Targeting activin receptor–like kinase 7 ameliorates adiposity and associated metabolic disorders
Min Zhao, … , Tadahiro Kitamura, Tetsuro Izumi
Min Zhao, … , Tadahiro Kitamura, Tetsuro Izumi
Published January 10, 2023
Citation Information: JCI Insight. 2023;8(4):e161229. https://doi.org/10.1172/jci.insight.161229.
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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 1

ALK7 mAb treatment reduces adiposity in ALK7-intact TSOD mice but not in ALK7-deficient counterparts.

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ALK7 mAb treatment reduces adiposity in ALK7-intact TSOD mice but not in...
TSOD mice and their ALK7-deficient counterparts, T.B-Nidd5/3 mice, were treated with ALK7 mAb (10 mg/kg) or PBS from 5 to 11 weeks of age (A–E). Similarly, TSOD mice were treated with ALK7 mAb or PBS from 5 to 20 weeks of age (F–I). Measurements were made of food intake, BW, adiposity as determined by CT (A and F), fat pad weight (B and G), serum leptin concentration (C and H), ATGL protein expression levels in epiWAT (D), and serum concentrations of NEFA and glycerol and those normalized by weights of epiWAT (E and I). Phenotypic measurement and sample preparation were performed at the end of each cohort, except that food intake and CT were analyzed at 1 week before killing the mice (n = 6 each). The quantification of the ATGL and β-actin protein levels was based on densitometric analyses of immunoblots (n = 9). A representative blot of epiWAT extracts (15 μg of protein) from 3 mice per group is shown (D). †P < 0.05, ††P < 0.01, †††P < 0.001 by 2-way ANOVA followed by Tukey multiple comparison. *P < 0.05, **P < 0.01, ***P < 0.001 by t test.