bims-kimdis 2022-08-28 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2022‒08‒28
nine papers selected by
Matías Javier Monsalves Álvarez

Ketogenic diet administration to mice after a high-fat-diet regimen promotes weight loss, glycemic normalization and induces adaptations of ketogenic pathways in liver and kidney.
β-Hydroxybutyrate and Medium-Chain Fatty Acids are Metabolized by Different Cell Types in Mouse Cerebral Cortex Slices.
Emerging roles of Sodium-glucose cotransporter 2 inhibitors in Diabetic kidney disease.
The role and mechanism of butyrate in the prevention and treatment of diabetic kidney disease.
The biological clock enhancer nobiletin ameliorates steatosis in obesity by restoring aberrant hepatic circadian rhythm.
The mitochondrial protein OPA1 regulates the quiescent state of adult muscle stem cells.
Fasting and Fasting Mimicking Diets in Obesity and Cardiometabolic Disease Prevention and Treatment.
Aerobic exercise training alleviates renal injury in db/db mice through inhibiting Nox4-mediated NLRP3 inflammasome activation.
Impairment of Mitochondrial Respiration in Metabolic Diseases: An Overview.

Mol Metab. 2022 Aug 19. pii: S2212-8778(22)00147-8. [Epub ahead of print] 101578

Ketogenic diet administration to mice after a high-fat-diet regimen promotes weight loss, glycemic normalization and induces adaptations of ketogenic pathways in liver and kidney.

Souad Nasser, Thomas Solé, Nathalie Vega, Thierry Thomas, Aneta Balcerczyk, Maura Strigini, Luciano Pirola.

  OBJECTIVE: The ketogenic diet (KD), characterized by very limited dietary carbohydrate intake and used as nutritional treatment for GLUT1-deficiency syndromes and pharmacologically refractory epilepsy, may promote weight loss and improve metabolic fitness, potentially alleviating the symptoms of osteoarthritis. Here, we have studied the effects of administration of a ketogenic diet in mice previously rendered obese by feeding a high fat diet (HFD) and submitted to surgical destabilization of the medial meniscus to mimic osteoarthritis.METHODS: 6-weeks old mice were fed an HFD for 10 weeks and then switched to a chow diet (CD), KD or maintained on a HFD for 8 weeks. Glycemia, β-hydroxybutyrate (BHB), body weight and fat mass were compared among groups. In liver and kidney, protein expression and histone post-translational modifications were assessed by Western blot, and gene expression by quantitative Real-Time PCR.
RESULTS: After a 10 weeks HDF feeding, administration for 8 weeks of a KD or CD induced a comparable weight loss and decrease in fat mass, with better glycemic normalization in the KD group. Histone β-hydroxybutyrylation, but not histone acetylation, was increased in the liver and kidney of mice fed the KD and the rate-limiting ketogenic enzyme HMGCS2 was upregulated - at the gene and protein level - in liver and, to an even greater extent, in kidney. KD-induced HMGCS2 overexpression may be dependent on FGF21, whose gene expression was increased by KD in liver.
CONCLUSIONS: Over a period of 8 weeks, KD is more effective than a chow diet to induce metabolic normalization. Besides acting as a fuel molecule, BHB may exert its metabolic effects through modulation of the epigenome - via histone β-hydroxybutyrylation - and extensive transcriptional modulation in liver and kidney.

Keywords:  HMGCS2; Ketogenesis; Ketogenic Diet; histone PTMs; β-hydroxybutyrate

DOI:  https://doi.org/10.1016/j.molmet.2022.101578
Neurochem Res. 2022 Aug 23.

β-Hydroxybutyrate and Medium-Chain Fatty Acids are Metabolized by Different Cell Types in Mouse Cerebral Cortex Slices.

Jens V Andersen, Emil W Westi, Elliott S Neal, Blanca I Aldana, Karin Borges.

  Ketogenic diets and medium-chain triglycerides are gaining attention as treatment of neurological disorders. Their major metabolites, β-hydroxybutyrate (βHB) and the medium-chain fatty acids (MCFAs) octanoic acid (C8) and decanoic acid (C10), are auxiliary brain fuels. To which extent these fuels compete for metabolism in different brain cell types is unknown. Here, we used acutely isolated mouse cerebral cortical slices to (1) compare metabolism of 200 µM [U-13C]C8, [U-13C]C10 and [U-13C]βHB and (2) assess potential competition between metabolism of βHB and MCFAs by quantifying metabolite 13C enrichment using gas chromatography-mass spectrometry (GC-MS) analysis. The 13C enrichment in most metabolites was similar with [U-13C]C8 and [U-13C]C10 as substrates, but several fold lower with [U-13C]βHB. The 13C enrichment in glutamate was in a similar range for all three substrates, whereas the 13C enrichments in citrate and glutamine were markedly higher with both [U-13C]C8 and [U-13C]C10 compared with [U-13C]βHB. As citrate and glutamine are indicators of astrocytic metabolism, the results indicate active MCFA metabolism in astrocytes, while βHB is metabolized in a different cellular compartment. In competition experiments, 12C-βHB altered 13C incorporation from [U-13C]C8 and [U-13C]C10 in only a few instances, while 12C-C8 and 12C-C10 only further decreased the low [U-13C]βHB-derived 13C incorporation into citrate and glutamine, signifying little competition for oxidative metabolism between βHB and the MCFAs. Overall, the data demonstrate that βHB and MCFAs are supplementary fuels in different cellular compartments in the brain without notable competition. Thus, the use of medium-chain triglycerides in ketogenic diets is likely to be beneficial in conditions with carbon and energy shortages in both astrocytes and neurons, such as GLUT1 deficiency.

Keywords:  Astrocytes; Decanoic acid; Epilepsy; Ketone bodies; MCFA; Octanoic acid

DOI:  https://doi.org/10.1007/s11064-022-03726-6
Mol Biol Rep. 2022 Aug 24.

Emerging roles of Sodium-glucose cotransporter 2 inhibitors in Diabetic kidney disease.

Tian Gan, Yi Song, Feng Guo, Guijun Qin.

  Diabetic kidney disease (DKD), a severe microvascular complication of diabetes mellitus, is the primary cause of end stage renal disease (ESRD). Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a class of novel anti-diabetic drugs for DKD, which have the potential to prevent renal function from failing. The involved mechanisms have garnered considerable attention. Besides hypoglycemic effect, it seems that various glucose-independent nephroprotective mechanisms also have a role. Among them, improvement in tubuloglomerular feedback is considered as the main reason, followed by reduced intraglomerular pressure and fluid load. In addition, reduced blood pressure, anti-inflammatory effects, nutrient deprivation signaling as well as improved endothelial function are also important. In the future, clinical trials and mechanistic studies might further complement the current knowledge on SGLT2 inhibitors and facilitate to translate these agents to clinical use. Here, we review these mechanisms of SGLT2 inhibitors with an emphasis on kidney protective effects.

Keywords:  Diabetes mellitus; Diabetic kidney disease; Sodium-glucose cotransporter 2 inhibitors

DOI:  https://doi.org/10.1007/s11033-022-07758-7
Front Microbiol. 2022 ;13 961536

The role and mechanism of butyrate in the prevention and treatment of diabetic kidney disease.

Xi Cheng, Tingting Zhou, Yanqiu He, Yumei Xie, Yong Xu, Wei Huang.

  Diabetic kidney disease (DKD) remains the leading cause of the end-stage renal disease and is a major burden on the healthcare system. The current understanding of the mechanisms responsible for the progression of DKD recognizes the involvement of oxidative stress, low-grade inflammation, and fibrosis. Several circulating metabolites that are the end products of the fermentation process, released by the gut microbiota, are known to be associated with systemic immune-inflammatory responses and kidney injury. This phenomenon has been recognized as the "gut-kidney axis." Butyrate is produced predominantly by gut microbiota fermentation of dietary fiber and undigested carbohydrates. In addition to its important role as a fuel for colonic epithelial cells, butyrate has been demonstrated to ameliorate obesity, diabetes, and kidney diseases via G-protein coupled receptors (GPCRs). It also acts as an epigenetic regulator by inhibiting histone deacetylase (HDAC), up-regulation of miRNAs, or induction of the histone butyrylation and autophagy processes. This review aims to outline the existing literature on the treatment of DKD by butyrate in animal models and cell culture experiments, and to explore the protective effects of butyrate on DKD and the underlying molecular mechanism.

Keywords:  butyrate; diabetic kidney disease; epigenetics; immune; inflammation

DOI:  https://doi.org/10.3389/fmicb.2022.961536
Am J Physiol Gastrointest Liver Physiol. 2022 Aug 23.

The biological clock enhancer nobiletin ameliorates steatosis in obesity by restoring aberrant hepatic circadian rhythm.

Sebastian Larion, Caleb A Padgett, Joshua T Butcher, James D Mintz, David J Fulton, David W Stepp.

  Non-alcoholic fatty liver disease (NAFLD) is associated with disruption of homeostatic lipid metabolism, but underlying processes are poorly understood. One possible mechanism is impairment in hepatic circadian rhythm, which regulates key lipogenic mediators in the liver and whose circadian oscillation is diminished in obesity. Nobiletin enhances biological rhythms by activating ROR nuclear receptor, protecting against metabolic syndrome in a clock-dependent manner. The effect of nobiletin in NAFLD is unclear. In this study, we investigate the clock-enhancing effects of nobiletin in genetically obese (db/db) PER2::LUCIFERASE reporter mice with fatty liver. We report microarray expression data suggesting hepatic circadian signaling is impaired in db/db mice with profound hepatic steatosis. Circadian PER2 activity, as assessed by mRNA and luciferase assay, was significantly diminished in liver of db/db PER2::LUCIFERASE reporter mice. Continuous animal monitoring systems and constant dark studies suggest the primary circadian defect in db/db mice lies within peripheral hepatic oscillators and not behavioral rhythms or the master clock. In vitro, nobiletin restored PER2 amplitude in lipid-laden PER2::LUCIFERASE reporter macrophages. In vivo, nobiletin dramatically upregulated core clock gene expression, hepatic PER2 activity, and ameliorated steatosis in db/db PER2::LUCIFERASE reporter mice. Mechanistically, nobiletin reduced serum insulin levels, decreased hepatic Srebp1c, Acaca1, Tnfα, and Fgf21 expression, but did not improve Plin2, Plin5, or Cpt1, suggesting nobiletin attenuates steatosis in db/db mice via downregulation of hepatic lipid accumulation. These data suggest restoring endogenous rhythm with nobiletin resolves steatosis in obesity, proposing that hypothesis that targeting the biological clock may be an attractive therapeutic strategy for NAFLD.

Keywords:  Circadian; NAFLD; clock; rhyhtm; steatosis

DOI:  https://doi.org/10.1152/ajpgi.00130.2022
Cell Stem Cell. 2022 Aug 19. pii: S1934-5909(22)00333-2. [Epub ahead of print]

The mitochondrial protein OPA1 regulates the quiescent state of adult muscle stem cells.

Nicole Baker, Steven Wade, Matthew Triolo, John Girgis, Damian Chwastek, Sarah Larrigan, Peter Feige, Ryo Fujita, Colin Crist, Michael A Rudnicki, Yan Burelle, Mireille Khacho.

  Quiescence regulation is essential for adult stem cell maintenance and sustained regeneration. Our studies uncovered that physiological changes in mitochondrial shape regulate the quiescent state of adult muscle stem cells (MuSCs). We show that MuSC mitochondria rapidly fragment upon an activation stimulus, via systemic HGF/mTOR, to drive the exit from deep quiescence. Deletion of the mitochondrial fusion protein OPA1 and mitochondrial fragmentation transitions MuSCs into G-alert quiescence, causing premature activation and depletion upon a stimulus. OPA1 loss activates a glutathione (GSH)-redox signaling pathway promoting cell-cycle progression, myogenic gene expression, and commitment. MuSCs with chronic OPA1 loss, leading to mitochondrial dysfunction, continue to reside in G-alert but acquire severe cell-cycle defects. Additionally, we provide evidence that OPA1 decline and impaired mitochondrial dynamics contribute to age-related MuSC dysfunction. These findings reveal a fundamental role for OPA1 and mitochondrial dynamics in establishing the quiescent state and activation potential of adult stem cells.

Keywords:  G-alert; GSH; OPA1; ROS; adult muscle stem cells; aging; glutathione; mTOR; mitochondrial dynamics; quiescence; reactive oxygen species; stem cell activation; stem cell maintenance; systemic factors

DOI:  https://doi.org/10.1016/j.stem.2022.07.010
Phys Med Rehabil Clin N Am. 2022 Aug;pii: S1047-9651(22)00039-0. [Epub ahead of print]33(3): 699-717

Fasting and Fasting Mimicking Diets in Obesity and Cardiometabolic Disease Prevention and Treatment.

Amrendra Mishra, Valter D Longo.

  Worldwide obesity has risen to record levels generating a major risk factor for metabolic syndrome, diabetes, hypertension, and cardiovascular disease as well as cancer and neurodegenerative diseases. Here we discuss the impact of obesity on lifespan and cardiometabolic disease in mice and humans and how different types of fasting can help prevent and treat them. We argue that specific types of fasting regimens which are associated with low burden, high long-term compliance and safety, can reduce obesity and other disease risk factors, lower morbidity and extend healthspan.

Keywords:  Cadiometabolic health; Fasting mimicking diet; Longevity; Obesity; Periodic fasting

DOI:  https://doi.org/10.1016/j.pmr.2022.04.009
Exp Gerontol. 2022 Aug 22. pii: S0531-5565(22)00242-X. [Epub ahead of print] 111934

Aerobic exercise training alleviates renal injury in db/db mice through inhibiting Nox4-mediated NLRP3 inflammasome activation.

Zhongyuan Zhou, Changjiang Ying, Xiaoyan Zhou, Yuanyuan Shi, Jian Xu, Yandong Zhu, Meng Wang, Yan Li, Xiaofei Li, Jie Xiang.

  Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease, with few therapeutic options available to slow its progression. Aerobic exercise training is an effective strategy for diabetes mellitus and its complications' prevention and treatment. The purpose of this study was to determine the effects of aerobic exercise training on diabetic kidney injury in db/db mice and to characterize the mechanism underlying the renal protective effects. The db/db mice were exercised 5 days a week for 60 min each day for 8 weeks at a speed of 5.6 m/min, after which renal function, morphology, oxidative stress, inflammation, fibrosis, and the expression of the Nox4/ROS/NF-κB/NLRP3 signaling pathway-related protein were assessed. Our results showed that aerobic exercise training significantly reduced body weight and microalbuminuria, improved renal function, and attenuated renal pathological changes in db/db mice independent of hyperglycemic state. Aerobic exercise training was also found to significantly improve oxidative stress and inflammation in the kidneys of db/db mice by decreasing the activity of complex I, the levels of MDA, 8-OHdG, Nox4, ROS, TNF-α, MCP-1, IL-6, and IL-18, increasing the activities of SOD and GSH-Px, the expression of klotho and NPHS2, and decreasing the phosphorylation of NF-κB p65 and IκBα, as well as the expression of NLRP3, ASC, caspase-1 p20, and IL-1β. Additionally, aerobic exercise training decreased TGF-β, collagen I, collagen IV, and α-SMA expression, thereby slowing the progression of kidney fibrosis in db/db mice. In conclusion, aerobic exercise training effectively reduces oxidative stress, inflammation, and renal fibrosis by modulating the Nox4/ROS/NF-κB/NLRP3 signaling pathway, implying that aerobic exercise training has significant potential to protect diabetic kidney injury and should be given more emphasis in DKD treatment.

Keywords:  Aerobic exercise training; Diabetic kidney disease; Fibrosis; NLRP3 inflammasome; Nox4; Oxidative stress

DOI:  https://doi.org/10.1016/j.exger.2022.111934
Int J Mol Sci. 2022 Aug 09. pii: 8852. [Epub ahead of print]23(16):

Impairment of Mitochondrial Respiration in Metabolic Diseases: An Overview.

Vlad Florian Avram, Adrian Petru Merce, Iasmina Maria Hâncu, Alina Doruța Bătrân, Gabrielle Kennedy, Mariana Georgeta Rosca, Danina Mirela Muntean.

  Mitochondrial dysfunction has emerged as a central pathomechanism in the setting of obesity and diabetes mellitus, linking these intertwined pathologies that share insulin resistance as a common denominator. High-resolution respirometry (HRR) is a state-of-the-art research method currently used to study mitochondrial respiration and its impairment in health and disease. Tissue samples, cells or isolated mitochondria are exposed to various substrate-uncoupler-inhibitor-titration protocols, which allows the measurement and calculation of several parameters of mitochondrial respiration. In this review, we discuss the alterations of mitochondrial bioenergetics in the main dysfunctional organs that contribute to the development of the obese and diabetic phenotypes in both animal models and human subjects. Herein we review data regarding the impairment of oxidative phosphorylation as integrated mitochondrial function assessed by means of HRR. We acknowledge the critical role of this method in determining the alterations in oxidative phosphorylation occurring in the early stages of metabolic pathologies. We conclude that there is a mutual two-way relationship between mitochondrial dysfunction and insulin insensitivity that characterizes these diseases.

Keywords:  diabetes mellitus; high-resolution respirometry; insulin resistance; mitochondrial respiration; obesity

DOI:  https://doi.org/10.3390/ijms23168852