Intrinsic cardiorespiratory fitness modulates clinical and molecular response to caloric restriction

Johanna Y Fleischman; Nathan R Qi; Mary K Treutelaar; Steven L Britton; Lauren G Koch; Jun Z Li; Charles F Burant

doi:10.1016/j.molmet.2023.101668

Intrinsic cardiorespiratory fitness modulates clinical and molecular response to caloric restriction

Mol Metab. 2023 Feb:68:101668. doi: 10.1016/j.molmet.2023.101668. Epub 2023 Jan 12.

Authors

Johanna Y Fleischman¹, Nathan R Qi², Mary K Treutelaar³, Steven L Britton⁴, Lauren G Koch⁵, Jun Z Li⁶, Charles F Burant⁷

Affiliations

¹ Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
² Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Michigan Mouse Metabolic Phenotyping Center, University of Michigan, Ann Arbor, MI, USA.
³ Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
⁴ Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA; Department of Anesthesiology, University of Michigan, Ann Arbor, MI, USA.
⁵ Department of Physiology and Pharmacology, The University of Toledo, Toledo, OH, USA.
⁶ Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
⁷ Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA. Electronic address: [email protected].

Abstract

Objective: Caloric restriction (CR) is one extrinsic intervention that can improve metabolic health, and it shares many phenotypical parallels with intrinsic high cardiorespiratory fitness (CRF), including reduced adiposity, increased cardiometabolic health, and increased longevity. CRF is a highly heritable trait in humans and has been established in a genetic rat model selectively bred for high (HCR) and low (LCR) CRF, in which the HCR live longer and have reduced body weight compared to LCR. This study addresses whether the inherited high CRF phenotype occurs through similar mechanisms by which CR promotes health and longevity.

Methods: We compared HCR and LCR male rats fed ad libitum (AL) or calorically restricted (CR) for multiple physiological, metabolic, and molecular traits, including running capacity at 2, 8, and 12 months; per-hour metabolic cage activity over daily cycles at 6 and 12 months; and plasma lipidomics, liver and muscle transcriptomics, and body composition after 12 months of treatment.

Results: LCR-CR developed a physiological profile that mirrors the high-CRF phenotype in HCR-AL, including reduced adiposity and increased insulin sensitivity. HCR show higher spontaneous activity than LCR. Temporal modeling of hourly energy expenditure (EE) dynamics during the day, adjusted for body weight and hourly activity levels, suggest that CR has an EE-suppressing effect, and high-CRF has an EE-enhancing effect. Pathway analysis of gene transcripts indicates that HCR and LCR both show a response to CR that is similar in the muscle and different in the liver.

Conclusions: CR provides LCR a health-associated positive effect on physiological parameters that strongly resemble HCR. Analysis of whole-body EE and transcriptomics suggests that HCR and LCR show line-dependent responses to CR that may be accreditable to difference in genetic makeup. The results do not preclude the possibility that CRF and CR pathways may converge.

Keywords: Caloric restriction; Cardiorespiratory fitness; Metabolism; Mitochondria; Muscle.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Body Weight
Caloric Restriction
Cardiorespiratory Fitness*
Humans
Male
Obesity / metabolism
Rats
Running* / physiology

Abstract

Publication types

MeSH terms

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