Ketogenic diet with aerobic exercise can induce fat browning: potential roles of β-hydroxybutyrate

Sujin Kim; Dong-Ho Park; Sohee Moon; Bonsang Gu; Keren Esther Kristina Mantik; Hyo-Bum Kwak; Ji-Kan Ryu; Ju-Hee Kang

doi:10.3389/fnut.2024.1443483

Ketogenic diet with aerobic exercise can induce fat browning: potential roles of β-hydroxybutyrate

Front Nutr. 2024 Aug 29:11:1443483. doi: 10.3389/fnut.2024.1443483. eCollection 2024.

Authors

Sujin Kim^#^{1

2}, Dong-Ho Park^#^{3

4}, Sohee Moon^{1

2}, Bonsang Gu^{1

2

3}, Keren Esther Kristina Mantik^{1

2

3}, Hyo-Bum Kwak^{3

4}, Ji-Kan Ryu^{2

3

5}, Ju-Hee Kang^{1

2

3}

Affiliations

¹ Department of Pharmacology, College of Medicine, Inha University, Incheon, Republic of Korea.
² Research Center for Controlling Intercellular Communication, College of Medicine, Inha University, Incheon, Republic of Korea.
³ Program in Biomedical Science and Engineering, Inha University, Incheon, Republic of Korea.
⁴ Department of Kinesiology, Inha University, Incheon, Republic of Korea.
⁵ Department of Urology, College of Medicine, Inha University, Incheon, Republic of Korea.

^# Contributed equally.

Abstract

Introduction: Despite evidence suggesting that metabolic intermediates like β-HB influence white adipose tissue (WAT) metabolism, the precise molecular mechanisms remain unclear. The aim of this study was to investigate the impact of beta-hydroxybutyrate (β-HB) on the fat browning program and to explore the underlying molecular mechanisms using both in vitro and in vivo models. We assessed the effects of β-HB on fat browning in adipocytes using 3T3-L1 cells and rat models.

Methods: We evaluated the effects of β-HB on fat browning, thermogenesis, lipid accumulation, adipokine expression, and mitochondrial biogenesis by treating mature 3T3-L1 adipocytes with sodium β-HB for 24 h or by continuously exposing preadipocytes to β-HB during the 8-day differentiation process. Male Sprague Dawley rats were divided into control, exercise only (EX), ketogenic diet only (KD), and combined exercise and ketogenic diet (KE) groups for an 8-week intervention involving diet and/or exercise. After intervention, we evaluated WAT histology, plasma lipids and adipokines, and the expression of markers related to fat browning, thermogenesis and mitochondrial biogenesis in WAT of rats.

Results: In our adipocyte culture experiments, β-HB reduced intracellular lipid accumulation by enhancing lipolysis and stimulated the expression of thermogenic and fat browning genes like uncoupling protein 1 (UCP1), PR domain containing 16 (PRDM16), and adipokines such as fibroblast growth factor 21 (FGF21) and Fibronectin type III domain-containing protein 5 (FDNC5). Additionally, β-HB activated the AMPK-SIRT1-PGC-1α pathway, with UCP1 and PRDM16 upregulation mediated by β-HB intracellular action and SIRT1 activity. In animal experiments, KE group raised β-HB levels, decreasing body weight and blood lipids. KD with EX promoted WAT browning possibly via AMPK-SIRT1-PGC-1α, augmenting PRDM16, UCP1, FGF21, and FNDC5 expression.

Conclusion: β-HB induction via KD and/or EX shows potential in promoting WAT browning by activating mitochondrial biogenesis, lipolysis, and thermogenesis, suggesting that dietary and physical intervention inducing β-HB may benefit metabolic health.

Keywords: adipokine; beta-hydroxybutyrate; exercise; fat browning; ketogenic diet; mitochondrial biogenesis.

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This work was supported by the Medical Research Center Program (2021R1A5A2031612), Basic Research Program (2017R1D1A1B03032860 and 2020R1F1A1073415) and Mid-Career Research Program (2018R1A2A3074577 and 2023R1A2C1004370) through the National Research Foundation of Korea (NRF) funded by the Korean government, and the NRF funded by the Ministry of Education, Republic of Korea (2022S1A5C2A03092407 and 2020S1A5B5A17089784).