bims-kimdis 2023-10-22 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2023–10–22
ten papers selected by
Matías Javier Monsalves Álvarez, Universidad de O’Higgins

Ketogenic propensity is differentially related to lipid-induced hepatic and peripheral insulin resistance.
Metabolic shift toward ketosis in asocial cavefish increases social-like affinity.
The impact of prolonged fasting on 24h energy metabolism and its 24h rhythmicity in healthy, lean males: A randomized cross-over trial.
NLRP3 inflammasome in hepatic diseases: A pharmacological target.
A low-carbohydrate diet with different fatty acids' sources in the treatment of obesity: Impact on insulin resistance and adipogenesis.
NLRP3-inflammasome inhibition by MCC950 attenuates cardiac and pulmonary artery remodelling in heart failure with preserved ejection fraction.
Editorial: Mitochondrial dysfunction in inflammation and autoimmunity.
Mechanism of Skeletal Muscle Atrophy by Muscle Fiber Types in Male Rats under Long-term Fasting Stress.
Roles of NAD+ in Health and Aging.
Monitoring metabolic changes during the menstrual cycle.

Acta Physiol (Oxf). 2023 Oct 16. e14054

Ketogenic propensity is differentially related to lipid-induced hepatic and peripheral insulin resistance.

J T Mey, B Vandagmansar, W S Dantas, K P Belmont, C L Axelrod, J P Kirwan.

   AIM: Determine the ketogenic response (β-hydroxybutyrate, a surrogate of hepatic ketogenesis) to a controlled lipid overload in humans.
METHODS: In total, nineteen young, healthy adults (age: 28.4 ± 1.7 years; BMI: 22.7 ± 0.3 kg/m2 ) received either a 12 h overnight lipid infusion or saline in a randomized, crossover design. Plasma ketones and inflammatory markers were quantified by colorimetric and multiplex assays. Hepatic and peripheral insulin sensitivity was assessed by the hyperinsulinemic-euglycemic clamp. Skeletal muscle biopsies were obtained to quantify gene expression related to ketone body metabolism and inflammation.
RESULTS: By design, the lipid overload-induced hepatic (50%, p < 0.001) and peripheral insulin resistance (73%, p < 0.01) in healthy adults. Ketones increased with hyperlipidemia and were subsequently reduced with hyperinsulinemia during the clamp procedure (Saline: Basal = 0.22 mM, Insulin = 0.07 mM; Lipid: Basal = 0.78 mM, Insulin = 0.51 mM; 2-way ANOVA: Lipid p < 0.001, Insulin p < 0.001, Interaction p = 0.07). In the saline control condition, ketones did not correlate with hepatic or peripheral insulin sensitivity. Conversely, in the lipid condition, ketones were positively correlated with hepatic insulin sensitivity (r = 0.59, p < 0.01), but inversely related to peripheral insulin sensitivity (r = -0.64, p < 0.01). Hyperlipidemia increased plasma inflammatory markers, but did not impact skeletal muscle inflammatory gene expression. Gene expression related to ketone and fatty acid metabolism in skeletal muscle increased in response to hyperlipidemia.
CONCLUSION: This work provides important insight into the role of ketones in human health and suggests that ketone body metabolism is altered at the onset of lipid-induced insulin resistance.

Keywords:  diabetes; free fatty acids; ketogenesis; metabolic disease; obesity; β-hydroxybutyrate

DOI:  https://doi.org/10.1111/apha.14054
BMC Biol. 2023 Oct 16. 21(1): 219

Metabolic shift toward ketosis in asocial cavefish increases social-like affinity.

Motoko Iwashita, Amity Tran, Marianne Garcia, Jia Cashon, Devanne Burbano, Vanessa Salgado, Malia Hasegawa, Rhoada Balmilero-Unciano, Kaylah Politan, Miki Wong, Ryan W Y Lee, Masato Yoshizawa.

   BACKGROUND: Social affinity and collective behavior are nearly ubiquitous in the animal kingdom, but many lineages feature evolutionarily asocial species. These solitary species may have evolved to conserve energy in food-sparse environments. However, the mechanism by which metabolic shifts regulate social affinity is not well investigated.
RESULTS: In this study, we used the Mexican tetra (Astyanax mexicanus), which features riverine sighted surface (surface fish) and cave-dwelling populations (cavefish), to address the impact of metabolic shifts on asociality and other cave-associated behaviors in cavefish, including repetitive turning, sleeplessness, swimming longer distances, and enhanced foraging behavior. After 1 month of ketosis-inducing ketogenic diet feeding, asocial cavefish exhibited significantly higher social affinity, whereas social affinity regressed in cavefish fed the standard diet. The ketogenic diet also reduced repetitive turning and swimming in cavefish. No major behavioral shifts were found regarding sleeplessness and foraging behavior, suggesting that other evolved behaviors are not largely regulated by ketosis. We further examined the effects of the ketogenic diet via supplementation with exogenous ketone bodies, revealing that ketone bodies are pivotal molecules positively associated with social affinity.
CONCLUSIONS: Our study indicated that fish that evolved to be asocial remain capable of exhibiting social affinity under ketosis, possibly linking the seasonal food availability and sociality.

Keywords:  Asociality; Cavefish; Fasting; Glycolysis; Ketone; Ketosis; Starvation

DOI:  https://doi.org/10.1186/s12915-023-01725-9
Clin Nutr. 2023 Oct 12. pii: S0261-5614(23)00328-X. [Epub ahead of print]42(12): 2353-2362

The impact of prolonged fasting on 24h energy metabolism and its 24h rhythmicity in healthy, lean males: A randomized cross-over trial.

Charlotte Andriessen, Daniel Doligkeit, Esther Moonen-Kornips, Marco Mensink, Matthijs K C Hesselink, Joris Hoeks, Patrick Schrauwen.

   OBJECTIVE: Human energy expenditure and substrate oxidation are under circadian control and food intake is a time cue for the human biological clock, leading to 24h feeding-fasting cycles in energy and substrate metabolism. In recent years, (intermittent) fasting protocols have also become popular to improve metabolic health. Here, we aimed to investigate the impact of food intake on the 24h patterns of energy metabolism as well as to provide data on the timeline of changes in energy metabolism that occur upon an extended period of fasting.
RESEARCH DESIGN AND METHODS: In a randomized, cross-over design, twelve healthy males underwent a 60h fast which was compared to a 60h fed condition. In the fed condition meals were provided at energy balance throughout the study. Conditions were separated by a two week period of habitual diet. Volunteers resided in a respiration chamber for the entire 60h to measure energy expenditure and substrate oxidation hour by hour. Volunteers performed a standardized activity protocol while in the chamber. Blood samples were drawn after 12, 36 and 60h.
RESULTS: Immediately following the breakfast meal (in the fed condition), fat oxidation became higher in the fasted condition compared to the fed condition and remained elevated throughout the study period. The initial rapid increase in fat oxidation corresponded with a decline in the hepatokine activin A (r = -0.86, p = 0.001). The contribution of fat oxidation to total energy expenditure gradually increased with extended abstinence from food, peaking after 51h of fasting at 160 mg/min. Carbohydrate oxidation stabilized at a low level during the second day of fasting and averaged around 60 mg/min with only modest elevations in response to physical activity. Although 24h energy expenditure was significantly lower with prolonged fasting (11.0 ± 0.4 vs 9.8 ± 0.2 and 10.9 ± 0.3 vs 10.3 ± 0.3 MJ in fed vs fasting, day 2 and 3 respectively, p < 0.01), the 24h fluctuations in energy expenditure were comparable between the fasted and fed condition. The fluctuations in substrate oxidation were, however, significantly (p < 0.001 for both carbohydrate and fat oxidation) altered in the fasted state, favouring fat oxidation.
CONCLUSIONS: Energy expenditure displays a day-night rhythm, which is independent of food intake. In contrast, the day-night rhythm of both carbohydrate and fat oxidation is mainly driven by food intake. Upon extended fasting, the absolute rate of fat oxidation rapidly increases and keeps increasing during a 60h fast, whereas carbohydrate oxidation becomes progressively diminished.
TRIAL REGISTRATION: www.trialregister.nl NTR 2042.

Keywords:  Circadian rhythm; Energy metabolism; Fasting; Human(s); Substrate oxidation

DOI:  https://doi.org/10.1016/j.clnu.2023.10.010
Biochem Pharmacol. 2023 Oct 18. pii: S0006-2952(23)00452-5. [Epub ahead of print] 115861

NLRP3 inflammasome in hepatic diseases: A pharmacological target.

Erika Ramos-Tovar, Pablo Muriel.

  The NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome pathway is mainly responsible for the activation and release of a cascade of proinflammatory mediators that contribute to the development of hepatic diseases. During alcoholic liver disease development, the NLRP3 inflammasome pathway contributes to the maturation of caspase-1, interleukin (IL)-1β, and IL-18, which induce a robust inflammatory response, leading to fibrosis by inducing profibrogenic hepatic stellate cell (HSC) activation. Substantial evidence demonstrates that nonalcoholic fatty liver disease (NAFLD) progresses to nonalcoholic steatohepatitis (NASH) via NLRP3 inflammasome activation, ultimately leading to fibrosis and hepatocellular carcinoma (HCC). Activation of the NLRP3 inflammasome in NASH can be attributed to several factors, such as reactive oxygen species (ROS), gut dysbiosis, leaky gut, which allow triggers such as cardiolipin, cholesterol crystals, endoplasmic reticulum stress, and uric acid to reach the liver. Because inflammation triggers HSC activation, the NLRP3 inflammasome pathway performs a central function in fibrogenesis regardless of the etiology. Chronic hepatic activation of the NLRP3 inflammasome can ultimately lead to HCC; however, inflammation also plays a role in decreasing tumor growth. Some data indicate that NLRP3 inflammasome activation plays an important role in autoimmune hepatitis, but the evidence is scarce. Most researchers have reported that NLRP3 inflammasome activation is essential in liver injury induced by a variety of drugs and hepatotropic virus infection; however, few reports indicate that this pathway can play a beneficial role by inducing liver regeneration. Modulation of the NLRP3 inflammasome appears to be a suitable strategy to treat liver diseases.

Keywords:  Alcoholic liver disease; Cirrhosis; Fibrosis; Hepatocellular carcinoma; Inflammation; Non-alcoholic steatohepatitis

DOI:  https://doi.org/10.1016/j.bcp.2023.115861
Clin Nutr. 2023 Oct 10. pii: S0261-5614(23)00313-8. [Epub ahead of print]42(12): 2381-2394

A low-carbohydrate diet with different fatty acids' sources in the treatment of obesity: Impact on insulin resistance and adipogenesis.

Aline B Santamarina, Laís V Mennitti, Esther A de Souza, Leonardo M de Souza Mesquita, Isaú H Noronha, José Ronnie C Vasconcelos, Carla M Prado, Luciana P Pisani.

   BACKGROUND: The search for nutritional intervention strategies against obesity has grown, highlighting the low-carbohydrate diet model. However, little is known about the impact of the quality of fatty acids consumed in this diet. Thus, we aim to investigate the influence of fatty acid quality on dietary strategy on obesity.
METHODS: Male Swiss mice were diet-induced to obesity. Afterward, mice consume a low-carb diet with different types of fat: saturated, polyunsaturated ω-3, ω-6, and monounsaturated ω-9 fatty acids. Weight gain and food consumption were monitored weekly. An oral glucose tolerance test was performed and blood and tissue samples were collected for analysis of insulin resistance markers. Protein expression of insulin signaling pathway molecules, lipid metabolism, mitochondrial function, macrophage polarization, and cytokine production were analyzed.
RESULTS: The high-fat diet was able to induce obesity and glucose intolerance. The switch to a low-carbohydrate dietary pattern reversed the glucose intolerance, with better results in the ω-3 and ω-9 groups. After the low-carbohydrate diet, groups ω-3 and ω-9 presented improved fasting serum glucose, insulin, and HOMA indexes. The low-carbohydrate diet also increased the activity of insulin pathway proteins such as IR, IRS1, and AKT. Furthermore, the ω-3 diet group showed greater activity of mitochondrial complexes and AMPK signaling pathway proteins. The ω-6 and ω-9 -rich diet induced M2-type macrophage polarization, as well as cytokine production modulation by the low-carbohydrate diet in the ω-3 and ω-9 groups.
CONCLUSIONS: Consuming a low-carbohydrate diet pattern promotes weight loss and improves glucose intolerance in obesity. Also, the quality of lipids has a direct influence, demonstrating that the consumption of ω-3 polyunsaturated and ω-9 monounsaturated lipids can lead to more favorable outcomes for the improvement of glucose intolerance, lipid metabolism, and anti-inflammatory effects.

Keywords:  Fatty acids; Inflammation; Insulin resistance; Lipid metabolism; Low-carbohydrate diet; Obesity

DOI:  https://doi.org/10.1016/j.clnu.2023.09.024
Life Sci. 2023 Oct 17. pii: S0024-3205(23)00820-2. [Epub ahead of print]333 122185

NLRP3-inflammasome inhibition by MCC950 attenuates cardiac and pulmonary artery remodelling in heart failure with preserved ejection fraction.

Xiaocheng Cheng, Hanru Zhao, Xuesong Wen, Guoxing Li, Shuliang Guo, Dongying Zhang.

   AIMS: The purpose of this study was to evaluate the role of the NLRP3-inflammasome in heart failure with preserved ejection fraction (HFpEF).
MAIN METHODS: Serum inflammatory cytokines were detected in patients with heart failure. Correlation analysis was performed to investigate the relationship between serum inflammatory cytokines and left ventricular diastolic function. A 'two-hit' (metabolic stress and mechanical stress) mouse model of HFpEF was established. Furthermore, MCC950 was used to determine the role of NLRP3-inflammasome inhibition in cardiac and pulmonary artery remodelling in HFpEF mice.
KEY FINDINGS: Compared with heart failure patients with reduced ejection fraction, patients with HFpEF have significantly elevated serum inflammatory cytokine levels. Serum NLRP3 and interleukin-1β levels were positively correlated with the diastolic function of HFpEF. In the HFpEF mouse model, the inhibition of the NLRP3-inflammasome by MCC950 improved exercise intolerance, glucose intolerance, and left ventricular diastolic function, but had no significant effect on systolic function. Meanwhile, MCC950 attenuated the release of inflammatory cytokines, cardiomyocyte hypertrophy and cardiac fibrosis. Mechanistically, the potential protective effects of MCC950 are achieved by inhibiting activation of the NLRP3-IL-1β pathway and cascade expansion of downstream inflammatory cytokines. Additionally, the inhibition of NLRP3-inflammasome by MCC950 reduced pulmonary artery pressure and improved pulmonary artery remodelling in HFpEF.
SIGNIFICANCE: The NLRP3-inflammasome plays a considerable role in inflammation and cardiac and pulmonary artery remodelling in HFpEF by activating the cascade reaction of inflammatory cytokines. This study is the first to comprehensively elucidate the role of the NLRP3-inflammasome in HFpEF, and will provide reference for future study.

Keywords:  Cardiac remodelling; HFpEF; NLRP3; Pulmonary artery

DOI:  https://doi.org/10.1016/j.lfs.2023.122185
Front Immunol. 2023 ;14 1304315

Editorial: Mitochondrial dysfunction in inflammation and autoimmunity.

Jens Staal, Luz Pamela Blanco, Andras Perl.



Keywords:  DAMP (damage-associated molecular pattern); ROS - reactive oxygen species; autoimmune diseases; ferroptosis; inflammation; interferonopathy; metabolism; mitochondria

DOI:  https://doi.org/10.3389/fimmu.2023.1304315
Steroids. 2023 Oct 18. pii: S0039-128X(23)00156-3. [Epub ahead of print] 109328

Mechanism of Skeletal Muscle Atrophy by Muscle Fiber Types in Male Rats under Long-term Fasting Stress.

Takahiro Ieko, Jumpei Fujiki, Yasuhiro Hasegawa, Tomohito Iwasaki, Hidetomo Iwano, Naoyuki Maeda.

  Fasting induces metabolic changes in muscles, which are differentiated by muscle fiber type. In this study, the mechanism of fasting-induced muscle atrophy in rats was examined to determine the differences between muscle fiber types in energy production. Fasting for 96 h did not alter the weight of the soleus (SOL), a fiber type I muscle, but did significantly reduce the weight of gastrocnemius (GM), a fiber type II muscle. GM, SOL and blood pregnenolone and testosterone levels decreased under fasting, which induced energy deprivation, whereas corticosterone (CORT) levels significantly increased. However, the expression of 3β-HSD and P45011β in GM was unaffected by fasting. The decrease in GM weight may be due to decreased levels of testosterone and reduced synthesis of mammalian target of rapamycin (mTOR). Significant increases in CORT both GM and SOL were associated with increases in the amount of branched-chain amino acids available for energy production. However, decreased levels of mTOR and IGF1 and increased levels of CORT and IL-6 in SOL suggest that GM proteolysis was followed by SOL proteolysis for additional energy production. In conclusion, IGF1 levels decreased significantly in SOL, whereas those of IL-6 significantly increased in SOL and blood but decreased in GM. Blood branched-chain amino acids (BCAA) levels were unaffected due to fasting, whereas an increase was noted in the levels of BCAA in GM and SOL. These results show that fasting for 96 h restricts energy supply, producing fast-twitch muscle atrophy followed by slow-twitch muscle atrophy.

Keywords:  and fasting stress; branched-chain amino acids; corticosterone; interleukin-6; mammalian target of rapamycin

DOI:  https://doi.org/10.1016/j.steroids.2023.109328
Cold Spring Harb Perspect Med. 2023 Oct 17. pii: a041193. [Epub ahead of print]

Roles of NAD+ in Health and Aging.

Sofie Lautrup, Yujun Hou, Evandro F Fang, Vilhelm A Bohr.

NAD+, the essential metabolite involved in multiple reactions such as the regulation of cellular metabolism, energy production, DNA repair, mitophagy and autophagy, inflammation, and neuronal function, has been the subject of intense research in the field of aging and disease over the last decade. NAD+ levels decline with aging and in some age-related diseases, and reduction in NAD+ affects all the hallmarks of aging. Here, we present an overview of the discovery of NAD+, the cellular pathways of producing and consuming NAD+, and discuss how imbalances in the production rate and cellular request of NAD+ likely contribute to aging and age-related diseases including neurodegeneration. Preclinical studies have revealed great potential for NAD+ precursors in promotion of healthy aging and improvement of neurodegeneration. This has led to the initiation of several clinical trials with NAD+ precursors to treat accelerated aging, age-associated dysfunctions, and diseases including Alzheimer's and Parkinson's. NAD supplementation has great future potential clinically, and these studies will also provide insight into the mechanisms of aging.

DOI: https://doi.org/10.1101/cshperspect.a041193
Nat Med. 2023 Oct 17.

Monitoring metabolic changes during the menstrual cycle.

Sonia Muliyil.



Keywords:  Brain; Metabolism

DOI:  https://doi.org/10.1038/d41591-023-00090-y