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

Karla J. Suchacki; Ben J. Thomas; Yoshiko M. Ikushima; Kuan Chan Chen; Claire Fyfe; Adriana A.S. Tavares; Richard J. Sulston; Andrea Lovdel; Holly J. Woodward; Xuan Han; Domenico Mattiucci; Eleanor J. Brain; Carlos J. Alcaide-Corral; Hiroshi Kobayashi; Gillian A. Gray; Phillip D. Whitfield; Roland H. Stimson; Nicholas M. Morton; Alexandra M. Johnstone; William P. Cawthorn

doi:10.7554/eLife.88080

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

Karla J. Suchacki, Ben J. Thomas, Yoshiko M. Ikushima, Kuan Chan Chen, Claire Fyfe, Adriana A.S. Tavares, Richard J. Sulston, Andrea Lovdel, Holly J. Woodward, Xuan Han, Domenico Mattiucci, Eleanor J. Brain, Carlos J. Alcaide-Corral, Hiroshi Kobayashi, Gillian A. Gray, Phillip D. Whitfield, Roland H. Stimson, Nicholas M. Morton, Alexandra M. Johnstone, William P. Cawthorn^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

8 Citations (Scopus)

12 Downloads (Pure)

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) with¹⁸F-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.

Original language	English
Article number	e88080
Journal	eLife
Volume	12
DOIs	https://doi.org/10.7554/eLife.88080
Publication status	Published - 25 Apr 2023

Bibliographical note

Funding Information:
This work was supported by grants from the Medical Research Council (MR/M021394/1 to W.P.C.), the British Heart Foundation (BHF) (RG/16/10/32375 and FS/19/34/34354 to A.A.S.T.; 4-year BHF PhD Studentship to B.J.T. and R.J.S.), the Takeda Science Foundation (Fellowship for Young Japanese MDs & PhDs Studying Abroad, to Y.M.I.), the Japan Society for the Promotion of Science (JSPS Overseas Research Fellowship, to Y.M.I.), the Japan Foundation for Applied Enzymology (to Y.M.I.), the University of Edinburgh (Chancellor’s Fellowship to W.P.C.; PhD Studentship to A.L.), the Carnegie Trust (RIG007416 to W.P.C.), the Wellcome Trust (Technology Development Award 221295/Z/20/Z to A.A.S.T.; Multi-user equipment grant 223818/Z/21/Z for the Promethion system), the Chief Scientist Office of the Scottish Government (SCAF/17/02 to R.H.S.), KAKENHI grants from MEXT/JSPS (21K08431 to H.K.), and a grant from the National Center for Global Health and Medicine (20A1010 to H.K.). C.F. and A.M.J. gratefully acknowledge financial support from the Scottish Government as part of the RESAS Strategic Research Programme at the Rowett Institute, University of Aberdeen. We thank Ami Onishi for assistance with indirect calorimetry studies using the Promethion system, and the BHF for supporting Ami Onishi’s salary through the Centre for Research Excellence Award III (RE/18/5/34216). The BHF also provided funding towards establishment of the Edinburgh Preclinical PET/CT laboratory (RE/13/3/30183) and support of the 2018 Very Important Project (VIP) PET prize, for which we are grateful. Finally, we thank Dr Matthew Bennett (University of Edinburgh) for advice analysing RNA-seq data; Prof Robert Semple (University of Edinburgh) and Prof Ormond MacDougald (University of Michigan) for helpful advice to interpret our findings; Stefanie Fung (University of Edinburgh) for assistance isolating RNA for RNA-seq; Dr Hai-Bin Ruan (University of Minnesota Medical School) and Dr Eleonora Pagano (Pontifical Catholic University of Argentina) for kindly providing a full text of Ballor and Poehlman’s 1994 study (78), and all staff at Edinburgh Bioresearch & Veterinary Services for their superb technical support. Finally, this manuscript was written entirely by the authors and without any use of large language models.

Publisher Copyright:
© 2023, eLife Sciences Publications Ltd. All rights reserved.

Keywords

adipose tissue
ageing
caloric restriction
energy balance
glucose homeostasis
insulin sensitivity
lipidomics
liver metabolism
PET/CT
Sex differences

Access to Document

10.7554/eLife.88080Licence: CC BY

Suchacki,_etal_elife_Effects_Calorific_Restriction_VOR
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. https://creativecommons.org/licenses/by/4.0/
Final published version, 7.65 MBLicence: CC BY

Cite this

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., & Cawthorn, W. P. (2023). The effects of caloric restriction on adipose tissue and metabolic health are sex-and age-dependent. eLife, 12, Article e88080. https://doi.org/10.7554/eLife.88080

Suchacki, KJ, Thomas, BJ, Ikushima, YM, Chen, KC, 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, Johnstone, AM & Cawthorn, WP 2023, 'The effects of caloric restriction on adipose tissue and metabolic health are sex-and age-dependent.', eLife, vol. 12, e88080. https://doi.org/10.7554/eLife.88080

@article{dd48d477c97d45bcac98d24671b899dc,

title = "The effects of caloric restriction on adipose tissue and metabolic health are sex-and age-dependent.",

abstract = "Caloric restriction (CR) is a nutritional intervention that reduces the risk of age-related diseases in numerous species, including humans. CR{\textquoteright}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{\textquoteright}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{\textquoteright} 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) with18F-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{\textquoteright}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.",

keywords = "adipose tissue, ageing, caloric restriction, energy balance, glucose homeostasis, insulin sensitivity, lipidomics, liver metabolism, PET/CT, Sex differences",

author = "Suchacki, {Karla J.} and Thomas, {Ben J.} and Ikushima, {Yoshiko M.} and Chen, {Kuan Chan} and Claire Fyfe and Tavares, {Adriana A.S.} and Sulston, {Richard J.} and Andrea Lovdel and Woodward, {Holly J.} and Xuan Han and Domenico Mattiucci and Brain, {Eleanor J.} and Alcaide-Corral, {Carlos J.} and Hiroshi Kobayashi and Gray, {Gillian A.} and Whitfield, {Phillip D.} and Stimson, {Roland H.} and Morton, {Nicholas M.} and Johnstone, {Alexandra M.} and Cawthorn, {William P.}",

note = "Funding Information: This work was supported by grants from the Medical Research Council (MR/M021394/1 to W.P.C.), the British Heart Foundation (BHF) (RG/16/10/32375 and FS/19/34/34354 to A.A.S.T.; 4-year BHF PhD Studentship to B.J.T. and R.J.S.), the Takeda Science Foundation (Fellowship for Young Japanese MDs & PhDs Studying Abroad, to Y.M.I.), the Japan Society for the Promotion of Science (JSPS Overseas Research Fellowship, to Y.M.I.), the Japan Foundation for Applied Enzymology (to Y.M.I.), the University of Edinburgh (Chancellor{\textquoteright}s Fellowship to W.P.C.; PhD Studentship to A.L.), the Carnegie Trust (RIG007416 to W.P.C.), the Wellcome Trust (Technology Development Award 221295/Z/20/Z to A.A.S.T.; Multi-user equipment grant 223818/Z/21/Z for the Promethion system), the Chief Scientist Office of the Scottish Government (SCAF/17/02 to R.H.S.), KAKENHI grants from MEXT/JSPS (21K08431 to H.K.), and a grant from the National Center for Global Health and Medicine (20A1010 to H.K.). C.F. and A.M.J. gratefully acknowledge financial support from the Scottish Government as part of the RESAS Strategic Research Programme at the Rowett Institute, University of Aberdeen. We thank Ami Onishi for assistance with indirect calorimetry studies using the Promethion system, and the BHF for supporting Ami Onishi{\textquoteright}s salary through the Centre for Research Excellence Award III (RE/18/5/34216). The BHF also provided funding towards establishment of the Edinburgh Preclinical PET/CT laboratory (RE/13/3/30183) and support of the 2018 Very Important Project (VIP) PET prize, for which we are grateful. Finally, we thank Dr Matthew Bennett (University of Edinburgh) for advice analysing RNA-seq data; Prof Robert Semple (University of Edinburgh) and Prof Ormond MacDougald (University of Michigan) for helpful advice to interpret our findings; Stefanie Fung (University of Edinburgh) for assistance isolating RNA for RNA-seq; Dr Hai-Bin Ruan (University of Minnesota Medical School) and Dr Eleonora Pagano (Pontifical Catholic University of Argentina) for kindly providing a full text of Ballor and Poehlman{\textquoteright}s 1994 study (78), and all staff at Edinburgh Bioresearch & Veterinary Services for their superb technical support. Finally, this manuscript was written entirely by the authors and without any use of large language models. Publisher Copyright: {\textcopyright} 2023, eLife Sciences Publications Ltd. All rights reserved.",

year = "2023",

month = apr,

day = "25",

doi = "10.7554/eLife.88080",

language = "English",

volume = "12",

journal = "eLife",

issn = "2050-084X",

publisher = "eLife Sciences Publications",

}

TY - JOUR

T1 - The effects of caloric restriction on adipose tissue and metabolic health are sex-and age-dependent.

AU - Suchacki, Karla J.

AU - Thomas, Ben J.

AU - Ikushima, Yoshiko M.

AU - Chen, Kuan Chan

AU - Fyfe, Claire

AU - Tavares, Adriana A.S.

AU - Sulston, Richard J.

AU - Lovdel, Andrea

AU - Woodward, Holly J.

AU - Han, Xuan

AU - Mattiucci, Domenico

AU - Brain, Eleanor J.

AU - Alcaide-Corral, Carlos J.

AU - Kobayashi, Hiroshi

AU - Gray, Gillian A.

AU - Whitfield, Phillip D.

AU - Stimson, Roland H.

AU - Morton, Nicholas M.

AU - Johnstone, Alexandra M.

AU - Cawthorn, William P.

N1 - Funding Information: This work was supported by grants from the Medical Research Council (MR/M021394/1 to W.P.C.), the British Heart Foundation (BHF) (RG/16/10/32375 and FS/19/34/34354 to A.A.S.T.; 4-year BHF PhD Studentship to B.J.T. and R.J.S.), the Takeda Science Foundation (Fellowship for Young Japanese MDs & PhDs Studying Abroad, to Y.M.I.), the Japan Society for the Promotion of Science (JSPS Overseas Research Fellowship, to Y.M.I.), the Japan Foundation for Applied Enzymology (to Y.M.I.), the University of Edinburgh (Chancellor’s Fellowship to W.P.C.; PhD Studentship to A.L.), the Carnegie Trust (RIG007416 to W.P.C.), the Wellcome Trust (Technology Development Award 221295/Z/20/Z to A.A.S.T.; Multi-user equipment grant 223818/Z/21/Z for the Promethion system), the Chief Scientist Office of the Scottish Government (SCAF/17/02 to R.H.S.), KAKENHI grants from MEXT/JSPS (21K08431 to H.K.), and a grant from the National Center for Global Health and Medicine (20A1010 to H.K.). C.F. and A.M.J. gratefully acknowledge financial support from the Scottish Government as part of the RESAS Strategic Research Programme at the Rowett Institute, University of Aberdeen. We thank Ami Onishi for assistance with indirect calorimetry studies using the Promethion system, and the BHF for supporting Ami Onishi’s salary through the Centre for Research Excellence Award III (RE/18/5/34216). The BHF also provided funding towards establishment of the Edinburgh Preclinical PET/CT laboratory (RE/13/3/30183) and support of the 2018 Very Important Project (VIP) PET prize, for which we are grateful. Finally, we thank Dr Matthew Bennett (University of Edinburgh) for advice analysing RNA-seq data; Prof Robert Semple (University of Edinburgh) and Prof Ormond MacDougald (University of Michigan) for helpful advice to interpret our findings; Stefanie Fung (University of Edinburgh) for assistance isolating RNA for RNA-seq; Dr Hai-Bin Ruan (University of Minnesota Medical School) and Dr Eleonora Pagano (Pontifical Catholic University of Argentina) for kindly providing a full text of Ballor and Poehlman’s 1994 study (78), and all staff at Edinburgh Bioresearch & Veterinary Services for their superb technical support. Finally, this manuscript was written entirely by the authors and without any use of large language models. Publisher Copyright: © 2023, eLife Sciences Publications Ltd. All rights reserved.

PY - 2023/4/25

Y1 - 2023/4/25

N2 - 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) with18F-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.

AB - 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) with18F-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.

KW - adipose tissue

KW - ageing

KW - caloric restriction

KW - energy balance

KW - glucose homeostasis

KW - insulin sensitivity

KW - lipidomics

KW - liver metabolism

KW - PET/CT

KW - Sex differences

UR - http://www.scopus.com/inward/record.url?scp=85156227925&partnerID=8YFLogxK

U2 - 10.7554/eLife.88080

DO - 10.7554/eLife.88080

M3 - Article

C2 - 37096321

AN - SCOPUS:85156227925

SN - 2050-084X

VL - 12

JO - eLife

JF - eLife

M1 - e88080

ER -

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

Abstract

Bibliographical note

Keywords

Access to Document

Other files and links

Fingerprint

Human Nutrition Unit

Cite this

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

Abstract

Bibliographical note

Keywords

Access to Document

Other files and links

Fingerprint

Equipment

Human Nutrition Unit

Cite this