Targeting activin receptor–like kinase 7 ameliorates adiposity and associated metabolic disorders
Min Zhao, Katsuhide Okunishi, Yun Bu, Osamu Kikuchi, Hao Wang, Tadahiro Kitamura, Tetsuro Izumi
Min Zhao, Katsuhide Okunishi, Yun Bu, Osamu Kikuchi, Hao Wang, Tadahiro Kitamura, Tetsuro Izumi
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Research Article Metabolism

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

Abstract

Activin receptor-like kinase 7 (ALK7) is a type I receptor in the TGF-β superfamily preferentially expressed in adipose tissue and associated with lipid metabolism. Inactivation of ALK7 signaling in mice results in increased lipolysis and resistance to both genetic and diet-induced obesity. Human genetic studies have recently revealed an association between ALK7 variants and both reduced waist to hip ratios and resistance to development of diabetes. In the present study, treatment with a neutralizing mAb against ALK7 caused a substantial loss of adipose mass and improved glucose intolerance and insulin resistance in both genetic and diet-induced mouse obesity models. The enhanced lipolysis increased fatty acid supply from adipocytes to promote fatty acid oxidation in muscle and oxygen consumption at the whole-body level. The treatment temporarily increased hepatic triglyceride levels, which resolved with long-term Ab treatment. Blocking of ALK7 signals also decreased production of its ligand, growth differentiation factor 3, by downregulating S100A8/A9 release from adipocytes and, subsequently, IL-1β release from adipose tissue macrophages. These findings support the feasibility of potential therapeutics targeting ALK7 as a treatment for obesity and diabetes.

Authors

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

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Figure 8

Signaling pathways of S100A8/A9-induced GDF3 upregulation in ATMs.

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Signaling pathways of S100A8/A9-induced GDF3 upregulation in ATMs. (A–G)...
(A–G) EpiWAT (0.5 g) isolated from 7-week-old TSOD or T.B-Nidd5/3 mice was incubated with GDF3, as described in Figure 7B. (C–G) ALK7 mAb (C and D; 30 minutes), the S100A8/A9 inhibitor, paquinimod (E; 900 μg/mL, 10 minutes), the RAGE antagonist, FPS-ZM1 (F; 30 μg/mL, 2 hours), or wortmannin (G; 100 nM, 10 minutes) was added at the indicated concentrations prior to the addition of GDF3. After a 24-hour culture, RNA and protein were extracted from 0.05 g and 0.1 g of epiWAT, respectively. SVF was isolated from the remaining approximately 0.35 g of epiWAT. The S100A8/A9 protein levels were measured as described in Figure 7C (A, n = 3; C, n = 4). The mRNA levels in SVF were determined (B, n = 3; D, n = 4; E, n = 4; F, n = 3; G, n = 6). (H) CD11c– ATMs isolated from epiWAT SVF of 7- to 10-week-old TSOD mice were cultured with or without MCC950 (10 μM) for 30 minutes followed by S100A8/A9 (10 μg/mL) for 24 hour. The GDF3 protein and its mRNA levels were measured (n = 3), as described in Figure 7A. (I) Schematic summary. GDF3 increases production of S100A8/A9 by adipocytes through its receptor ALK7. S100A8/A9 increases production of pro–IL-1β in ATMs. Pro–IL-1β can be cleaved to form bioactive mature IL-1β by NLRP3 inflammasome. S100A8/A9 may also directly enhance GDF3 production by ATMs via activation of PI3K. Secreted mature IL-1β increases GDF3 production by ATMs in autocrine and/or paracrine manners via a PI3K-dependent pathway. As such, GDF3 released from ATMs and ALK7 signals in adipocytes forms a positive feedback loop to drive fat accumulation. #P < 0.05, ##P < 0.01 by 1-way ANOVA. **P < 0.01 by t test.