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Exploring the relationship between alpha-actinin-3 deficiency and obesity in mice and humans


Obesity is a worldwide health crisis, and the identification of genetic modifiers of weight gain is crucial in understanding this complex disorder. A common null polymorphism in the fast fiber-specific gene ACTN3 (R577X) is known to influence skeletal muscle function and metabolism. alpha-Actinin-3 deficiency occurs in an estimated 1.5 billion people worldwide, and results in reduced muscle strength and a shift towards a more efficient oxidative metabolism. The X-allele has undergone strong positive selection during recent human evolution, and in this study, we sought to determine whether ACTN3 genotype influences weight gain and obesity in mice and humans. An Actn3 KO mouse has been generated on two genetic backgrounds (129X1/SvJ and C57BL/6J) and fed a high-fat diet (HFD, 45% calories from fat). Anthropomorphic features (including body weight) were examined and show that Actn3 KO 129X1/SvJ mice gained less weight compared to WT. In addition, six independent human cohorts were genotyped for ACTN3 R577X (Rs1815739) and body mass index (BMI), waist-to-hip ratio-adjusted BMI (WHRadjBMI) and obesity-related traits were assessed. In humans, ACTN3 genotype alone does not contribute to alterations in BMI or obesity.

Type Journal
ISBN 1476-5497 (Electronic) 0307-0565 (Linking)
Authors Houweling, P. J.; Berman, Y. D.; Turner, N.; Quinlan, K. G. R.; Seto, J. T.; Yang, N.; Lek, M.; Macarthur, D. G.; Cooney, G.; North, K. N.
Responsible Garvan Author (missing name)
Published Date 2017-04-11
Published Volume 41
Published Issue 7
Published Pages 1154-1157
Status Published in-print
DOI 10.1038/ijo.2017.72
URL link to publisher's version
OpenAccess link to author's accepted manuscript version