tissue. The accumulation of fat mass induces low-grade chronic inflammation by producing proinflammatory cytokines such as TNF-α, IL-6, and MCP-1 in adipose tissue, and obesity-induced inflammation induces insulin resistance in the liver and muscles [75,76]. Nuclear factor (NF)-κB is a central transcription factor that controls the expression of genes involved in inflammation, and SIRT1 represses the activity of NF-κB by deacetylating the p65 subunit of NF-κB [77]. Thus, SIRT1 exerts anti-inflammatory effects in adipose tissue by regulating proinflammatory transcription and also improves insulin sensitivity [78,79].
SIRT6 also has an anti-inflammatory role. SIRT6 is recruited to the promoters of NF-κB target genes through interactions with NF-κB and suppresses the expression of NF-κB target genes by deacetylating histone H3K9 at the target gene promoters [80]. Consistently, adipocyte-specific Sirt6 KO mice exhibit increased insulin resistance and inflammation in the adipose tissue [64,81].
In contrast, SIRT7 deficiency ameliorates inflammatory responses such as induction of Tnfa and Il6 both in vitro and in vivo [32,82,83,84]. SIRT7 interacts with a small GTPase, Ras-related nuclear antigen (Ran), and deacetylates Ran at K37. In the absence of SIRT7, acetylation of Ran facilitates the formation of the NF-κB export cargo complex, thereby enhancing the nuclear exclusion of NF-κB (Figure 1D) [32]. Indeed, the expression of genes involved in inflammation was decreased in the WAT of Sirt7 KO mice [85]. Further studies are needed to elucidate the roles of SIRT7 in adipose tissue inflammation, but findings to date suggest that SIRT7 might control inflammation in WAT.

2.5. Hepatic Lipid Metabolism

The liver also plays an important role in the regulation of lipid metabolism. After uptake by the liver, FFAs, which are released from adipocytes, are β-oxidized (β-oxidization) to acetyl-CoA in order to produce ATP. In the fed state, fatty acids are synthesized from acetyl-CoA in the liver (lipogenesis). PPARα is a key transcription factor for the regulation of genes involved in fatty acid uptake and β-oxidation, and PGC1α stimulates the transcriptional activity of PPARα [86]. SIRT1 increases PPARα target genes, including Mcadh (encoding medium-chain acyl-CoA dehydrogenase), Aox (encoding acyl CoA oxidase), and Ehhadh (encoding enoyl-CoA hydratase/3-hydroxyacyl CoA dehydrogenase), by deacetylating and activating PGC1α [87]. Hepatic deletion of SIRT1 in mice resulted in hepatic lipid accumulation under HFD feeding [87]. SREBP1c is a key transcription factor that regulates the expression of lipogenic genes, including Fasn, Acaca, and Scd1 in the liver. SIRT1 deacetylates and inhibits SREBP1c activity, and transgenic mice overexpressing SIRT1 are protected from HFD-induced hepatic steatosis [88,89]. Therefore, SIRT1 both promotes β-oxidation and inhibits fat synthesis in the liver.
SIRT6 also stimulates fatty acid β-oxidation and inhibits lipogenesis in the liver, and liver-specific SIRT6 KO mice exhibited hepatic lipid accumulation [90]. MicroRNA-122 (miR-122) is a key regulator of fatty acid metabolism, and the inhibition of hepatic miR-122 expression stimulates β-oxidation and reduces fatty acid synthesis [91]. SIRT6 decreases hepatic lipid accumulation by suppressing the expression of miR-122 through the deacetylation of H3K56 in the promoter region [92]. SIRT6 also inhibits hepatic lipogenesis by repressing Srebp1 and its target genes [93].
In contrast to SIRT1 and SIRT6, SIRT7 functions as a positive regulator of hepatic lipid accumulation, and Sirt7 KO mice are resistant to HFD-induced fatty liver [85]. The nuclear receptor TR4 stimulates lipid uptake, triacylglycerol synthesis, and storage in the liver by regulating the expression of Cd36, Cidea (encoding cell death inducing DNA fragmentation factor A (DFFA)-like effector a), Cidec (encoding cell death inducing DFFA like effector c), Mogat1 (encoding monoacylglycerol O-acyltransferase 1), and Pparg. SIRT7 increases TR4 protein expression by deacetylating DDB1 and inhibiting the degradation of TR4 via the CUL4B/DDB1/DCAF1 E3 ubiquitin ligase complex, leading to hepatic lipid accumulation (Figure 1E) [19,85]. However, contradictory results have also been reported [94]. GA-binding protein (GABP) is a nuclear transcription factor that controls mitochondrial biogenesis and function. Because SIRT7 increases GABP activity by deacetylating GABPβ1, aged Sirt7 KO mice are reported to exhibit hepatic microvesicular steatosis due to mitochondrial dysfunction (Figure 1F) [22]. However, the expression of several nuclear-encoded mitochondrial transcripts regulated by GABP was not altered in the liver of young Sirt7 KO mice [21]. Therefore, SIRT7 has different roles in hepatic lipid homeostasis depending on the conditions.

3. Nuclear Sirtuins in Glucose Metabolism

Glucose is a major fuel for most tissues. In the fed state, glucose is metabolized to pyruvate by glycolysis. In aerobic tissues, pyruvate is further metabolized to acetyl-CoA, which can enter the citric acid cycle for complete oxidation; this is linked to the formation of ATP in the process of oxidative phosphorylation. In the fasting state, glucose is produced from noncarbohydrate precursors, including amino acids, lactate, and glycerol, in the process of gluconeogenesis. Along with SIRT1 and SIRT6, SIRT7 is also involved in the regulation of these metabolic pathways.

3.1. Gluconeogenesis

The liver is the main site of gluconeogenic tissue. SIRT1 enhances gluconeogenesis by increasing transcription of the gluconeogenic genes G6pc (encoding glucose-6-phosphatase) and Pck1 (encoding phosphoenolpyruvate carboxykinase 1) in the liver through the deacetylation of PGC1α and FOXO1 [95,96,97]. However, SIRT1 also inhibits gluconeogenesis by promoting the ubiquitin-mediated degradation of CREB-regulated transcription coactivator 2 (CRTC2), a coactivator of gluconeogenesis [98]. Therefore, SIRT1 has a dual role in the control of gluconeogenesis.
SIRT6 suppresses gluconeogenesis by deacetylating general control non-repressed protein 5 (GCN5), which then increases PGC1α acetylation and suppresses its stimulation of gluconeogenesis [99]. SIRT6 also downregulates the transcription of G6pc and Pck1 through the deacetylation of FOXO1 [100]. However, it has also been reported that liver-specific SIRT6 transgenic mice and control mice showed similar blood glucose levels [101].
SIRT7 also plays a critical role in the regulation of gluconeogenesis [23,85]. Circadian protein cryptochrome 1 (CRY1) represses hepatic gluconeogenesis by promoting FOXO1 degradation [102,103]. SIRT7 destabilizes CRY1 protein expression through its deacetylation, thereby inhibiting the CRY1-mediated suppression of gluconeogenesis (Figure 2A) [23]. SIRT7 is also reported to increase the transcription of G6pc through the deacetylation of H3K18 in the G6pc promoter (Figure 2B) [104].

3.2. Glycolysis and Mitochondrial Function

Glycolysis is a major route for glucose metabolism, in which glucose is catabolized to pyruvate. When oxygen is in short supply, pyruvate is the end-product of glycolysis. Under aerobic conditions, pyruvate is further metabolized in the mitochondria. SIRT1 inhibits glycolysis by activating PGC1α, which suppresses glycolytic genes in the fasting state [95]. SIRT1 also suppresses glycolysis through the deacetylation of phosphoglycerate mutase 1 [105]. Hypoxia inducible factor 1 (HIF1) is a central transcription factor in the cellular response to oxygen and nutrient stress. HIF1 enhances glycolytic flux by upregulating the expression of glycolytic genes and inhibits mitochondrial oxidation of pyruvate via the stimulation of Pdk (encoding pyruvate dehydrogenase kinase) genes [106]. SIRT1 also inhibits glycolysis by suppressing the activity of HIF1 [107].
SIRT6 functions as a corepressor of HIF1 and suppresses the expression of multiple glycolytic genes [108]. Consequently, SIRT6 deficiency increases glucose uptake with upregulation of glycolytic enzymes, causing severe hypoglycemia in mice [108].
SIRT7 is also implicated in the regulation of glycolysis. SIRT7 overexpression decreases HIF1 protein expression levels, and the effect is independent of the enzymatic activity of SIRT7 (Figure 2C) [109]. In addition, SIRT7 is reported to reduce the activity of phosphoglycerate kinase 1 (PGK1) through its deacetylation in cancer cells (Figure 2D) [25]. Although the roles of SIRT7 in glycolysis are not directly explored in vivo, these observations suggest that SIRT7 contributes to the inhibition of glycolysis. Furthermore, SIRT7 modulates mitochondrial biogenesis and function. As described above, SIRT7 functions as a crucial regulator of mitochondria in hepatocytes by activating GABP through the deacetylation of GABPβ1 [22]. In high-glucose conditions, SIRT7 is methylated at arginine 388 (R388), which inhibits the H3K18-deacetylase activity of SIRT7 and stimulates mitochondrial biogenesis [110]. SIRT7 also suppresses mitochondrial biogenesis and respiration by interacting with nuclear respiratory factor 1 (NRF1) in hematopoietic stem cells [37].
Cells 13 00048 g002
Figure 2. Roles of SIRT7 in glucose metabolism. (A) SIRT7 stimulates gluconeogenesis through the destabilization of CRY1 [23]. (B) SIRT7 increases transcription of the gluconeogenic gene G6pc through the deacetylation of histone H3K18 [104]. (C) SIRT7 inhibits glycolysis by decreasing the HIF1 protein expression levels [109]. (D) SIRT7 also suppresses glycolysis through the deacetylation of PGK1 [25]. (E) SIRT7 deficiency increases energy expenditure by increasing the expression levels of the batokines Fgf21 and Nrg4 in BAT [21]. (F) SIRT7 suppresses AKT activation by deacetylating FKBP51 [26].
Figure 2. Roles of SIRT7 in glucose metabolism. (A) SIRT7 stimulates gluconeogenesis through the destabilization of CRY1 [23]. (B) SIRT7 increases transcription of the gluconeogenic gene G6pc through the deacetylation of histone H3K18 [104]. (C) SIRT7 inhibits glycolysis by decreasing the HIF1 protein expression levels [109]. (D) SIRT7 also suppresses glycolysis through the deacetylation of PGK1 [25]. (E) SIRT7 deficiency increases energy expenditure by increasing the expression levels of the batokines Fgf21 and Nrg4 in BAT [21]. (F) SIRT7 suppresses AKT activation by deacetylating FKBP51 [26].
Cells 13 00048 g002

3.3. Insulin Action and Glucose Tolerance

Insulin resistance, characterized by an attenuation of the metabolic actions of insulin in the liver, skeletal muscle, and adipose tissue, results from an imbalance between energy intake and expenditure. Obesity is the most common cause of insulin resistance, and endocrine, inflammatory, neural, and cell-intrinsic pathways have been shown to link obesity to insulin resistance [111,112,113,114]. SIRT1 activation by small molecule activators or SIRT1 overexpression improves insulin sensitivity and glucose homeostasis by enhancing fat oxidation in the liver, skeletal muscles, and BAT [69,115,116].
SIRT6 suppresses insulin signaling through the inhibition of key factors in these pathways, including insulin receptor, insulin receptor substrate (IRS)-1, IRS-2, and AKT kinase [117]. SIRT6 deficiency increases insulin-stimulated glucose uptake by activating insulin signaling, which may be involved in severe hypoglycemia in global Sirt6 KO mice [117]. Consistent with this, pharmacological inhibition of SIRT6 improves glucose tolerance and insulin sensitivity in mice [118]. In contrast, fat-specific and muscle-specific Sirt6 KO mice exhibit insulin resistance and glucose intolerance [72,81,119]. Transgenic mice overexpressing Sirt6 are reported to show improved glucose homeostasis [120,121]. Therefore, the regulation of blood glucose levels by SIRT6 is complicated.
Sirt7 KO mice are resistant to HFD-induced obesity, insulin resistance, and glucose intolerance, indicating that SIRT7 deficiency improves insulin sensitivity and glucose homeostasis in vivo [85]. In contrast, SIRT1 functions to improve insulin sensitivity and glucose homeostasis [69,115,116]. Therefore, SIRT7 and SIRT1 seem to affect insulin sensitivity and glucose tolerance in opposing directions. As stated above, SIRT7 deficiency increases energy expenditure with increased UCP1 expression in BAT [21]. The batokines FGF21 and NRG4 augment insulin sensitivity by increasing energy expenditure in the body [122,123]. Intriguingly, the expression levels of Fgf21 and Nrg4 are increased in the BAT of Sirt7 KO mice (Figure 2E) [21]. Furthermore, hepatic Fgf21 mRNA expression and the serum FGF21 levels of aged Sirt7 KO mice are higher than those of control mice [124]. These findings suggest that SIRT7 deficiency improves insulin sensitivity, at least in part, through the enhancement of BAT thermogenesis and overexpression of insulin-sensitizing batokines. Furthermore, SIRT7 suppresses AKT activation by deacetylating FK506-binding protein (FKBP51) in cancer cells under stressed conditions (Figure 2F) [26]. Thus, SIRT7 may directly affect the insulin signaling pathway.

4. Conclusions and Future Perspectives

A decade of research has established SIRT7 as an important regulator of glucose and lipid metabolism. As described in this review, SIRT7 regulates numerous metabolic pathways, including adipogenesis, lipogenesis, thermogenesis, and gluconeogenesis, through the deacetylation/deacylation of various target substrates. Intriguingly, the metabolic roles of SIRT7 are quite different from those of SIRT1 and SIRT6 (Figure 3). For example, SIRT1 stimulates lipolysis in WAT in order to stimulate fat oxidation of fatty acids. In contrast, SIRT7 promotes fat synthesis in WAT and the liver. SIRT1 and SIRT6 stimulate thermogenesis in BAT, whereas SIRT7 inhibits thermogenesis. When considering these observations together, it seems that SIRT7 and SIRT1 or SIRT6 regulate metabolism in opposing directions. SIRT1 and SIRT6 play important roles in insulin secretion and control energy balance in the body through modulation of the hypothalamic neurons [125,126,127,128]. It may be interesting to evaluate whether the roles of SIRT7 in pancreatic β-cells and hypothalamic neurons, including proopiomelanocortin (POMC) and agouti-related peptide (AgRP) neurons, are also opposite to those of SIRT1 and SIRT6. SIRT1, SIRT6, and SIRT7 are all located in the nucleus. Another interesting question is how these sirtuins coordinate their actions within cells. Further studies are needed to identify the molecular mechanisms underlying their integration. SIRT1 activation by small-molecule activators improves insulin sensitivity and glucose homeostasis by enhancing fat oxidation in the liver, skeletal muscles, and BAT [69,115,116]. In contrast, SIRT7 deficiency results in resistance to HFD-induced metabolic diseases, including obesity, fatty liver, and glucose intolerance [85]. Therefore, SIRT7 inhibition may be a potential strategy for treating metabolic diseases. There are reports on the development of SIRT7 inhibitors [129,130,131], but further studies are needed to develop more potent and specific SIRT7 inhibitors. In addition, we need to be cautious when considering inhibiting SIRT7 function, given its important role in bone formation and cardiac remodeling [30,43]. Further research will provide new knowledge about the metabolic functions of SIRT7 as well as the effectiveness of SIRT7-selective inhibitors for the treatment of obesity and type 2 diabetes.

Author Contributions

Conceptualization, K.Y.; writing, K.Y., T.M. and T.Y. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by Grant-in-Aid for Scientific Research (B) (22H03129).

Acknowledgments

We thank the members of Yamagata Laboratory for the discussion. The authors apologize to all the researchers whose work could not be included due to space limitations.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Giblin, W.; Skinner, M.E.; Lombard, D.B. Sirtuins: Guardians of Mammalian Healthspan. Trends Genet. 2014, 30, 271–286. [Google Scholar] [CrossRef]
  2. Houtkooper, R.H.; Pirinen, E.; Auwerx, J. Sirtuins as Regulators of Metabolism and Healthspan. Nat. Rev. Mol. Cell Biol. 2012, 13, 225–238. [Google Scholar] [CrossRef]
  3. Sebastiań, C.; Satterstrom, F.K.; Haigis, M.C.; Mostoslavsky, R. From Sirtuin Biology to Human Diseases: An Update. J. Biol. Chem. 2012, 287, 42444–42452. [Google Scholar] [CrossRef]
  4. Finkel, T.; Deng, C.X.; Mostoslavsky, R. Recent Progress in the Biology and Physiology of Sirtuins. Nature 2009, 460, 587–591. [Google Scholar] [CrossRef]
  5. Haigis, M.C.; Mostoslavsky, R.; Haigis, K.M.; Fahie, K.; Christodoulou, D.C.; Murphy, A.J.J.; Valenzuela, D.M.; Yancopoulos, G.D.; Karow, M.; Blander, G.; et al. SIRT4 Inhibits Glutamate Dehydrogenase and Opposes the Effects of Calorie Restriction in Pancreatic β Cells. Cell 2006, 126, 941–954. [Google Scholar] [CrossRef]
  6. Du, J.; Zhou, Y.; Su, X.; Yu, J.J.; Khan, S.; Jiang, H.; Kim, J.; Woo, J.; Kim, J.H.; Choi, B.H.; et al. Sirt5 Is a NAD-Dependent Protein Lysine Demalonylase and Desuccinylase. Science 2011, 334, 806–809. [Google Scholar] [CrossRef]
  7. Jiang, H.; Khan, S.; Wang, Y.; Charron, G.; He, B.; Sebastian, C.; Du, J.; Kim, R.; Ge, E.; Mostoslavsky, R.; et al. SIRT6 Regulates TNF-α Secretion through Hydrolysis of Long-Chain Fatty Acyl Lysine. Nature 2013, 496, 110–113. [Google Scholar] [CrossRef]
  8. Feldman, J.L.; Baeza, J.; Denu, J.M. Activation of the Protein Deacetylase SIRT6 by Long-Chain Fatty Acids and Widespread Deacylation by Mammalian Sirtuins. J. Biol. Chem. 2013, 288, 31350–31356. [Google Scholar] [CrossRef]
  9. Ford, E.; Voit, R.; Liszt, G.; Magin, C.; Grummt, I.; Guarente, L. Mammalian Sir2 Homolog SIRT7 Is an Activator of RNA Polymerase I Transcription. Genes. Dev. 2006, 20, 1075–1080. [Google Scholar] [CrossRef]
  10. Barber, M.F.; Michishita-Kioi, E.; Xi, Y.; Tasselli, L.; Kioi, M.; Moqtaderi, Z.; Tennen, R.I.; Paredes, S.; Young, N.L.; Chen, K.; et al. SIRT7 Links H3K18 Deacetylation to Maintenance of Oncogenic Transformation. Nature 2012, 487, 114–118. [Google Scholar] [CrossRef]
  11. Vazquez, B.N.; Thackray, J.K.; Simonet, N.G.; Kane-Goldsmith, N.; Martinez-Redondo, P.; Nguyen, T.; Bunting, S.; Vaquero, A.; Tischfield, J.A.; Serrano, L. SIRT 7 Promotes Genome Integrity and Modulates Non-homologous End Joining DNA Repair. EMBO J. 2016, 35, 1488–1503. [Google Scholar] [CrossRef]
  12. Wang, W.W.; Angulo-Ibanez, M.; Lyu, J.; Kurra, Y.; Tong, Z.; Wu, B.; Zhang, L.; Sharma, V.; Zhou, J.; Lin, H.; et al. A Click Chemistry Approach Reveals the Chromatin-Dependent Histone H3K36 Deacylase Nature of SIRT7. J. Am. Chem. Soc. 2019, 141, 2462–2473. [Google Scholar] [CrossRef] [PubMed]
  13. Chen, S.; Seiler, J.; Santiago-Reichelt, M.; Felbel, K.; Grummt, I.; Voit, R. Repression of RNA Polymerase I upon Stress Is Caused by Inhibition of RNA-Dependent Deacetylation of PAF53 by SIRT7. Mol. Cell 2013, 52, 303–313. [Google Scholar] [CrossRef] [PubMed]
  14. Chen, S.; Blank, M.F.; Iyer, A.; Huang, B.; Wang, L.; Grummt, I.; Voit, R. SIRT7-Dependent Deacetylation of the U3-55k Protein Controls Pre-RRNA Processing. Nat. Commun. 2016, 7, 10734. [Google Scholar] [CrossRef] [PubMed]
  15. Iyer-Bierhoff, A.; Krogh, N.; Tessarz, P.; Ruppert, T.; Nielsen, H.; Grummt, I. SIRT7-Dependent Deacetylation of Fibrillarin Controls Histone H2A Methylation and RRNA Synthesis during the Cell Cycle. Cell Rep. 2018, 25, 2946–2954.e5. [Google Scholar] [CrossRef] [PubMed]
  16. Blank, M.F.; Chen, S.; Poetz, F.; Schnölzer, M.; Voit, R.; Grummt, I. SIRT7-Dependent Deacetylation of CDK9 Activates RNA Polymerase II Transcription. Nucleic Acids Res. 2017, 45, 2675–2686. [Google Scholar] [CrossRef] [PubMed]
  17. Song, C.; Hotz-Wagenblatt, A.; Voit, R.; Grummt, I. SIRT7 and the DEAD-Box Helicase DDX21 Cooperate to Resolve Genomic R Loops and Safeguard Genome Stability. Genes. Dev. 2017, 31, 1370–1381. [Google Scholar] [CrossRef]
  18. Tang, M.; Li, Z.; Zhang, C.; Lu, X.; Tu, B.; Cao, Z.; Li, Y.; Chen, Y.; Jiang, L.; Wang, H.; et al. SIRT7-Mediated ATM Deacetylation Is Essential for Its Deactivation and DNA Damage Repair. Sci. Adv. 2019, 5, eaav1118. [Google Scholar] [CrossRef]
  19. Karim, M.F.; Yoshizawa, T.; Sobuz, S.U.; Sato, Y.; Yamagata, K. Sirtuin 7-Dependent Deacetylation of DDB1 Regulates the Expression of Nuclear Receptor TR4. Biochem. Biophys. Res. Commun. 2017, 490, 423–428. [Google Scholar] [CrossRef]
  20. Akter, F.; Tsuyama, T.; Yoshizawa, T.; Sobuz, S.U.; Yamagata, K. SIRT7 Regulates Lipogenesis in Adipocytes through Deacetylation of PPARγ2. J. Diabetes Investig. 2021, 12, 1765–1774. [Google Scholar] [CrossRef]
  21. Yoshizawa, T.; Sato, Y.; Sobuz, S.U.; Mizumoto, T.; Tsuyama, T.; Karim, M.F.; Miyata, K.; Tasaki, M.; Yamazaki, M.; Kariba, Y.; et al. SIRT7 Suppresses Energy Expenditure and Thermogenesis by Regulating Brown Adipose Tissue Functions in Mice. Nat. Commun. 2022, 13, 7439. [Google Scholar] [CrossRef] [PubMed]
  22. Ryu, D.; Jo, Y.S.; Lo Sasso, G.; Stein, S.; Zhang, H.; Perino, A.; Lee, J.U.; Zeviani, M.; Romand, R.; Hottiger, M.O.; et al. A SIRT7-Dependent Acetylation Switch of GABPβ1 Controls Mitochondrial Function. Cell Metab. 2014, 20, 856–869. [Google Scholar] [CrossRef] [PubMed]
  23. Liu, Z.; Qian, M.; Tang, X.; Hu, W.; Sun, S.; Li, G.; Zhang, S.; Meng, F.; Cao, X.; Sun, J.; et al. SIRT7 Couples Light-Driven Body Temperature Cues to Hepatic Circadian Phase Coherence and Gluconeogenesis. Nat. Metab. 2019, 1, 1141–1156. [Google Scholar] [CrossRef] [PubMed]
  24. Qi, H.; Shi, X.; Yu, M.; Liu, B.; Liu, M.; Song, S.; Chen, S.; Zou, J.; Zhu, W.G.; Luo, J. Sirtuin 7–Mediated Deacetylation of WD Repeat Domain 77 (WDR77) Suppresses Cancer Cell Growth by Reducing WDR77/ PRMT5 Transmethylase Complex Activity. J. Biol. Chem. 2018, 293, 17769–17779. [Google Scholar] [CrossRef] [PubMed]
  25. Hu, H.; Zhu, W.; Qin, J.; Chen, M.; Gong, L.; Li, L.; Liu, X.; Tao, Y.; Yin, H.; Zhou, H.; et al. Acetylation of PGK1 Promotes Liver Cancer Cell Proliferation and Tumorigenesis. Hepatology 2017, 65, 515–528. [Google Scholar] [CrossRef]
  26. Yu, J.; Qin, B.; Wu, F.; Qin, S.; Nowsheen, S.; Shan, S.; Zayas, J.; Pei, H.; Lou, Z.; Wang, L. Regulation of Serine-Threonine Kinase Akt Activation by NAD+-Dependent Deacetylase SIRT7. Cell Rep. 2017, 18, 1229–1240. [Google Scholar] [CrossRef] [PubMed]
  27. Tang, X.; Shi, L.; Xie, N.; Liu, Z.; Qian, M.; Meng, F.; Xu, Q.; Zhou, M.; Cao, X.; Zhu, W.G.; et al. SIRT7 Antagonizes TGF-β Signaling and Inhibits Breast Cancer Metastasis. Nat. Commun. 2017, 8, 318. [Google Scholar] [CrossRef]
  28. Dong, L.; Yu, L.; Li, H.; Shi, L.; Luo, Z.; Zhao, H.; Liu, Z.; Yin, G.; Yan, X.; Lin, Z. An NAD+-Dependent Deacetylase SIRT7 Promotes HCC Development Through Deacetylation of USP39. iScience 2020, 23, 101351. [Google Scholar] [CrossRef]
  29. Liu, X.; Li, C.; Li, Q.; Chang, H.C.; Tang, Y.C. SIRT7 Facilitates CENP-A Nucleosome Assembly and Suppresses Intestinal Tumorigenesis. iScience 2020, 23, 101461. [Google Scholar] [CrossRef]
  30. Yamamura, S.; Izumiya, Y.; Araki, S.; Nakamura, T.; Kimura, Y.; Hanatani, S.; Yamada, T.; Ishida, T.; Yamamoto, M.; Onoue, Y.; et al. Cardiomyocyte Sirt (Sirtuin) 7 Ameliorates Stress-Induced Cardiac Hypertrophy by Interacting With and Deacetylating GATA4. Hypertension 2020, 75, 98–108. [Google Scholar] [CrossRef]
  31. Noriega, L.G.; Melo, Z.; Rajaram, R.D.; Mercado, A.; Tovar, A.R.; Velazquez-Villegas, L.A.; Castañeda-Bueno, M.; Reyes-López, Y.; Ryu, D.; Rojas-Vega, L.; et al. SIRT7 Modulates the Stability and Activity of the Renal K-Cl Cotransporter KCC4 through Deacetylation. EMBO Rep. 2021, 22, e50766. [Google Scholar] [CrossRef] [PubMed]
  32. Sobuz, S.U.; Sato, Y.; Yoshizawa, T.; Karim, F.; Ono, K.; Sawa, T.; Miyamoto, Y.; Oka, M.; Yamagata, K. SIRT7 Regulates the Nuclear Export of NF-κB P65 by Deacetylating Ran. Biochim. Biophys. Acta Mol. Cell Res. 2019, 1866, 1355–1367. [Google Scholar] [CrossRef] [PubMed]
  33. Lee, N.; Kim, D.K.; Kim, E.S.; Park, S.J.; Kwon, J.H.; Shin, J.; Park, S.M.; Moon, Y.H.; Wang, H.J.; Gho, Y.S.; et al. Comparative Interactomes of SIRT6 and SIRT7: Implication of Functional Links to Aging. Proteomics 2014, 14, 1610–1622. [Google Scholar] [CrossRef] [PubMed]
  34. Li, Z.; Bridges, B.; Olson, J.; Weinman, S.A. The Interaction between Acetylation and Serine-574 Phosphorylation Regulates the Apoptotic Function of FOXO3. Oncogene 2017, 36, 1887–1898. [Google Scholar] [CrossRef] [PubMed]
  35. Vakhrusheva, O.; Smolka, C.; Gajawada, P.; Kostin, S.; Boettger, T.; Kubin, T.; Braun, T.; Bober, E. Sirt7 Increases Stress Resistance of Cardiomyocytes and Prevents Apoptosis and Inflammatory Cardiomyopathy in Mice. Circ. Res. 2008, 102, 703–710. [Google Scholar] [CrossRef] [PubMed]
  36. Yu, M.; Shi, X.; Ren, M.; Liu, L.; Qi, H.; Zhang, C.; Zou, J.; Qiu, X.; Zhu, W.G.; Zhang, Y.E.; et al. SIRT7 Deacetylates Strap to Regulate P53 Activity and Stability. Int. J. Mol. Sci. 2020, 21, 4122. [Google Scholar] [CrossRef] [PubMed]
  37. Mohrin, M.; Shin, J.; Liu, Y.; Brown, K.; Luo, H.; Xi, Y.; Haynes, C.M.; Chen, D. Stem cell aging. A mitochondrial UPR-mediated metabolic checkpoint regulates hematopoietic stem cell aging. Science 2015, 347, 1374–1377. [Google Scholar] [CrossRef] [PubMed]
  38. Li, G.; Tang, X.; Zhang, S.; Jin, M.; Wang, M.; Deng, Z.; Liu, Z.; Qian, M.; Shi, W.; Wang, Z.; et al. SIRT 7 Activates Quiescent Hair Follicle Stem Cells to Ensure Hair Growth in Mice. EMBO J. 2020, 39, e104365. [Google Scholar] [CrossRef]
  39. Li, L.; Shi, L.; Yang, S.; Yan, R.; Zhang, D.; Yang, J.; He, L.; Li, W.; Yi, X.; Sun, L.; et al. SIRT7 Is a Histone Desuccinylase That Functionally Links to Chromatin Compaction and Genome Stability. Nat. Commun. 2016, 7, 12235. [Google Scholar] [CrossRef]
  40. Yuan, H.F.; Zhao, M.; Zhao, L.N.; Yun, H.L.; Yang, G.; Geng, Y.; Wang, Y.F.; Zheng, W.; Yuan, Y.; Song, T.Q.; et al. PRMT5 Confers Lipid Metabolism Reprogramming, Tumour Growth and Metastasis Depending on the SIRT7-Mediated Desuccinylation of PRMT5 K387 in Tumours. Acta Pharmacol. Sin. 2022, 43, 2373–2385. [Google Scholar] [CrossRef]
  41. Bao, X.; Liu, Z.; Zhang, W.; Gladysz, K.; Fung, Y.M.E.; Tian, G.; Xiong, Y.; Wong, J.W.H.; Yuen, K.W.Y.; Li, X.D. Glutarylation of Histone H4 Lysine 91 Regulates Chromatin Dynamics. Mol. Cell 2019, 76, 660–675. [Google Scholar] [CrossRef] [PubMed]
  42. Yu, A.Q.; Wang, J.; Jiang, S.T.; Yuan, L.Q.; Ma, H.Y.; Hu, Y.M.; Han, X.M.; Tan, L.M.; Wang, Z.X. SIRT7-Induced PHF5A Decrotonylation Regulates Aging Progress Through Alternative Splicing-Mediated Downregulation of CDK2. Front. Cell Dev. Biol. 2021, 9, 710479. [Google Scholar] [CrossRef] [PubMed]
  43. Fukuda, M.; Yoshizawa, T.; Karim, M.F.; Sobuz, S.U.; Korogi, W.; Kobayasi, D.; Okanishi, H.; Tasaki, M.; Ono, K.; Sawa, T.; et al. SIRT7 Has a Critical Role in Bone Formation by Regulating Lysine Acylation of SP7/Osterix. Nat. Commun. 2018, 9, 2833. [Google Scholar] [CrossRef] [PubMed]
  44. Simonet, N.G.; Thackray, J.K.; Vazquez, B.N.; Ianni, A.; Espinosa-Alcantud, M.; Morales-Sanfrutos, J.; Hurtado-Bagès, S.; Sabidó, E.; Buschbeck, M.; Tischfield, J.; et al. SirT7 Auto-ADP-Ribosylation Regulates Glucose Starvation Response through MH2A1. Sci. Adv. 2020, 6, eaaz2590. [Google Scholar] [CrossRef] [PubMed]
  45. Chang, A.R.; Ferrer, C.M.; Mostoslavsky, R. SIRT6, a Mammalian Deacylase with Multitasking Abilities. Physiol. Rev. 2020, 100, 145–169. [Google Scholar] [CrossRef] [PubMed]
  46. Guo, Z.; Li, P.; Ge, J.; Li, H. SIRT6 in Aging, Metabolism, Inflammation and Cardiovascular Diseases. Aging Dis. 2022, 13, 1787–1822. [Google Scholar] [CrossRef] [PubMed]
  47. Yamagata, K.; Yoshizawa, T. Transcriptional Regulation of Metabolism by SIRT1 and SIRT7. Int. Rev. Cell Mol. Biol. 2018, 335, 143–166. [Google Scholar] [CrossRef] [PubMed]
  48. Tang, M.; Tang, H.; Tu, B.; Zhu, W.G. SIRT7: A Sentinel of Genome Stability. Open Biol. 2021, 11, 210047. [Google Scholar] [CrossRef]
  49. Lagunas-Rangel, F.A. SIRT7 in the Aging Process. Cell Mol. Life Sci. 2022, 79, 297. [Google Scholar] [CrossRef]
  50. Wu, S.; Jia, S. Functional Diversity of SIRT7 Across Cellular Compartments: Insights and Perspectives. Cell Biochem. Biophys. 2023, 81, 409–419. [Google Scholar] [CrossRef]
  51. Raza, U.; Tang, X.; Liu, Z.; Liu, B. SIRT7: The Seventh Key to Unlocking the Mystery of Aging. Physiol. Rev. 2024, 104, 253–280. [Google Scholar] [CrossRef] [PubMed]
  52. Lefterova, M.I.; Lazar, M.A. New Developments in Adipogenesis. Trends Endocrinol. Metab. 2009, 20, 107–114. [Google Scholar] [CrossRef] [PubMed]
  53. Ali, A.T.; Hochfeld, W.E.; Myburgh, R.; Pepper, M.S. Adipocyte and Adipogenesis. Eur. J. Cell Biol. 2013, 92, 229–236. [Google Scholar] [CrossRef] [PubMed]
  54. Ahmadian, M.; Suh, J.M.; Hah, N.; Liddle, C.; Atkins, A.R.; Downes, M.; Evans, R.M. Pparγ Signaling and Metabolism: The Good, the Bad and the Future. Nat. Med. 2013, 19, 557–566. [Google Scholar] [CrossRef] [PubMed]
  55. Picard, F.; Kurtev, M.; Chung, N.; Topark-Ngarm, A.; Senawong, T.; De Oliveira, R.M.; Leid, M.; McBurney, M.W.; Guarente, L. Sirt1 Promotes Fat Mobilization in White Adipocytes by Repressing PPAR-Gamma. Nature 2004, 429, 771–776. [Google Scholar] [CrossRef]
  56. Chen, Q.; Hao, W.; Xiao, C.; Wang, R.; Xu, X.; Lu, H.; Chen, W.; Deng, C.X. SIRT6 Is Essential for Adipocyte Differentiation by Regulating Mitotic Clonal Expansion. Cell Rep. 2017, 18, 3155–3166. [Google Scholar] [CrossRef]
  57. Hong, J.; Mei, C.; Abbas Raza, S.H.; Khan, R.; Cheng, G.; Zan, L. SIRT6 Cooperates with SIRT5 to Regulate Bovine Preadipocyte Differentiation and Lipid Metabolism via the AMPKα Signaling Pathway. Arch. Biochem. Biophys. 2020, 681, 108260. [Google Scholar] [CrossRef]
  58. Cioffi, M.; Vallespinos-Serrano, M.; Trabulo, S.M.; Fernandez-Marcos, P.J.; Firment, A.N.; Vazquez, B.N.; Vieira, C.R.; Mulero, F.; Camara, J.A.; Cronin, U.P.; et al. MiR-93 Controls Adiposity via Inhibition of Sirt7 and Tbx3. Cell Rep. 2015, 12, 1594–1605. [Google Scholar] [CrossRef]
  59. Fang, J.; Ianni, A.; Smolka, C.; Vakhrusheva, O.; Nolte, H.; Krüger, M.; Wietelmann, A.; Simonet, N.G.; Adrian-Segarra, J.M.; Vaquero, A.; et al. Sirt7 Promotes Adipogenesis in the Mouse by Inhibiting Autocatalytic Activation of Sirt1. Proc. Natl. Acad. Sci. USA 2017, 114, E8352–E8361. [Google Scholar] [CrossRef]
  60. Rangwala, S.M.; Lazar, M.A. Peroxisome Proliferator-Activated Receptor γ in Diabetes and Metabolism. Trends Pharmacol. Sci. 2004, 25, 331–336. [Google Scholar] [CrossRef]
  61. Zimmermann, R.; Strauss, J.G.; Haemmerle, G.; Schoiswohl, G.; Birner-Gruenberger, R.; Riederer, M.; Lass, A.; Neuberger, G.; Eisenhaber, F.; Hermetter, A.; et al. Fat Mobilization in Adipose Tissue Is Promoted by Adipose Triglyceride Lipase. Science 2004, 306, 1383–1386. [Google Scholar] [CrossRef] [PubMed]
  62. Haemmerle, G.; Lass, A.; Zimmermann, R.; Gorkiewicz, G.; Meyer, C.; Rozman, J.; Heldmaier, G.; Maier, R.; Theussl, C.; Eder, S.; et al. Defective Lipolysis and Altered Energy Metabolism in Mice Lacking Adipose Triglyceride Lipase. Science 2006, 312, 734–737. [Google Scholar] [CrossRef] [PubMed]
  63. Chakrabarti, P.; Kandror, K.V. FoxO1 Controls Insulin-Dependent Adipose Triglyceride Lipase (ATGL) Expression and Lipolysis in Adipocytes. J. Biol. Chem. 2009, 284, 13296–13300. [Google Scholar] [CrossRef] [PubMed]
  64. Kuang, J.; Zhang, Y.; Liu, Q.; Shen, J.; Pu, S.; Cheng, S.; Chen, L.; Li, H.; Wu, T.; Li, R.; et al. Fat-Specific Sirt6 Ablation Sensitizes Mice to High-Fat Diet-Induced Obesity and Insulin Resistance by Inhibiting Lipolysis. Diabetes 2017, 66, 1159–1171. [Google Scholar] [CrossRef] [PubMed]
  65. Rosen, E.D.; Spiegelman, B.M. What We Talk about When We Talk about Fat. Cell 2014, 156, 20–44. [Google Scholar] [CrossRef] [PubMed]
  66. Ikeda, K.; Maretich, P.; Kajimura, S. The Common and Distinct Features of Brown and Beige Adipocytes. Trends Endocrinol. Metab. 2018, 29, 191–200. [Google Scholar] [CrossRef] [PubMed]
  67. Lowell, B.B.; Spiegelman, B.M. Towards a Molecular Understanding of Adaptive Thermogenesis. Nature 2000, 404, 652–660. [Google Scholar] [CrossRef] [PubMed]
  68. Richard, D.; Carpentier, A.C.; Doré, G.; Ouellet, V.; Picard, F. Determinants of Brown Adipocyte Development and Thermogenesis. Int. J. Obes. 2010, 34 (Suppl. S2), S59–S66. [Google Scholar] [CrossRef]
  69. Boutant, M.; Joffraud, M.; Kulkarni, S.S.; García-Casarrubios, E.; García-Roves, P.M.; Ratajczak, J.; Fernández-Marcos, P.J.; Valverde, A.M.; Serrano, M.; Cantó, C. SIRT1 Enhances Glucose Tolerance by Potentiating Brown Adipose Tissue Function. Mol. Metab. 2015, 4, 118–131. [Google Scholar] [CrossRef]
  70. Xu, F.; Zheng, X.; Lin, B.; Liang, H.; Cai, M.; Cao, H.; Ye, J.; Weng, J. Diet-Induced Obesity and Insulin Resistance Are Associated with Brown Fat Degeneration in SIRT1-Deficient Mice. Obesity 2016, 24, 634–642. [Google Scholar] [CrossRef]
  71. Qiang, L.; Wang, L.; Kon, N.; Zhao, W.; Lee, S.; Zhang, Y.; Rosenbaum, M.; Zhao, Y.; Gu, W.; Farmer, S.R.; et al. Brown Remodeling of White Adipose Tissue by SirT1-Dependent Deacetylation of Pparγ. Cell 2012, 150, 620–632. [Google Scholar] [CrossRef]
  72. Yao, L.; Cui, X.; Chen, Q.; Yang, X.; Fang, F.; Zhang, J.; Liu, G.; Jin, W.; Chang, Y. Cold-Inducible SIRT6 Regulates Thermogenesis of Brown and Beige Fat. Cell Rep. 2017, 20, 641–654. [Google Scholar] [CrossRef]
  73. Jung, S.M.; Hung, C.M.; Hildebrand, S.R.; Sanchez-Gurmaches, J.; Martinez-Pastor, B.; Gengatharan, J.M.; Wallace, M.; Mukhopadhyay, D.; Martinez Calejman, C.; Luciano, A.K.; et al. Non-Canonical MTORC2 Signaling Regulates Brown Adipocyte Lipid Catabolism through SIRT6-FoxO1. Mol. Cell 2019, 75, 807–822. [Google Scholar] [CrossRef]
  74. Dai, N.; Zhao, L.; Wrighting, D.; Krämer, D.; Majithia, A.; Wang, Y.; Cracan, V.; Borges-Rivera, D.; Mootha, V.K.; Nahrendorf, M.; et al. IGF2BP2/IMP2-Deficient Mice Resist Obesity through Enhanced Translation of Ucp1 MRNA and Other MRNAs Encoding Mitochondrial Proteins. Cell Metab. 2015, 21, 609–621. [Google Scholar] [CrossRef]
  75. Shoelson, S.E.; Herrero, L.; Naaz, A. Obesity, Inflammation, and Insulin Resistance. Gastroenterology 2007, 132, 2169–2180. [Google Scholar] [CrossRef]
  76. Lumeng, C.N.; Saltiel, A.R. Inflammatory Links between Obesity and Metabolic Disease. J. Clin. Investig. 2011, 121, 2111–2117. [Google Scholar] [CrossRef]
  77. Yeung, F.; Hoberg, J.E.; Ramsey, C.S.; Keller, M.D.; Jones, D.R.; Frye, R.A.; Mayo, M.W. Modulation of NF-κB-Dependent Transcription and Cell Survival by the SIRT1 Deacetylase. EMBO J. 2004, 23, 2369–2380. [Google Scholar] [CrossRef]
  78. Yoshizaki, T.; Milne, J.C.; Imamura, T.; Schenk, S.; Sonoda, N.; Babendure, J.L.; Lu, J.-C.; Smith, J.J.; Jirousek, M.R.; Olefsky, J.M. SIRT1 Exerts Anti-Inflammatory Effects and Improves Insulin Sensitivity in Adipocytes. Mol. Cell Biol. 2009, 29, 1363–1374. [Google Scholar] [CrossRef]
  79. Gillum, M.P.; Kotas, M.E.; Erion, D.M.; Kursawe, R.; Chatterjee, P.; Nead, K.T.; Muise, E.S.; Hsiao, J.J.; Frederick, D.W.; Yonemitsu, S.; et al. SirT1 Regulates Adipose Tissue Inflammation. Diabetes 2011, 60, 3235–3245. [Google Scholar] [CrossRef]
  80. Kawahara, T.L.A.; Michishita, E.; Adler, A.S.; Damian, M.; Berber, E.; Lin, M.; McCord, R.A.; Ongaigui, K.C.L.; Boxer, L.D.; Chang, H.Y.; et al. SIRT6 Links Histone H3 Lysine 9 Deacetylation to NF-κB-Dependent Gene Expression and Organismal Life Span. Cell 2009, 136, 62–74. [Google Scholar] [CrossRef]
  81. Xiong, X.; Zhang, C.; Zhang, Y.; Fan, R.; Qian, X.; Dong, X.C. Fabp4-Cre-Mediated Sirt6 Deletion Impairs Adipose Tissue Function and Metabolic Homeostasis in Mice. J. Endocrinol. 2017, 233, 307–314. [Google Scholar] [CrossRef] [PubMed]
  82. Miyasato, Y.; Yoshizawa, T.; Sato, Y.; Nakagawa, T.; Miyasato, Y.; Kakizoe, Y.; Kuwabara, T.; Adachi, M.; Ianni, A.; Braun, T.; et al. Sirtuin 7 Deficiency Ameliorates Cisplatin-Induced Acute Kidney Injury Through Regulation of the Inflammatory Response. Sci. Rep. 2018, 8, 5927. [Google Scholar] [CrossRef] [PubMed]
  83. Araki, S.; Izumiya, Y.; Rokutanda, T.; Ianni, A.; Hanatani, S.; Kimura, Y.; Onoue, Y.; Senokuchi, T.; Yoshizawa, T.; Yasuda, O.; et al. Sirt7 Contributes to Myocardial Tissue Repair by Maintaining Transforming Growth Factor-β Signaling Pathway. Circulation 2015, 132, 1081–1093. [Google Scholar] [CrossRef] [PubMed]
  84. Wyman, A.E.; Nguyen, T.T.T.; Karki, P.; Tulapurkar, M.E.; Zhang, C.O.; Kim, J.; Feng, T.G.; Dabo, A.J.; Todd, N.W.; Luzina, I.G.; et al. SIRT7 Deficiency Suppresses Inflammation, Induces EndoMT, and Increases Vascular Permeability in Primary Pulmonary Endothelial Cells. Sci. Rep. 2020, 10, 12497. [Google Scholar] [CrossRef] [PubMed]
  85. Yoshizawa, T.; Karim, M.F.; Sato, Y.; Senokuchi, T.; Miyata, K.; Fukuda, T.; Go, C.; Tasaki, M.; Uchimura, K.; Kadomatsu, T.; et al. SIRT7 Controls Hepatic Lipid Metabolism by Regulating the Ubiquitin-Proteasome Pathway. Cell Metab. 2014, 19, 712–721. [Google Scholar] [CrossRef] [PubMed]
  86. Vega, R.B.; Huss, J.M.; Kelly, D.P. The Coactivator PGC-1 Cooperates with Peroxisome Proliferator-Activated Receptor α in Transcriptional Control of Nuclear Genes Encoding Mitochondrial Fatty Acid Oxidation Enzymes. Mol. Cell Biol. 2000, 20, 1868–1876. [Google Scholar] [CrossRef] [PubMed]
  87. Purushotham, A.; Schug, T.T.; Xu, Q.; Surapureddi, S.; Guo, X.; Li, X. Hepatocyte-Specific Deletion of SIRT1 Alters Fatty Acid Metabolism and Results in Hepatic Steatosis and Inflammation. Cell Metab. 2009, 9, 327–338. [Google Scholar] [CrossRef]
  88. Pfluger, P.T.; Herranz, D.; Velasco-Miguel, S.; Serrano, M.; Tschöp, M.H. Sirt1 Protects against High-Fat Diet-Induced Metabolic Damage. Proc. Natl. Acad. Sci. USA 2008, 105, 9793–9798. [Google Scholar] [CrossRef]
  89. Ponugoti, B.; Kim, D.H.; Xiao, Z.; Smith, Z.; Miao, J.; Zang, M.; Wu, S.Y.; Chiang, C.M.; Veenstra, T.D.; Kemper, J.K. SIRT1 Deacetylates and Inhibits SREBP-1C Activity in Regulation of Hepatic Lipid Metabolism. J. Biol. Chem. 2010, 285, 33959–33970. [Google Scholar] [CrossRef]
  90. Kim, H.S.; Xiao, C.; Wang, R.H.; Lahusen, T.; Xu, X.; Vassilopoulos, A.; Vazquez-Ortiz, G.; Jeong, W.I.; Park, O.; Ki, S.H.; et al. Hepatic-Specific Disruption of SIRT6 in Mice Results in Fatty Liver Formation Due to Enhanced Glycolysis and Triglyceride Synthesis. Cell Metab. 2010, 12, 224–236. [Google Scholar] [CrossRef]
  91. Esau, C.; Davis, S.; Murray, S.F.; Yu, X.X.; Pandey, S.K.; Pear, M.; Watts, L.; Booten, S.L.; Graham, M.; McKay, R.; et al. MiR-122 Regulation of Lipid Metabolism Revealed by in Vivo Antisense Targeting. Cell Metab. 2006, 3, 87–98. [Google Scholar] [CrossRef] [PubMed]
  92. Elhanati, S.; Ben-Hamo, R.; Kanfi, Y.; Varvak, A.; Glazz, R.; Lerrer, B.; Efroni, S.; Cohen, H.Y. Reciprocal Regulation between SIRT6 and MiR-122 Controls Liver Metabolism and Predicts Hepatocarcinoma Prognosis. Cell Rep. 2016, 14, 234–242. [Google Scholar] [CrossRef] [PubMed]
  93. Elhanati, S.; Kanfi, Y.; Varvak, A.; Roichman, A.; Carmel-Gross, I.; Barth, S.; Gibor, G.; Cohen, H.Y. Multiple Regulatory Layers of SREBP1/2 by SIRT6. Cell Rep. 2013, 4, 905–912. [Google Scholar] [CrossRef] [PubMed]
  94. Shin, J.; He, M.; Liu, Y.; Paredes, S.; Villanova, L.; Brown, K.; Qiu, X.; Nabavi, N.; Mohrin, M.; Wojnoonski, K.; et al. SIRT7 Represses Myc Activity to Suppress Er Stress and Prevent Fatty Liver Disease. Cell Rep. 2013, 5, 654–665. [Google Scholar] [CrossRef] [PubMed]
  95. Rodgers, J.T.; Lerin, C.; Haas, W.; Gygi, S.P.; Spiegelman, B.M.; Puigserver, P. Nutrient Control of Glucose Homeostasis through a Complex of PGC-1alpha and SIRT1. Nature 2005, 434, 113–118. [Google Scholar] [CrossRef] [PubMed]
  96. Frescas, D.; Valenti, L.; Accili, D. Nuclear Trapping of the Forkhead Transcription Factor FoxO1 via Sirt-Dependent Deacetylation Promotes Expression of Glucogenetic Genes. J. Biol. Chem. 2005, 280, 20589–20595. [Google Scholar] [CrossRef]
  97. Rodgers, J.T.; Lerin, C.; Gerhart-Hines, Z.; Puigserver, P. Metabolic Adaptations through the PGC-1α and SIRT1 Pathways. FEBS Lett. 2008, 582, 46–53. [Google Scholar] [CrossRef]
  98. Liu, Y.; Dentin, R.; Chen, D.; Hedrick, S.; Ravnskjaer, K.; Schenk, S.; Milne, J.; Meyers, D.J.; Cole, P.; Yates, J.; et al. A Fasting Inducible Switch Modulates Gluconeogenesis via Activator/Coactivator Exchange. Nature 2008, 456, 269–273. [Google Scholar] [CrossRef]
  99. Dominy, J.E.; Lee, Y.; Jedrychowski, M.P.; Chim, H.; Jurczak, M.J.; Camporez, J.P.; Ruan, H.B.; Feldman, J.; Pierce, K.; Mostoslavsky, R.; et al. The Deacetylase Sirt6 Activates the Acetyltransferase GCN5 and Suppresses Hepatic Gluconeogenesis. Mol. Cell 2012, 48, 900–913. [Google Scholar] [CrossRef]
  100. Zhang, P.; Tu, B.; Wang, H.; Cao, Z.; Tang, M.; Zhang, C.; Gu, B.; Li, Z.; Wang, L.; Yang, Y.; et al. Tumor Suppressor P53 Cooperates with SIRT6 to Regulate Gluconeogenesis by Promoting FoxO1 Nuclear Exclusion. Proc. Natl. Acad. Sci. USA 2014, 111, 10684–10689. [Google Scholar] [CrossRef]
  101. Roichman, A.; Elhanati, S.; Aon, M.A.; Abramovich, I.; Di Francesco, A.; Shahar, Y.; Avivi, M.Y.; Shurgi, M.; Rubinstein, A.; Wiesner, Y.; et al. Restoration of Energy Homeostasis by SIRT6 Extends Healthy Lifespan. Nat. Commun. 2021, 12, 3208. [Google Scholar] [CrossRef]
  102. Jang, H.; Lee, G.Y.; Selby, C.P.; Lee, G.; Jeon, Y.G.; Lee, J.H.; Cheng, K.K.Y.; Titchenell, P.; Birnbaum, M.J.; Xu, A.; et al. SREBP1c-CRY1 Signalling Represses Hepatic Glucose Production by Promoting FOXO1 Degradation during Refeeding. Nat. Commun. 2016, 7, 12180. [Google Scholar] [CrossRef]
  103. Tong, X.; Zhang, D.; Charney, N.; Jin, E.; Vandommelon, K.; Stamper, K.; Gupta, N.; Saldate, J.; Yin, L. DDB1-Mediated CRY1 Degradation Promotes FOXO1-Driven Gluconeogenesis in Liver. Diabetes 2017, 66, 2571–2582. [Google Scholar] [CrossRef]
  104. Jiang, L.; Xiong, J.; Zhan, J.; Yuan, F.; Tang, M.; Zhang, C.; Cao, Z.; Chen, Y.; Lu, X.; Li, Y.; et al. Ubiquitin-Specific Peptidase 7 (USP7)-Mediated Deubiquitination of the Histone Deacetylase SIRT7 Regulates Gluconeogenesis. J. Biol. Chem. 2017, 292, 13296–13311. [Google Scholar] [CrossRef]
  105. Hallows, W.C.; Yu, W.; Denu, J.M. Regulation of Glycolytic Enzyme Phosphoglycerate Mutase-1 by Sirt1 Protein-Mediated Deacetylation. J. Biol. Chem. 2012, 287, 3850–3858. [Google Scholar] [CrossRef]
  106. Aragonés, J.; Fraisl, P.; Baes, M.; Carmeliet, P. Oxygen Sensors at the Crossroad of Metabolism. Cell Metab. 2009, 9, 11–22. [Google Scholar] [CrossRef]
  107. Lim, J.H.; Lee, Y.M.; Chun, Y.S.; Chen, J.; Kim, J.E.; Park, J.W. Sirtuin 1 Modulates Cellular Responses to Hypoxia by Deacetylating Hypoxia-Inducible Factor 1α. Mol. Cell 2010, 38, 864–878. [Google Scholar] [CrossRef]
  108. Zhong, L.; D’Urso, A.; Toiber, D.; Sebastian, C.; Henry, R.E.; Vadysirisack, D.D.; Guimaraes, A.; Marinelli, B.; Wikstrom, J.D.; Nir, T.; et al. The Histone Deacetylase Sirt6 Regulates Glucose Homeostasis via Hif1α. Cell 2010, 140, 280–293. [Google Scholar] [CrossRef]
  109. Hubbi, M.E.; Hu, H.; Kshitiz; Gilkes, D.M.; Semenza, G.L. Sirtuin-7 Inhibits the Activity of Hypoxia-Inducible Factors. J. Biol. Chem. 2013, 288, 20768–20775. [Google Scholar] [CrossRef]
  110. Yan, W.; Liang, Y.; Zhang, Q.; Wang, D.; Lei, M.; Qu, J.; He, X.; Lei, Q.; Wang, Y. Arginine Methylation of SIRT 7 Couples Glucose Sensing with Mitochondria Biogenesis. EMBO Rep. 2018, 19, e46377. [Google Scholar] [CrossRef]
  111. Roden, M.; Shulman, G.I. The Integrative Biology of Type 2 Diabetes. Nature 2019, 576, 51–60. [Google Scholar] [CrossRef] [PubMed]
  112. Czech, M.P. Mechanisms of Insulin Resistance Related to White, Beige, and Brown Adipocytes. Mol. Metab. 2020, 34, 27–42. [Google Scholar] [CrossRef] [PubMed]
  113. Shulman, G.I. Ectopic Fat in Insulin Resistance, Dyslipidemia, and Cardiometabolic Disease. N. Engl. J. Med. 2014, 371, 1131–1141. [Google Scholar] [CrossRef] [PubMed]
  114. Qatanani, M.; Lazar, M.A. Mechanisms of Obesity-Associated Insulin Resistance: Many Choices on the Menu. Genes Dev. 2007, 21, 1443–1455. [Google Scholar] [CrossRef] [PubMed]
  115. Feige, J.N.; Lagouge, M.; Canto, C.; Strehle, A.; Houten, S.M.; Milne, J.C.; Lambert, P.D.; Mataki, C.; Elliott, P.J.; Auwerx, J. Specific SIRT1 Activation Mimics Low Energy Levels and Protects against Diet-Induced Metabolic Disorders by Enhancing Fat Oxidation. Cell Metab. 2008, 8, 347–358. [Google Scholar] [CrossRef] [PubMed]
  116. Milne, J.C.; Lambert, P.D.; Schenk, S.; Carney, D.P.; Smith, J.J.; Gagne, D.J.; Jin, L.; Boss, O.; Perni, R.B.; Vu, C.B.; et al. Small Molecule Activators of SIRT1 as Therapeutics for the Treatment of Type 2 Diabetes. Nature 2007, 450, 712–716. [Google Scholar] [CrossRef] [PubMed]
  117. Xiao, C.; Kim, H.S.; Lahusen, T.; Wang, R.H.; Xu, X.; Gavrilova, O.; Jou, W.; Gius, D.; Deng, C.X. SIRT6 Deficiency Results in Severe Hypoglycemia by Enhancing Both Basal and Insulin-Stimulated Glucose Uptake in Mice. J. Biol. Chem. 2010, 285, 36776–36784. [Google Scholar] [CrossRef]
  118. Sociali, G.; Magnone, M.; Ravera, S.; Damonte, P.; Vigliarolo, T.; von Holtey, M.; Vellone, V.G.; Millo, E.; Caffa, I.; Cea, M.; et al. Pharmacological Sirt6 Inhibition Improves Glucose Tolerance in a Type 2 Diabetes Mouse Model. FASEB J. 2017, 31, 3138–3149. [Google Scholar] [CrossRef]
  119. Cui, X.; Yao, L.; Yang, X.; Gao, Y.; Fang, F.; Zhang, J.; Wang, Q.; Chang, Y. SIRT6 Regulates Metabolic Homeostasis in Skeletal Muscle through Activation of AMPK. Am. J. Physiol. Endocrinol. Metab. 2017, 313, 493–505. [Google Scholar] [CrossRef]
  120. Kanfi, Y.; Peshti, V.; Gil, R.; Naiman, S.; Nahum, L.; Levin, E.; Kronfeld-Schor, N.; Cohen, H.Y. SIRT6 Protects against Pathological Damage Caused by Diet-Induced Obesity. Aging Cell 2010, 9, 162–173. [Google Scholar] [CrossRef]
  121. Kanfi, Y.; Naiman, S.; Amir, G.; Peshti, V.; Zinman, G.; Nahum, L.; Bar-Joseph, Z.; Cohen, H.Y. The Sirtuin SIRT6 Regulates Lifespan in Male Mice. Nature 2012, 483, 218–221. [Google Scholar] [CrossRef] [PubMed]
  122. BonDurant, L.D.; Potthoff, M.J. Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis. Annu. Rev. Nutr. 2018, 38, 173–196. [Google Scholar] [CrossRef] [PubMed]
  123. Chen, Z.; Wang, G.X.; Ma, S.L.; Jung, D.Y.; Ha, H.; Altamimi, T.; Zhao, X.Y.; Guo, L.; Zhang, P.; Hu, C.R.; et al. Nrg4 Promotes Fuel Oxidation and a Healthy Adipokine Profile to Ameliorate Diet-Induced Metabolic Disorders. Mol. Metab. 2017, 6, 863–872. [Google Scholar] [CrossRef] [PubMed]
  124. Mizumoto, T.; Yoshizawa, T.; Sato, Y.; Ito, T.; Tsuyama, T.; Satoh, A.; Araki, S.; Tsujita, K.; Tamura, M.; Oike, Y.; et al. SIRT7 Deficiency Protects against Aging-Associated Glucose Intolerance and Extends Lifespan in Male Mice. Cells 2022, 11, 3609. [Google Scholar] [CrossRef] [PubMed]
  125. Moynihan, K.A.; Grimm, A.A.; Plueger, M.M.; Bernal-Mizrachi, E.; Ford, E.; Cras-Méneur, C.; Permutt, M.A.; Imai, S.I. Increased Dosage of Mammalian Sir2 in Pancreatic β Cells Enhances Glucose-Stimulated Insulin Secretion in Mice. Cell Metab. 2005, 2, 105–117. [Google Scholar] [CrossRef] [PubMed]
  126. Qin, K.; Zhang, N.; Zhang, Z.; Nipper, M.; Zhu, Z.; Leighton, J.; Xu, K.; Musi, N.; Wang, P. SIRT6-Mediated Transcriptional Suppression of Txnip Is Critical for Pancreatic Beta Cell Function and Survival in Mice. Diabetologia 2018, 61, 906–918. [Google Scholar] [CrossRef] [PubMed]
  127. Ramadori, G.; Fujikawa, T.; Fukuda, M.; Anderson, J.; Morgan, D.A.; Mostoslavsky, R.; Stuart, R.C.; Perello, M.; Vianna, C.R.; Nillni, E.A.; et al. SIRT1 Deacetylase in POMC Neurons Is Required for Homeostatic Defenses against Diet-Induced Obesity. Cell Metab. 2010, 12, 78–87. [Google Scholar] [CrossRef] [PubMed]
  128. Tang, Q.; Gao, Y.; Liu, Q.; Yang, X.; Wu, T.; Huang, C.; Huang, Y.; Zhang, J.; Zhang, Z.; Li, R.; et al. Sirt6 in Pro-Opiomelanocortin Neurons Controls Energy Metabolism by Modulating Leptin Signaling. Mol. Metab. 2020, 37, 100994. [Google Scholar] [CrossRef]
  129. Li, S.; Wu, B.; Zheng, W. Cyclic Tripeptide-Based Potent Human SIRT7 Inhibitors. Bioorg Med. Chem. Lett. 2019, 29, 461–465. [Google Scholar] [CrossRef]
  130. Kim, J.H.; Kim, D.; Cho, S.J.; Jung, K.Y.; Kim, J.H.; Lee, J.M.; Jung, H.J.; Kim, K.R. Identification of a Novel SIRT7 Inhibitor as Anticancer Drug Candidate. Biochem. Biophys. Res. Commun. 2019, 508, 451–457. [Google Scholar] [CrossRef]
  131. Zhang, C.; Li, Y.; Liu, B.; Ning, C.; Li, Y.; Wang, Y.; Li, Z. Discovery of SIRT7 Inhibitor as New Therapeutic Options Against Liver Cancer. Front. Cell Dev. Biol. 2022, 9, 813233. [Google Scholar] [CrossRef] [PubMed]
Cells 13 00048 g001
Figure 1. Roles of SIRT7 in lipid metabolism. (A) SIRT7 promotes adipogenesis by inhibiting SIRT1 and enhancing the activity of PPARγ [59]. (B) SIRT7 also promotes lipogenesis in WAT through the deacetylation of PPARγ2 [20]. (C) SIRT7 suppresses thermogenesis in BAT by deacetylating IMP2, an RNA-binding protein that inhibits the translation of Ucp1 mRNA [21]. (D) SIRT7 stimulates inflammation through the nuclear retention of the RAN-NF-κB complex. In the absence of SIRT7, acetylated RAN facilitates the formation of the NF-κB export cargo complex, thereby enhancing the nuclear exclusion of NF-κB [32]. (E) SIRT7 deacetylates DDB1, a component of CUL4B/DDB1/DCAF1 E3 ubiquitin ligase complex. SIRT7 increases TR4 protein expression and lipid accumulation in the liver by inhibiting the degradation of TR4 via the suppression of the E3 ubiquitin ligase complex [19]. (F) SIRT7 increases mitochondrial gene expression through the deacetylation of GABPβ1 [22].
Figure 1. Roles of SIRT7 in lipid metabolism. (A) SIRT7 promotes adipogenesis by inhibiting SIRT1 and enhancing the activity of PPARγ [59]. (B) SIRT7 also promotes lipogenesis in WAT through the deacetylation of PPARγ2 [20]. (C) SIRT7 suppresses thermogenesis in BAT by deacetylating IMP2, an RNA-binding protein that inhibits the translation of Ucp1 mRNA [21]. (D) SIRT7 stimulates inflammation through the nuclear retention of the RAN-NF-κB complex. In the absence of SIRT7, acetylated RAN facilitates the formation of the NF-κB export cargo complex, thereby enhancing the nuclear exclusion of NF-κB [32]. (E) SIRT7 deacetylates DDB1, a component of CUL4B/DDB1/DCAF1 E3 ubiquitin ligase complex. SIRT7 increases TR4 protein expression and lipid accumulation in the liver by inhibiting the degradation of TR4 via the suppression of the E3 ubiquitin ligase complex [19]. (F) SIRT7 increases mitochondrial gene expression through the deacetylation of GABPβ1 [22].
Cells 13 00048 g001
Cells 13 00048 g003
Figure 3. Roles of SIRT1, SIRT6, and SIRT7 in metabolism. Comparison of the metabolic roles of SIRT1, SIRT6, and SIRT7. SIRT1 and SIRT6 stimulate lipolysis in WAT. In contrast, SIRT7 promotes lipogenesis in WAT. In addition, SIRT1 and SIRT6 stimulate thermogenesis in BAT, whereas SIRT7 inhibits it. Although SIRT1 and SIRT6 attenuate lipid accumulation in the liver, SIRT7 increases it. These observations indicate that SIRT7 regulates metabolism in opposite directions from SIRT1 and SIRT6 in some cases.
Figure 3. Roles of SIRT1, SIRT6, and SIRT7 in metabolism. Comparison of the metabolic roles of SIRT1, SIRT6, and SIRT7. SIRT1 and SIRT6 stimulate lipolysis in WAT. In contrast, SIRT7 promotes lipogenesis in WAT. In addition, SIRT1 and SIRT6 stimulate thermogenesis in BAT, whereas SIRT7 inhibits it. Although SIRT1 and SIRT6 attenuate lipid accumulation in the liver, SIRT7 increases it. These observations indicate that SIRT7 regulates metabolism in opposite directions from SIRT1 and SIRT6 in some cases.
Cells 13 00048 g003
Table 1. Target proteins and functions of SIRT7.
Table 1. Target proteins and functions of SIRT7.
Activity Target ProteinFunction
DeacetylationGene expression
☐
☐
☐
☐
☐		Histone H3K18Tumorigenesis and DNA repair [10,11]
Histone H3K36/K37Heterochromatin silencing [12]
PAF53Synthesis of pre-rRNA [13]
U3-55kProcessing of pre-rRNA [14]
FibrillarinrRNA synthesis [15]
CDK9RNA polymerase II transcription [16]
DNA stability
☐		DDX21Genome stability [17]
ATMDNA repair [18]
Metabolism
☐
☐
☐
☐		DDB1Lipid metabolism [19]
PPARγ2Lipogenesis [20]
IMP2/IGF2BP2Thermogenesis [21]
GABPβ1Mitochondrial homeostasis [22]
CRY1Circadian phase [23]
Cancer
☐
☐
☐
☐
☐		WDR77Transmethylase activity [24]
PGK1Glycolysis [25]
FKBP51Akt inactivation [26]
SMAD4Cancer metastasis [27]
USP39Cancer growth [28]
HAT1Tumorigenesis [29]
Cardiorenal disease
☐		GATA4Regulation of cardiac hypertrophy [30]
KCC4Regulation of ion flux [31]
ImmunityRANRegulation of inflammation [32]
Stress response
☐
☐
☐		NPM1Aging and p53 stability [33]
FOXO3Regulation of apoptosis [34]
p53Apoptosis [35]
STRAPp53 activity and stability [36]
Stem cellNRF1Mitochondrial homeostasis [37]
NFATc1Hair follicle initiation [38]
Desuccinylation Histone H3K122Chromatin compaction [39]
PRMT5Lipid metabolism [40]
Deglutarylation Histone H4K91Chromatin structure [41]
Decrotonylation PHF5AAging [42]
Deacylation OsterixBone formation [43]
Mono-ADP ribosylation SIRT7Stress response [44]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Yamagata, K.; Mizumoto, T.; Yoshizawa, T. The Emerging Role of SIRT7 in Glucose and Lipid Metabolism. Cells 2024, 13, 48. https://doi.org/10.3390/cells13010048

AMA Style

Yamagata K, Mizumoto T, Yoshizawa T. The Emerging Role of SIRT7 in Glucose and Lipid Metabolism. Cells. 2024; 13(1):48. https://doi.org/10.3390/cells13010048

Chicago/Turabian Style

Yamagata, Kazuya, Tomoya Mizumoto, and Tatsuya Yoshizawa. 2024. "The Emerging Role of SIRT7 in Glucose and Lipid Metabolism" Cells 13, no. 1: 48. https://doi.org/10.3390/cells13010048

APA Style

Yamagata, K., Mizumoto, T., & Yoshizawa, T. (2024). The Emerging Role of SIRT7 in Glucose and Lipid Metabolism. Cells, 13(1), 48. https://doi.org/10.3390/cells13010048

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop