bims-kimdis 2022-08-21 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2022–08–21
sixteen papers selected by
Matías Javier Monsalves Álvarez, Universidad de O’Higgins

Investigating effects of sodium beta-hydroxybutyrate on metabolism in placebo-controlled, bilaterally infused human leg with focus on skeletal muscle protein dynamics.
The ketogenic diet prevents steatosis and insulin resistance by reducing lipogenesis, diacylglycerol accummulation, and PKC activity in male rat liver.
Acetate, a gut bacterial product, ameliorates ischemia-reperfusion induced acute lung injury in rats.
Exercise training enhances muscle mitochondrial metabolism in diet-resistant obesity.
Butyrate-Producing Bacteria and Insulin Homeostasis: The Microbiome and Insulin Longitudinal Evaluation Study (MILES).
Metabolic changes in aging humans: current evidence and therapeutic strategies.
Fatty acids produced by the gut microbiota dampen host inflammatory responses by modulating intestinal SUMOylation.
Regular exercise combined with ferulic acid exhibits antiobesity effect and regulates metabolic profiles in high-fat diet-induced mice.
Mechanisms of cardio-renal protection of sodium-glucose cotransporter-2 inhibitors.
ER stress and inflammation crosstalk in obesity.
Quantifying the inflammatory secretome of human intermuscular adipose tissue.
Effects of lifelong spontaneous exercise on skeletal muscle and angiogenesis in super-aged mice.
The physiology of experimental overfeeding in animals.
The NLRP3 inflammasome contributes to inflammation-induced morphological and metabolic alterations in skeletal muscle.
The janus face of ketone bodies in hypertension.
Calorie Restriction Enhanced Glycogen Metabolism to Compensate for Lipid Insufficiency.

Physiol Rep. 2022 Aug;10(16): e15399

Investigating effects of sodium beta-hydroxybutyrate on metabolism in placebo-controlled, bilaterally infused human leg with focus on skeletal muscle protein dynamics.

Henrik Holm Thomsen, Jonas Franck Olesen, Rasmus Aagaard, Bent Roni Ranghøj Nielsen, Thomas Schmidt Voss, Mads Vandsted Svart, Mogens Johannsen, Niels Jessen, Jens Otto L Jørgensen, Nikolaj Rittig, Ermina Bach, Niels Møller.

  Systemic administration of beta-hydroxybutyrate (BHB) decreases whole-body protein oxidation and muscle protein breakdown in humans. We aimed to determine any direct effect of BHB on skeletal muscle protein turnover when administered locally in the femoral artery. Paired design with each subject being investigated on one single occasion with one leg being infused with BHB and the opposing leg acting as a control. We studied 10 healthy male volunteers once with bilateral femoral vein and artery catheters. One artery was perfused with saline (Placebo) and one with sodium-BHB. Labelled phenylalanine and palmitate were used to assess local leg fluxes. Femoral vein concentrations of BHB were significantly higher in the intervention leg (3.4 (3.2, 3.6) mM) compared with the placebo-controlled leg (1.9 (1.8, 2.1) mM) with a peak difference of 1.4 (1.1, 1.7) mM, p < 0.0005. Net loss of phenylalanine for BHB vs Placebo -6.7(-10.8, -2.7) nmol/min vs -8.7(-13.8, -3.7) nmol/min, p = 0.52. Palmitate flux and arterio-venous difference of glucose did not differ between legs. Under these experimental conditions, we failed to observe the direct effects of BHB on skeletal muscle protein turnover. This may relate to a combination of high concentrations of BHB (close to 2 mM) imposed systemically by spillover leading to high BHB concentrations in the saline-infused leg and a lack of major differences in concentration gradients between the two sides-implying that observations were made on the upper part of the dose-response curve for BHB and the relatively small number of subjects studied.

Keywords:  amino acid tracer; beta-hydroxybutyrate; ketone bodies; ketosis; perfused leg

DOI:  https://doi.org/10.14814/phy2.15399
J Physiol. 2022 Aug 16.

The ketogenic diet prevents steatosis and insulin resistance by reducing lipogenesis, diacylglycerol accummulation, and PKC activity in male rat liver.

Shailee Jani, Daniel Da Eira, Mateja Stefanovic, Rolando B Ceddia.

   KEY POINTS: The accumulation of diacylglycerol (DAG), ceramides and inflammation are key factors that cause insulin resistance and nonalcoholic fatty liver (NAFLD). This study provides evidence that a ketogenic diet (KD) rich in fat and devoid of carbohydrate reduced DAG content and preserved insulin signalling in the liver. The KD shifted metabolism away from lipogenesis by enhancing genes involved in mitochondrial biogenesis and fatty acid oxidations in the liver. The KD also promoted the production of beneficial very long-chain ceramides instead of potentially harmful long-chain ceramides. Through multiple mechanisms, the KD exerted anti-steatogenic and insulin-sensitizing effects in the liver, which supports the use of this dietary intervention to treat NAFLD.
ABSTRACT: Obesity-associated insulin resistance plays a major role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). The accumulation of diacylglycerol (DAG), ceramides and inflammation are key factors that cause NAFLD. In recent years, the ketogenic diet (KD) has emerged as an effective non-pharmacological intervention for the treatment of NAFLD and other obesity-related metabolic disorders. What remains undetermined is how the KD affects DAG and ceramides content and insulin sensitivity in the liver. Thus, this research was designed to assess these variables, as well as glucose and fat metabolism and markers of inflammation in livers of rats exposed for 8 weeks to one of the following diets: standard chow (SC), obesogenic high-fat, sucrose-enriched diet (HFS), or a KD. Despite having a higher fat content than the HFS diet, the KD did not cause steatosis and preserved hepatic insulin signalling. The KD reduced DAG content and protein kinase C epsilon (PKCε) activity, but markedly increased liver ceramides content. However, whereas the KD increased ceramide synthase 2 (CerS2) expression, it suppressed CerS6 expression, an effect that promoted the production of beneficial very long-chain ceramides instead of harmful long-chain ceramides. The KD also enhanced the liver expression of key genes involved in mitochondrial biogenesis and fatty acid oxidation (Pgc-1α and Fgf21), suppressed inflammatory genes (Tnfα, Nf-kb, Tlr4, and Il6), and shifted substrate away from de-novo lipogenesis. Thus, through multiple mechanisms the KD exerted anti-steatogenic and insulin-sensitizing effects in the liver, which supports the use of this dietary intervention to treat NAFLD. Abstract figure legend This article is protected by copyright. All rights reserved.

Keywords:  AKT; NAFLD; TAG; ceramides; glycogen; obesity; type 2 diabetes

DOI:  https://doi.org/10.1113/JP283552
Int Immunopharmacol. 2022 Aug 11. pii: S1567-5769(22)00620-8. [Epub ahead of print]111 109136

Acetate, a gut bacterial product, ameliorates ischemia-reperfusion induced acute lung injury in rats.

Kuei-Yi Hung, Shu-Yu Wu, Hsin-Ping Pao, Wen-I Liao, Shi-Jye Chu.

  Recent data suggest that short-chain fatty acids (SCFAs), the major fermentation product from gut microbial degradation of dietary fiber, have protective effects against renal ischemia-reperfusion (IR) injury, colitis, and allergic asthma. However, the effect of SCFAs on acute lung injury (ALI) caused by IR is still unclear. In this study, we examine whether SCFAs have protective effects against IR-induced ALI and explore possible protective mechanisms. IR-induced ALI was established by 40 min ischemia followed by 60 min reperfusion in isolated perfused rat lungs. Rats were randomly assigned to one of six groups: control, control + acetate (400 mg/kg), IR, and IR + acetate at one of three dosages (100, 200, 400 mg/kg). Bronchoalveolar lavage fluids (BALF) and lung tissues were obtained and analyzed at the end of the experiment. In vitro, mouse lung epithelial cells (MLE-12) subjected to hypoxia-reoxygenation (HR) were pretreated with acetate (25 mmol/L) and GPR41 or GPR43 siRNA. Acetate decreased lung weight gain, lung weight/body weight ratios, wet/dry weight ratios, pulmonary artery pressure, and protein concentration of the BALF in a dose-dependent manner for IR-induced ALI. Acetate also significantly inhibited the production of TNF-α, IL-6 and CINC-1 in the BALF. Moreover, acetate treatment restored suppressed IκB-α levels and reduced nuclear NF-κB p65 levels in lung tissues. In addition, acetate mitigated IR-induced apoptosis and tight junction disruption in injured lung tissue. In vitro analyses showed that acetate attenuated NF-κB activation and KC/CXCL-1 levels in MLE-12 cells exposed to HR. The protective effects of acetate in vitro were significantly abrogated by GPR41 or GPR43 siRNA. Acetate ameliorates IR-induced acute lung inflammation and its protective mechanism appears to be via the GPR41/43 signaling pathway. Based on our findings, acetate may provide a novel adjuvant therapeutic approach for IR-induced lung injury.

Keywords:  Acetate; Acute lung injury; Ischemia-reperfusion; Microbiota; Short-chain fatty acids

DOI:  https://doi.org/10.1016/j.intimp.2022.109136
EBioMedicine. 2022 Aug 01. pii: S2352-3964(22)00373-5. [Epub ahead of print] 104192

Exercise training enhances muscle mitochondrial metabolism in diet-resistant obesity.

Chantal A Pileggi, Denis P Blondin, Breana G Hooks, Gaganvir Parmar, Irina Alecu, David A Patten, Alexanne Cuillerier, Conor O'Dwyer, A Brianne Thrush, Morgan D Fullerton, Steffany Al Bennett, Éric Doucet, François Haman, Miroslava Cuperlovic-Culf, Ruth McPherson, Robert R M Dent, Mary-Ellen Harper.

   BACKGROUND: Current paradigms for predicting weight loss in response to energy restriction have general validity but a subset of individuals fail to respond adequately despite documented diet adherence. Patients in the bottom 20% for rate of weight loss following a hypocaloric diet (diet-resistant) have been found to have less type I muscle fibres and lower skeletal muscle mitochondrial function, leading to the hypothesis that physical exercise may be an effective treatment when diet alone is inadequate. In this study, we aimed to assess the efficacy of exercise training on mitochondrial function in women with obesity with a documented history of minimal diet-induced weight loss.
METHODS: From over 5000 patient records, 228 files were reviewed to identify baseline characteristics of weight loss response from women with obesity who were previously classified in the top or bottom 20% quintiles based on rate of weight loss in the first 6 weeks during which a 900 kcal/day meal replacement was consumed. A subset of 20 women with obesity were identified based on diet-resistance (n=10) and diet sensitivity (n=10) to undergo a 6-week supervised, progressive, combined aerobic and resistance exercise intervention.
FINDINGS: Diet-sensitive women had lower baseline adiposity, higher fasting insulin and triglycerides, and a greater number of ATP-III criteria for metabolic syndrome. Conversely in diet-resistant women, the exercise intervention improved body composition, skeletal muscle mitochondrial content and metabolism, with minimal effects in diet-sensitive women. In-depth analyses of muscle metabolomes revealed distinct group- and intervention- differences, including lower serine-associated sphingolipid synthesis in diet-resistant women following exercise training.
INTERPRETATION: Exercise preferentially enhances skeletal muscle metabolism and improves body composition in women with a history of minimal diet-induced weight loss. These clinical and metabolic mechanism insights move the field towards better personalised approaches for the treatment of distinct obesity phenotypes.
FUNDING: Canadian Institutes of Health Research (CIHR-INMD and FDN-143278; CAN-163902; CIHR PJT-148634).

Keywords:  Exercise; Metabolomics; Mitochondria; Mitochondrial supercomplexes; Muscle physiology; Obesity; Serine; Sphingolipids; Uncoupling; Weight loss

DOI:  https://doi.org/10.1016/j.ebiom.2022.104192
Diabetes. 2022 Aug 12. pii: db220168. [Epub ahead of print]

Butyrate-Producing Bacteria and Insulin Homeostasis: The Microbiome and Insulin Longitudinal Evaluation Study (MILES).

Jinrui Cui, Gautam Ramesh, Martin Wu, Elizabeth T Jensen, Osa Crago, Alain G Bertoni, Chunxu Gao, Kristi L Hoffman, Patricia A Sheridan, Kari E Wong, Alexis C Wood, Yii-Der I Chen, Jerome I Rotter, Joseph F Petrosino, Stephen S Rich, Mark O Goodarzi.

Gut microbiome studies have documented depletion of butyrate-producing taxa in type 2 diabetes. We analyzed associations between butyrate-producing taxa and detailed measures of insulin homeostasis whose dysfunction underlies diabetes in 224 non-Hispanic Whites and 129 African Americans, all of whom completed an oral glucose tolerance test. Stool microbiome was assessed by whole metagenome shotgun sequencing with taxonomic profiling. We examined associations between 36 butyrate-producing taxa (7 genera, 29 species) and insulin sensitivity, insulin secretion, disposition index, insulin clearance, and prevalence of dysglycemia (prediabetes plus diabetes, 46% of cohort), adjusting for age, sex, body mass index, and race. Genus Coprococcus was associated with higher insulin sensitivity (β=0.14, P=0.002) and disposition index (β=0.12, P=0.012) and a lower rate of dysglycemia (odds ratio 0.91, 95% confidence interval (CI) 0.85-0.97, P=0.0025); in contrast, Flavonifractor was associated with lower insulin sensitivity (β=-0.13, P=0.004) and disposition index (β=-0.11, P=0.04) and higher prevalence of dysglycemia (OR 1.22, 95% CI 1.08-1.38, P=0.0013). Species-level analyses found 10 bacteria associated with beneficial directions of effects and two bacteria with adverse associations on insulin homeostasis and dysglycemia. While most butyrate-producers analyzed appear to be metabolically beneficial, this is not the case for all such bacteria, suggesting that microbiome-directed therapeutic measures to prevent or treat diabetes should be targeted to specific butyrate-producing taxa rather than all butyrate producers.

DOI: https://doi.org/10.2337/db22-0168
J Clin Invest. 2022 Aug 15. pii: e158451. [Epub ahead of print]132(16):

Metabolic changes in aging humans: current evidence and therapeutic strategies.

Allyson K Palmer, Michael D Jensen.

Aging and metabolism are inextricably linked, and many age-related changes in body composition, including increased central adiposity and sarcopenia, have underpinnings in fundamental aging processes. These age-related changes are further exacerbated by a sedentary lifestyle and can be in part prevented by maintenance of activity with aging. Here we explore the age-related changes seen in individual metabolic tissues - adipose, muscle, and liver - as well as globally in older adults. We also discuss the available evidence for therapeutic interventions such as caloric restriction, resistance training, and senolytic and senomorphic drugs to maintain healthy metabolism with aging, focusing on data from human studies.

DOI: https://doi.org/10.1172/JCI158451
Gut Microbes. 2022 Jan-Dec;14(1):14(1): 2108280

Fatty acids produced by the gut microbiota dampen host inflammatory responses by modulating intestinal SUMOylation.

Chaima Ezzine, Léa Loison, Nadine Montbrion, Christine Bôle-Feysot, Pierre Déchelotte, Moïse Coëffier, David Ribet.

  The gut microbiota produces a wide variety of metabolites, which interact with intestinal cells and contribute to host physiology. The effect of gut commensal bacteria on host protein SUMOylation, an essential ubiquitin-like modification involved in various intestinal functions, remains, however, unknown. Here, we show that short chain fatty acids (SCFAs) and branched chain fatty acids (BCFAs) produced by the gut microbiota increase protein SUMOylation in intestinal cells in a pH-dependent manner. We demonstrate that these metabolites inactivate intestinal deSUMOylases and promote the hyperSUMOylation of nuclear matrix-associated proteins. We further show that BCFAs inhibit the NF-κB pathway, decrease pro-inflammatory cytokine expression, and promote intestinal epithelial integrity. Together, our results reveal that fatty acids produced by gut commensal bacteria regulate intestinal physiology by modulating SUMOylation and illustrate a new mechanism of dampening of host inflammatory responses triggered by the gut microbiota.

Keywords:  Branched Chain Fatty Acids (BCFAs); Gut microbiota; Inflammation; Microbiota; SUMOylation; Short Chain Fatty Acids (SCFAs); Ubiquitin-like proteins; host-bacteria interactions; intestinal inflammation; post-translational modifications

DOI:  https://doi.org/10.1080/19490976.2022.2108280
Front Nutr. 2022 ;9 957321

Regular exercise combined with ferulic acid exhibits antiobesity effect and regulates metabolic profiles in high-fat diet-induced mice.

Ou Wang, Nanhai Zhang, Chao Han, Jian Huang.

  Exercise (Ex) has been recognized as an effective way of obesity prevention, but it shows a dual effect on the body's antioxidant system. Ferulic acid (FA) is a kind of phenolic acid with well-known antioxidant capacity and numerous health benefits. Therefore, the aim of the study was to compare the antiobesity effect of Ex, FA, and Ex combined with FA (Ex-FA) in vivo and to illustrate the potential mechanisms. Mice were fed a high-fat diet (HFD) with or without administration of Ex, FA, and Ex-FA for 13 weeks. The body weight, antioxidant ability, Ex performance, and lipid profiles in the serum, liver, and skeletal muscle were compared among the groups, and serum metabolomics analysis was conducted. The results showed that Ex, FA, and Ex-FA exhibited a similar effect on body weight management. Ex had a more beneficial function by alleviating HFD-induced dyslipidemia than FA, while FA exerted a more efficient effect in mitigating lipid deposition in the liver and skeletal muscle. Ex-FA showed comprehensive effects in the regulation of the lipid contents in serum, liver, and skeletal muscle, and provoked enhancement effects on antioxidant ability and Ex capacity. Mice administered with Ex, FA, and Ex-FA showed different metabolic profiles, which might be achieved through different metabolic pathways. The findings of this research implied that Ex coupled with FA could become an effective and safe remedy for the management of dietary-induced obesity.

Keywords:  exercise; ferulic acid; lipid metabolism; metabolic profiles; obesity; oxidative stress

DOI:  https://doi.org/10.3389/fnut.2022.957321
Curr Opin Pharmacol. 2022 Aug 11. pii: S1471-4892(22)00099-6. [Epub ahead of print]66 102272

Mechanisms of cardio-renal protection of sodium-glucose cotransporter-2 inhibitors.

Martina Chiriacò, Domenico Tricò, Anna Solini.

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are glucose-lowering drugs used in the treatment of type 2 diabetes (T2D) that have shown additional cardiac and renal benefits. The mechanisms of SGLT2i-mediated cardiorenal protection include blood pressure lowering and endothelial function improvements, enhancement of cardiac and renal hemodynamics, optimization of energetic efficiency through metabolic changes and cellular ion exchanges, reduction of inflammation and oxidative stress with consequent fibrosis reduction, and sympathetic activity modulation. This review explores the most recent data regarding the physiological mechanisms of SGLT2i cardiac and renal benefits, which lie at the root of the solid clinical evidence on cardiorenal protection, making SGLT2i a promising new pharmacological approach to the treatment of patients at high risk of cardiorenal syndrome.

DOI: https://doi.org/10.1016/j.coph.2022.102272
Med Res Rev. 2022 Aug 17.

ER stress and inflammation crosstalk in obesity.

Amir Ajoolabady, Cynthia Lebeaupin, Ne N Wu, Randal J Kaufman, Jun Ren.

  The endoplasmic reticulum (ER) governs the proper folding of polypeptides and proteins through various chaperones and enzymes residing within the ER organelle. Perturbation in the ER folding process ensues when overwhelmed protein folding exceeds the ER handling capacity, leading to the accumulation of misfolded/unfolded proteins in the ER lumen-a state being referred to as ER stress. In turn, ER stress induces a gamut of signaling cascades, termed as the "unfolded protein response" (UPR) that reinstates the ER homeostasis through a panel of gene expression modulation. This type of UPR is usually deemed "adaptive UPR." However, persistent or unresolved ER stress hyperactivates UPR response, which ultimately, triggers cell death and inflammatory pathways, termed as "maladaptive/terminal UPR." A plethora of evidence indicates that crosstalks between ER stress (maladaptive UPR) and inflammation precipitate obesity pathogenesis. In this regard, the acquisition of the mechanisms linking ER stress to inflammation in obesity might unveil potential remedies to tackle this pathological condition. Herein, we aim to elucidate key mechanisms of ER stress-induced inflammation in the context of obesity and summarize potential therapeutic strategies in the management of obesity through maneuvering ER stress and ER stress-associated inflammation.

Keywords:  ER stress; adipocytes; inflammation; insulin resistance; obesity

DOI:  https://doi.org/10.1002/med.21921
Physiol Rep. 2022 Aug;10(16): e15424

Quantifying the inflammatory secretome of human intermuscular adipose tissue.

Darcy Kahn, Emily Macias, Simona Zarini, Amanda Garfield, Karin Zemski Berry, Robert Gerszten, Jonathan Schoen, Melanie Cree-Green, Bryan C Bergman.

  Adipose tissue secretes an abundance of lipid and protein mediators, and this secretome is depot-specific, with local and systemic effects on metabolic regulation. Intermuscular adipose tissue (IMAT) accumulates within the skeletal muscle compartment in obesity, and is associated with insulin resistance and metabolic disease. While the human IMAT secretome decreases insulin sensitivity in vitro, its composition is entirely unknown. The current study was conducted to investigate the composition of the human IMAT secretome, compared to that of the subcutaneous (SAT) and visceral adipose tissue (VAT) depots. IMAT, SAT, and VAT explants from individuals with obesity were used to generate conditioned media. Proteomics analysis of conditioned media was performed using multiplex proximity extension assays, and eicosanoid analysis using liquid chromatography-tandem mass spectrometry. Compared to SAT and/or VAT, IMAT secreted significantly more cytokines (IL2, IL5, IL10, IL13, IL27, FGF23, IFNγ and CSF1) and chemokines (MCP1, IL8, CCL11, CCL20, CCL25 and CCL27). Adipokines hepatocyte growth factor and resistin were secreted significantly more by IMAT than SAT or VAT. IMAT secreted significantly more eicosanoids (PGE2, TXB2 , 5-HETE, and 12-HETE) compared to SAT and/or VAT. In the context of obesity, IMAT is a distinct adipose tissue with a highly immunogenic and inflammatory secretome, and given its proximity to skeletal muscle, may be critical to glucose regulation and insulin resistance.

Keywords:  IMAT; conditioned media; inflammation; insulin sensitivity; paracrine signaling

DOI:  https://doi.org/10.14814/phy2.15424
PLoS One. 2022 ;17(8): e0263457

Effects of lifelong spontaneous exercise on skeletal muscle and angiogenesis in super-aged mice.

Kyung-Wan Baek, So-Jeong Kim, Bo-Gyu Kim, Youn-Kwan Jung, Young-Sool Hah, Hyo Youl Moon, Jun-Il Yoo, Jin Sung Park, Ji-Seok Kim.

There has been an increasing awareness of sarcopenia, which is characterized by a concomitant decrease in skeletal muscle mass and quality due to aging. Resistance exercise is considered more effective than aerobic exercise in terms of therapeutic exercise. To confirm the effect of long-term aerobic exercise in preventing sarcopenia, we evaluated the skeletal muscle mass, quality, and angiogenic capacity of super-aged mice that had undergone lifelong spontaneous exercise (LSE) through various experiments. Our findings show that LSE could maintain skeletal muscle mass, quality, and fitness levels in super-aged mice. In addition, ex vivo experiments showed that the angiogenic capacity was maintained at a high level. However, these results were not consistent with the related changes in the expression of genes and/or proteins involved in protein synthesis or angiogenesis. Based on the results of previous studies, it seems certain that the expression at the molecular level does not represent the phenotypes of skeletal muscle and angiogenesis. This is because aging and long-term exercise are variables that can affect both protein synthesis and the expression patterns of angiogenesis-related genes and proteins. Therefore, in aging and exercise-related research, various physical fitness and angiogenesis variables and phenotypes should be analyzed. In conclusion, LSE appears to maintain the potential of angiogenesis and slow the aging process to maintain skeletal muscle mass and quality. Aerobic exercise may thus be effective for the prevention of sarcopenia.

DOI: https://doi.org/10.1371/journal.pone.0263457
Mol Metab. 2022 Aug 12. pii: S2212-8778(22)00142-9. [Epub ahead of print] 101573

The physiology of experimental overfeeding in animals.

Pablo Ranea-Robles, Jens Lund, Christoffer Clemmensen.

   BACKGROUND: Body weight is defended by strong homeostatic forces. Several of the key biological mechanisms that counteract weight loss have been unraveled over the last decades. In contrast, the mechanisms that protect body weight and fat mass from becoming too high remain largely unknown. Understanding this aspect of energy balance regulation holds great promise for curbing the obesity epidemic. Decoding the physiological and molecular pathways that defend against weight gain can be achieved by an intervention referred to as "experimental overfeeding".
SCOPE OF THE REVIEW: In this review, we define experimental overfeeding and summarize the studies that have been conducted on animals. This field of research shows that experimental overfeeding induces a potent and prolonged hypophagic response that seems to be conserved across species and mediated by unidentified endocrine factors. In addition, the literature shows that experimental overfeeding can be used to model the development of non-alcoholic steatohepatitis and that forced intragastric infusion of surplus calories lowers survival from infections. Finally, we highlight studies indicating that experimental overfeeding can be employed to study the transgenerational effects of a positive energy balance and how dietary composition and macronutrient content might impact energy homeostasis and obesity development in animals.
MAJOR CONCLUSIONS: Experimental overfeeding of animals is a powerful yet underappreciated method to investigate the defense mechanisms against weight gain. This intervention also represents an alternative approach for studying the pathophysiology of metabolic liver diseases and the links between energy balance and infection biology. Future research in this field could help uncover why humans respond differently to an obesogenic environment and reveal novel pathways with therapeutic potential against obesity and cardiometabolic disorders.

Keywords:  Animal models; Body weight; Energy balance; Experimental Overfeeding; Intragastric overfeeding; Leptin; NASH; Obesity

DOI:  https://doi.org/10.1016/j.molmet.2022.101573
J Cachexia Sarcopenia Muscle. 2022 Aug 17.

The NLRP3 inflammasome contributes to inflammation-induced morphological and metabolic alterations in skeletal muscle.

Moritz Eggelbusch, Andi Shi, Bonnie C Broeksma, Mariana Vázquez-Cruz, Madu N Soares, Gerard M J de Wit, Bart Everts, Richard T Jaspers, Rob C I Wüst.

   BACKGROUND: Systemic inflammation is associated with skeletal muscle atrophy and metabolic dysfunction. Although the nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome contributes to cytokine production in immune cells, its role in skeletal muscle is poorly understood. Here, we studied the link between inflammation, NLRP3, muscle morphology, and metabolism in in vitro cultured C2C12 myotubes, independent of immune cell involvement.
METHODS: Differentiated C2C12 myotubes were treated with lipopolysaccharide (LPS; 0, 10, and 100-200 ng/mL) to induce activation of the NLRP3 inflammasome with and without MCC950, a pharmacological inhibitor of NLRP3-induced IL-1β production. We assessed markers of the NLRP3 inflammasome, cell diameter, reactive oxygen species, and mitochondrial function.
RESULTS: NLRP3 gene expression and protein concentrations increased in a time-dependent and dose-dependent manner. Intracellular IL-1β concentration significantly increased (P < 0.0001), but significantly less with MCC950 (P = 0.03), suggestive of moderate activation of the NLRP3 inflammasome in cultured myotubes upon LPS stimulation. LPS suppressed myotube growth after 24 h (P = 0.03), and myotubes remained smaller up to 72 h (P = 0.0009). Exposure of myotubes to IL-1β caused similar alterations in cell morphology, and MCC950 mitigated these LPS-induced differences in cell diameter. NLRP3 appeared to co-localize with mitochondria, more so upon exposure to LPS. Mitochondrial reactive oxygen species were higher after LPS (P = 0.03), but not after addition of MCC950. Myotubes had higher glycolytic rates, and mitochondria were more fragmented upon LPS exposure, which was not altered by MCC950 supplementation.
CONCLUSIONS: LPS-induced activation of the NLRP3 inflammasome in cultured myotubes contributes to morphological and metabolic alterations, likely due to its mitochondrial association.

Keywords:  Metabolism; Morphology; NLRP3 inflammasome; Skeletal muscle; Systemic inflammation

DOI:  https://doi.org/10.1002/jcsm.13062
J Hypertens. 2022 Aug 09.

The janus face of ketone bodies in hypertension.

Tiago J Costa, Braxton A Linder, Seth Hester, Milene Fontes, Laena Pernomian, Camilla F Wenceslau, Austin T Robinson, Cameron G McCarthy.

Hypertension is the most important risk factor for the development of terminal cardiovascular diseases, such as heart failure, chronic kidney disease, and atherosclerosis. Lifestyle interventions to lower blood pressure are generally desirable prior to initiating pharmaceutical drug treatments, which may have undesirable side effects. Ketogenic interventions are popular but the scientific literature supporting their efficacy is specific to certain interventions and outcomes in animal models and patient populations. For example, although caloric restriction has its own inherent difficulties (e.g. it requires high levels of motivation and adherence is difficult), it has unequivocally been associated with lowering blood pressure in hypertensive patients. On the other hand, the antihypertensive efficacy of ketogenic diets is inconclusive, and this is surprising, given that these diets have been largely helpful in mitigating metabolic syndrome and promoting longevity. It is possible that side effects associated with ketogenic diets (e.g. dyslipidemia) aggravate the hypertensive phenotype. However, given the recent data from our group, and others, reporting that the most abundant ketone body, β-hydroxybutyrate, can have positive effects on endothelial and vascular health, there is hope that ketone bodies can be harnessed as a therapeutic strategy to combat hypertension. Therefore, we conclude this review with a summary of the type and efficacy of ketone supplements. We propose that ketone supplements warrant investigation as low-dose antihypertensive therapy that decreases total peripheral resistance with minimal adverse side effects. Graphical abstract:http://links.lww.com/HJH/C54.

DOI: https://doi.org/10.1097/HJH.0000000000003243
Mol Nutr Food Res. 2022 Aug 16. e2200182

Calorie Restriction Enhanced Glycogen Metabolism to Compensate for Lipid Insufficiency.

Lili Hu, Xinyi Xia, Yue Zong, Yunjie Gu, Li Wei, Jun Yin.

   SCOPE: This study aimed to investigate the metabolic phenotype and mechanism of 40% calorie restriction (CR) in mice.
METHODS AND RESULTS: CR mice exhibited super-stable blood glucose, as evidenced by increased fasting blood glucose (FBG), decreased postprandial blood glucose, and reduced glucose fluctuations. Additionally, both fasting plasma insulin and the homeostasis model assessment of insulin resistance increased significantly in CR mice. Compared with control, the phosphorylation of insulin receptor substrates-1 and serine/threonine kinase decreased in liver and fat but increased in muscle of CR mice after insulin administration, indicating hepatic and adipose insulin resistance, and muscle insulin sensitization. CR reduced visceral fat much more than subcutaneous fat. The elevated FBG was negatively correlated with low-level fasting β-hydroxybutyrate, which may result from insufficient free fatty acids and diminished ketogenic ability in CR mice. Furthermore, liver glycogen increased dramatically in CR mice. Analysis of glycogen metabolism related proteins indicated active glycogen synthesis and decomposition. Additionally, CR elevated plasma corticosterone and hypothalamic orexigenic gene expression.
CONCLUSION: CR induced lipid insufficiency and stress, resulting in global physiological insulin resistance except muscle and enhanced glycogen metabolism, culminating in the stability of blood glucose manifested in increased FBG, which compensated for insufficient blood ketones. This article is protected by copyright. All rights reserved.

Keywords:  GSK3β; HOMA-IR; hunger; ketogenesis; starvation

DOI:  https://doi.org/10.1002/mnfr.202200182