RNA sequencing reveals niche gene expression effects of beta-hydroxybutyrate in primary myotubes

Ruppert, Philip M.M.; Deng, Lie; Hooiveld, Guido; Hangelbroek, Roland W. J.; Zeigerer, Anja; Kersten, Sander

doi:10.26508/lsa.202101037

Cited by 5 publications

(3 citation statements)

References 77 publications

(112 reference statements)

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“…In the particular case of muscles, the ketone body β-hydroxybutyrate inhibits the loss of muscle by activating mTORC1 [ 11 ]. This finding coincides with transcriptomic signatures elicited by β-hydroxybutyrate specifically in myocytes [ 20 ].…”

Section: Introductionsupporting

confidence: 82%

Long-Term Fasting-Induced Ketosis in 1610 Subjects: Metabolic Regulation and Safety

Grundler,

Mesnage,

Ruppert

et al. 2024

Nutrients

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Background: There is a growing consensus that fasting-induced ketosis has beneficial effects on human physiology. Despite these compelling benefits, fasting-induced ketosis raises concerns in some clinicians because it is often inappropriately compared with the pathologic uncontrolled ketone production in diabetic ketoacidosis. The determinants of the inter-individual differences in the intensity of ketosis during long-term fasting is unknown. Methods: We monitored daily variations in fasting ketonemia, as well as ketonuria, which is less invasive, in a large cohort of 1610 subjects, fasting between 4 and 21 days with the Buchinger Wilhelmi program, minimally supplemented with ~75–250 kcal (daily fruit juice, vegetable soup, and honey). Results: Ketonuria was detected in more than 95% of fasting subjects from day 4 onwards. Subjects consuming only soups, without fruit juice or honey, exhibited reduced caloric intake (72 kcal instead of 236 kcal) and carbohydrate intake (15.6 g instead of 56.5 g), leading to more intense ketonuria. Participants with high ketonuria were, in the majority, males, young, had a higher body weight, and had lower HDL-C and urea values. They had a larger decrease in blood glucose, glycated haemoglobin levels, body weight, and waist circumference. Furthermore, in the high-ketonuria group, a larger increase in blood uric acid concentration was observed. Conclusion: Our study showed that long-term fasting triggered ketosis, never reaching pathological levels, and that ketosis is influenced by age, gender, health, and the level of physical activity. Furthermore, it is modulated but not suppressed by minimal carbohydrate intake. Our study paves the way for better understanding how supplementation can modulate the therapeutic effects and tolerability of long-term fasting.

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Section: Introductionsupporting

confidence: 82%

Long-Term Fasting-Induced Ketosis in 1610 Subjects: Metabolic Regulation and Safety

Grundler,

Mesnage,

Ruppert

et al. 2024

Nutrients

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“…Among the endogenous ketone bodies, βHB can act as an epigenetic regulator through the inhibition of histone deacetylases (HDACs) in the brain, which in turn increases the acetylation of histones occupying loci related to brain-derived neurotrophic factor (BDNF). Previous studies have presented similar results that βHB can act as an epigenetic regulator in various cell types (Dabek et al, 2020 ; Zhang et al, 2020 ; Ruppert et al, 2021 ). More specifically, βHB can modulate the expression of BDNF with histone modifications on several locations (Xie et al, 2016 ; Hu et al, 2020 ; Mierziak et al, 2021 ).…”

Section: Introductionsupporting

confidence: 57%

Environmental Enrichment and Estrogen Upregulate Beta-Hydroxybutyrate Underlying Functional Improvement

Pyo

Kim

Hwang

et al. 2022

Front. Mol. Neurosci.

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Environmental enrichment (EE) is a promising therapeutic strategy in improving metabolic and neuronal responses, especially due to its non-invasive nature. However, the exact mechanism underlying the sex-differential effects remains unclear. The aim of the current study was to investigate the effects of EE on metabolism, body composition, and behavioral phenotype based on sex. Long-term exposure to EE for 8 weeks induced metabolic changes and fat reduction. In response to the change in metabolism, the level of βHB were influenced by sex and EE possibly in accordance to the phases of estrogen cycle. The expression of β-hydroxybutyrate (βHB)-related genes and proteins such as monocarboxylate transporters, histone deacetylases (HDAC), and brain-derived neurotrophic factor (BDNF) were significantly regulated. In cerebral cortex and hippocampus, EE resulted in a significant increase in the level of βHB and a significant reduction in HDAC, consequently enhancing BDNF expression. Moreover, EE exerted significant effects on motor and cognitive behaviors, indicating a significant functional improvement in female mice under the condition that asserts the influence of estrogen cycle. Using an ovariectomized mice model, the effects of EE and estrogen treatment proved the hypothesis that EE upregulates β-hydroxybutyrate and BDNF underlying functional improvement in female mice. The above findings demonstrate that long-term exposure to EE can possibly alter metabolism by increasing the level of βHB, regulate the expression of βHB-related proteins, and improve behavioral function as reflected by motor and cognitive presentation following the changes in estrogen level. This finding may lead to a marked improvement in metabolism and neuroplasticity by EE and estrogen level.

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“…To our knowledge, no publications have investigated the in vitro transcriptomic effects of BHB on both neuronal and glial brain cells. Using RNA-seq, Ruppert et al analyzed the transcriptional changes induced by BHB and butyrate in various primary cell types, such as BMDMs 70 . During the experiments, a 5 mM salt form of R-BHB (Na-R-BHB) was used for six hours without any stimulation, such as LPS.…”

Section: Discussionmentioning

confidence: 99%

A ketogenic diet reduces age-induced chronic neuroinflammation in mice

Nomura,

Murad,

Madhavan

et al. 2023

Preprint

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Beta-hydroxybutyrate (BHB) is a ketone body synthesized during fasting or strenuous exercise. Our previous study demonstrated that a cyclic ketogenic diet (KD), which induces BHB levels similar to fasting every other week, reduces midlife mortality and improves memory in aging mice. BHB actively regulates gene expression and inflammatory activation through non-energetic signaling pathways. Neither of these activities has been well-characterized in the brain and they may represent mechanisms by which BHB affects brain function during aging. First, we analyzed hepatic gene expression in an aging KD-treated mouse cohort using bulk RNA-seq. In addition to the downregulation of TOR pathway activity, cyclic KD reduces inflammatory gene expression in the liver. We observed via flow cytometry that KD also modulates age-related systemic T cell functions. Next, we investigated whether BHB affects brain cells transcriptionallyin vitro. Gene expression analysis in primary human brain cells (microglia, astrocytes, neurons) using RNA-seq shows that BHB causes a mild level of inflammation in all three cell types. However, BHB inhibits the more pronounced LPS-induced inflammatory gene activation in microglia. Furthermore, we confirmed that BHB similarly reduces LPS-induced inflammation in primary mouse microglia and bone marrow-derived macrophages (BMDMs). BHB is recognized as an inhibitor of histone deacetylase (HDAC), an inhibitor of NLRP3 inflammasome, and an agonist of the GPCR Hcar2. Nevertheless, in microglia, BHB’s anti-inflammatory effects are independent of these known mechanisms. Finally, we examined the brain gene expression of 12-month-old male mice fed with one-week and one-year cyclic KD. While a one-week KD increases inflammatory signaling, a one-year cyclic KD reduces neuroinflammation induced by aging. In summary, our findings demon-strate that BHB mitigates the microglial response to inflammatory stimuli, like LPS, possibly leading to decreased chronic inflammation in the brain after long-term KD treatment in aging mice.

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RNA sequencing reveals niche gene expression effects of beta-hydroxybutyrate in primary myotubes

Cited by 5 publications

References 77 publications

Long-Term Fasting-Induced Ketosis in 1610 Subjects: Metabolic Regulation and Safety

Long-Term Fasting-Induced Ketosis in 1610 Subjects: Metabolic Regulation and Safety

Environmental Enrichment and Estrogen Upregulate Beta-Hydroxybutyrate Underlying Functional Improvement

A ketogenic diet reduces age-induced chronic neuroinflammation in mice

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