Targeting activin receptor–like kinase 7 ameliorates adiposity and associated metabolic disorders

Zhao, Min; Okunishi, Katsuhide; Bu, Yun; Kikuchi, Osamu; Wang, Hao; Kitamura, Tadahiro; Izumi, Tetsuro

doi:10.1172/jci.insight.161229

Cited by 12 publications

(16 citation statements)

References 58 publications

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“…In fact, we found no alternations in glucose-stimulated insulin secretion from isolated islets of genetically ALK7deficient mice [12] or mice treated with ALK7 neutralizing antibody [13]. Furthermore, the protein and mRNA levels of ALK7 in islets were negligible compared with those in WAT, which is consistent with the previous findings that ALK7 transcripts are predominantly expressed in adipose tissues compared with other tissues in both mice and humans [14,15].…”

Section: Introductionsupporting

confidence: 91%

“…In any case, it should be kept in mind that this BATspecific ALK7-knockout mouse may display phenotypes indirectly or partly reflecting ALK7 deficiency in WAT, because UCP1 is expressed in 'beige' or 'brite' adipocytes in WAT [28], especially after fasting or cold exposure. In fact, we found that UCP1 is induced in WAT of mice treated with ALK7 neutralizing antibody [13].…”

Section: Fat-specific Alk7-knockout Micementioning

confidence: 74%

“…GDF3-producing ATMs are markedly decreased in WAT of both ALK7deficient mice [25] and ALK7-intact mice treated with ALK7 neutralizing antibody [13]. Mechanistically, ALK7 signaling upregulates release of S100A8/A9 protein from adipocytes, which subsequently activates NLRP3 inflammasome and the downstream gene product, interleukin-1β (IL-1β), and upregulates GDF3 in ATMs [13] (Fig. 2).…”

Section: Activins and Gdf3 As Alk7 Ligandsmentioning

confidence: 99%

“…Because nonspecific macrophage depletion highlights the ALK7dependent differences, the GDF3-ALK7 signaling pathway could represent a major link between macrophages and adipocytes in the regulation of whole-body lipid metabolism and fat accumulation. GDF3-producing ATMs are markedly decreased in WAT of both ALK7deficient mice [25] and ALK7-intact mice treated with ALK7 neutralizing antibody [13]. Mechanistically, ALK7 signaling upregulates release of S100A8/A9 protein from adipocytes, which subsequently activates NLRP3 inflammasome and the downstream gene product, interleukin-1β (IL-1β), and upregulates GDF3 in ATMs [13] (Fig.…”

Section: Activins and Gdf3 As Alk7 Ligandsmentioning

confidence: 99%

“…Insulin upregulates GDF3 specifically in ATMs, but not in macrophages from other tissues [25]. NLRP3 inflammasome and the downstream IL-1β are also involved in GDF3 expression [13,37]. S100A8/A9 protein released from adipocytes by ALK7-dependent signals also upregulates GDF3 via the receptor for advanced glycation end products (RAGE) in ATMs, which forms the reciprocal positive feedback pathway from ALK7 to GDF3 [13].…”

Section: Activins and Gdf3 As Alk7 Ligandsmentioning

confidence: 99%

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The GDF3-ALK7 signaling axis in adipose tissue: a possible therapeutic target for obesity and associated diabetes?

Izumi

2023

Endocr J

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ALK7, a type I receptor for the transforming growth factor-β superfamily, is known to be predominantly expressed in adipocytes in both mice and humans. The present review describes recent findings suggesting that ALK7 plays a major role in regulating lipid metabolism and fat mass. Furthermore, the ligands and upstream regulators that activate ALK7 signaling are discussed. The focus is on findings in mice and their derivative tissues and cells that harbor the mutations of ALK7 and related molecules. Particular attention is paid to the contradictory nature of the current literature about the loss-of-function phenotypes and the relationship with insulin secretion and sensitivity. Additional attention is paid to the ALK7 gene variants found in humans and their associated traits. The goal is to seek a parsimonious, and preferably singular and unified, description of the underlying mechanism. This review also introduces recent promising findings about ALK7 neutralizing treatment to obese mice.

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Section: Introductionsupporting

confidence: 91%

Section: Fat-specific Alk7-knockout Micementioning

confidence: 74%

Section: Activins and Gdf3 As Alk7 Ligandsmentioning

confidence: 99%

Section: Activins and Gdf3 As Alk7 Ligandsmentioning

confidence: 99%

Section: Activins and Gdf3 As Alk7 Ligandsmentioning

confidence: 99%

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The GDF3-ALK7 signaling axis in adipose tissue: a possible therapeutic target for obesity and associated diabetes?

Izumi

2023

Endocr J

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Dapagliflozin alleviates high‐fat‐induced obesity cardiomyopathy by inhibiting ferroptosis

Chen,

Shi,

et al. 2024

ESC Heart Failure

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Aim: Dapagliflozin (Dapa) is a novel hypoglycaemic agent with multiple cardiovascular protective effects, and it is widely used in treatment of heart failure patients, but whether it can improve obese phenotype of heart failure and its mechanism is still unclear. Ferroptosis is an iron dependent form of cell death and has been proved to be an important role in heart failure. The aim of this study is to determine whether Dapa improves obesity‐related heart failure by regulating ferroptosis in high‐fat diet rats. Methods and results: Male SD rats were fed a high‐fat diet for 12 weeks and confirmed of obese heart failure by metabolic parameters and cardiac ultrasound. Being overweight by 20% compared with the normal group, with elevated systolic blood pressure and abnormal levels of insulin and blood lipid (TG and LDL‐c), is recognized as obesity. The obese rats with reduced EF, FS, and E/A shown on ultrasound are defined as the obese heart failure (OHF) group. Histological tests confirmed the more pronounced cardiac fibrosis, mitochondrial volume and collagen deposition in OHF group. Dapa treatment effectively reduced body weight, INS, ISI/IRI index, TG and HDL‐C levels (P < 0.05). Also, Dapa administration can slightly decrease the SBP and DBP levels; however, there was no statistical difference among those four groups. Furthermore, Dapa treatment can significantly improve high‐fat induced systolic and diastolic dysfunction via regulating cardiac histological abnormalities, including less obvious mitochondrial swelling, muscle fibre dissolution and collagen deposition. Additionally, genes from the OHF group were used by GO enrichment analysis, and it shows that ferroptosis metabolic pathway participated in the development of obese phenotype of heart failure. More importantly, Dapa significantly inhibited Fe2+ and MDA levels (P < 0.05), but augmented GSH content (P < 0.05). In addition, the mRNAs and protein expression of some important regulators of ferroptosis, like GPX4, SLC7A11, FTH1 and FPN1, were all decreased after Dapa intervention. Conclusion: Dapa improved high‐fat induced obese cardiac dysfunction via regulating ferroptosis pathway.

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Hepatic Activin E mediates liver-adipose inter-organ communication, suppressing adipose lipolysis in response to elevated serum fatty acids

Griffin,

Buxton,

Culver

et al. 2023

Molecular Metabolism

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Targeting activin receptor–like kinase 7 ameliorates adiposity and associated metabolic disorders

Cited by 12 publications

References 58 publications

The GDF3-ALK7 signaling axis in adipose tissue: a possible therapeutic target for obesity and associated diabetes?

The GDF3-ALK7 signaling axis in adipose tissue: a possible therapeutic target for obesity and associated diabetes?

Dapagliflozin alleviates high‐fat‐induced obesity cardiomyopathy by inhibiting ferroptosis

Hepatic Activin E mediates liver-adipose inter-organ communication, suppressing adipose lipolysis in response to elevated serum fatty acids

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