The effects of caloric restriction on adipose tissue and metabolic health are sex- and age-dependent
- University of Edinburgh, United Kingdom
- University of Aberdeen, United Kingdom
- National Center for Global Health and Medicine, Japan
- University of Glasgow, United Kingdom
Abstract
Caloric restriction (CR) is a nutritional intervention that reduces the risk of age-related diseases in numerous species, including humans. CR's metabolic effects, including decreased fat mass and improved insulin sensitivity, play an important role in 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 female mice. Females' resistance to fat and weight loss was associated with decreased lipolysis, lower systemic energy expenditure and fatty acid oxidation, and increased postprandial lipogenesis compared to males. Positron emission tomography-computed tomography (PET/CT) with 18F-fluorodeoxyglucose (18F-FDG) showed that peripheral glucose uptake was comparable between sexes. Instead, the sex differences in glucose homeostasis were associated with altered hepatic ceramide content and substrate metabolism: compared to CR males, CR females had lower TCA cycle activity but 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, thereby 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 to a similar extent 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.
Data availability
All source data and code from which the figures are based is available through University of Edinburgh DataShare at https://doi.org/10.7488/ds/3758. Any other relevant data are available from the authors upon reasonable request.
Article and author information
Author details
Carlos Jose Alcaide-Corral
Alexandra M Johnstone
William P Cawthorn
Funding
Medical Research Council (MR/M021394/1)
- William P Cawthorn
British Heart Foundation (RG/16/10/32375)
- Adriana AS Tavares
British Heart Foundation (FS/19/34/34354)
- Adriana AS Tavares
British Heart Foundation (4-year PhD studentship)
- Benjamin J Thomas
- Richard J Sulston
Carnegie Trust for the Universities of Scotland (RIG007416)
- William P Cawthorn
Wellcome Trust (221295/Z/20/Z)
- Adriana AS Tavares
Chief Scientist Office (SCAF/17/02)
- Roland H Stimson
Scottish Government (RESAS Strategic Research Programme)
- Claire Fyfe
British Heart Foundation (RE/13/3/30183)
- Adriana AS Tavares
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Mone Zaidi, Icahn School of Medicine at Mount Sinai, United States
Ethics
Animal experimentation: Studies in C57BL/6NCrl and C57BL/6JCrl mice were approved by the University of Edinburgh Animal Welfare and Ethical Review Board and were done under project licenses granted by the UK Home Office (project license numbers 708617 and PP2299608).
Human subjects: Written, informed consent was obtained, and the study was reviewed by the NHS North of Scotland Research Ethics Service (ethics number 09/S0801/80).
Version history
- Preprint posted: February 22, 2022 (view preprint)
- Received: March 24, 2023
- Accepted: March 26, 2023
- Accepted Manuscript published: April 25, 2023 (version 1)
- Version of Record published: May 9, 2023 (version 2)
Copyright
© 2023, Suchacki et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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The effects of caloric restriction on adipose tissue and metabolic health are sex- and age-dependent
eLife 12:e88080.
https://doi.org/10.7554/eLife.88080
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