The effects of caloric restriction on adipose tissue and metabolic health are sex- and age-dependent

Suchacki, KJ, Thomas, BJ, Ikushima, YM, Chen, K-C, Fyfe, C, Tavares, AAS, Sulston, RJ, Lovdel, A, Woodward, HJ, Han, X, Mattiucci, D, Brain, EJ, Alcaide-Corral, CJ, Kobayashi, H, Gray, GA, Whitfield, PD, Stimson, RH, Morton, NM ORCID: https://orcid.org/0000-0001-8218-8462, Johnstone, AM and Cawthorn, WP, 2023. The effects of caloric restriction on adipose tissue and metabolic health are sex- and age-dependent. eLife, 12: e88080. ISSN 2050-084X

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Abstract

Caloric restriction (CR) reduces the risk of age-related diseases in numerous species, including humans. CR’s metabolic effects, including decreased adiposity and improved insulin sensitivity, are important for its broader health benefits; however, the extent and basis of sex differences in CR’s health benefits are unknown. We found that 30% CR in young (3-month-old) male mice decreased fat mass and improved glucose tolerance and insulin sensitivity, whereas these effects were blunted or absent in young females. Females’ resistance to fat loss was associated with decreased lipolysis, energy expenditure and fatty acid oxidation, and increased postprandial lipogenesis, compared to males. The sex differences in glucose homeostasis were not associated with differential glucose uptake but with altered hepatic ceramide content and substrate metabolism: compared to CR males, CR females had lower TCA cycle activity and higher blood ketone concentrations, a marker of hepatic acetyl-CoA content. This suggests that males use hepatic acetyl-CoA for the TCA cycle whereas in females it accumulates, stimulating gluconeogenesis and limiting hypoglycaemia during CR. In aged mice (18-months old), when females are anoestrus, CR decreased fat mass and improved glucose homeostasis similarly in both sexes. Finally, in a cohort of overweight and obese humans, CR-induced fat loss was also sex- and age-dependent: younger females (<45 years) resisted fat loss compared to younger males while in older subjects (>45 years) this sex difference was absent. Collectively, these studies identify age-dependent sex differences in the metabolic effects of CR and highlight adipose tissue, the liver and oestrogen as key determinants of CR’s metabolic benefits. These findings have important implications for understanding the interplay between diet and health, and for maximising the benefits of CR in humans.

Item Type:	Journal article
Publication Title:	eLife
Creators:	Suchacki, K.J., Thomas, B.J., Ikushima, Y.M., Chen, K.-C., Fyfe, C., Tavares, A.A.S., Sulston, R.J., Lovdel, A., Woodward, H.J., Han, X., Mattiucci, D., Brain, E.J., Alcaide-Corral, C.J., Kobayashi, H., Gray, G.A., Whitfield, P.D., Stimson, R.H., Morton, N.M., Johnstone, A.M. and Cawthorn, W.P.
Publisher:	NLM
Date:	25 April 2023
Volume:	12
ISSN:	2050-084X
Identifiers:	Number Type 10.7554/eLife.88080 DOI 2465339 Other
Rights:	© 2023, Suchacki, Thomas, Ikushima et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Divisions:	Schools > School of Science and Technology
Record created by:	Jonathan Gallacher
Date Added:	09 Jul 2025 14:04
Last Modified:	09 Jul 2025 14:04
URI:	https://irep.ntu.ac.uk/id/eprint/53924

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