bims-kimdis Biomed News
on Ketones, inflammation and mitochondria in disease
Issue of 2024–11–10
nine papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello
  1. Targeting the NLRP3 inflammasome-IL-1β pathway in type 2 diabetes and obesity.
  2. Analysis of mitochondrial biogenesis regulation by oxidative stress.
  3. Impaired suppression of fatty acid release by insulin is a strong predictor of reduced whole-body insulin-mediated glucose uptake and skeletal muscle insulin receptor activation.
  4. Cardiovascular handgrip responses during treadmill exercise: randomized pilot trial.
  5. Leptin in humans: Evidence from clinical studies and current and future clinical applications.
  6. Methods to analyze the mitochondrial unfolded protein response (UPRmt).
  7. Heart failure with preserved ejection fraction and the first law of thermodynamics.
  8. Division of labour: mitochondria split to meet energy demands.
  9. Molecular mechanism of skeletal muscle loss and its prevention by natural resources.
  1. Diabetologia. 2024 Nov 04.
    Targeting the NLRP3 inflammasome-IL-1β pathway in type 2 diabetes and obesity.
    Daniel T Meier, Joyce de Paula Souza, Marc Y Donath.
      Increased activity of the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome-IL-1β pathway is observed in obesity and contributes to the development of type 2 diabetes and its complications. In this review, we describe the pathological activation of IL-1β by metabolic stress, ageing and the microbiome and present data on the role of IL-1β in metabolism. We explore the physiological role of the IL-1β pathway in insulin secretion and the relationship between circulating levels of IL-1β and the development of diabetes and associated diseases. We highlight the paradoxical nature of IL-1β as both a friend and a foe in glucose regulation and provide details on clinical translation, including the glucose-lowering effects of IL-1 antagonism and its impact on disease modification. We also discuss the potential role of IL-1β in obesity, Alzheimer's disease, fatigue, gonadal dysfunction and related disorders such as rheumatoid arthritis and gout. Finally, we address the safety of NLRP3 inhibition and IL-1 antagonists and the prospect of using this therapeutic approach for the treatment of type 2 diabetes and its comorbidities.
    Keywords:  Clinical study; Diabetes; IL-1β; Inflammasome; Inflammation; Insulin; NLRP3; Obesity; Pancreatic islet; Review
    DOI:  https://doi.org/10.1007/s00125-024-06306-1
  2. Methods Enzymol. 2024 ;pii: S0076-6879(24)00405-1. [Epub ahead of print]707 519-539
    Analysis of mitochondrial biogenesis regulation by oxidative stress.
    Dheeraj Pathak, Thanuja Krishnamoorthy, Naresh Babu V Sepuri.
      Of all the causes of metabolic and neurological disorders, oxidative stress distinguishes itself by its sweeping effect on the dynamic cellular redox homeostasis and, in its wake, exposing the vulnerabilities of the protein machinery of the cell. High levels of Reactive Oxygen Species (ROS) that mitochondria produce during ATP synthesis can damage mtDNA, lipids, and essential mitochondrial proteins. ROS majorly oxidizes cysteine and methionine amino acids in peptides, which can lead to protein unfolding or misfolding of proteins, which ultimately can have a toll on their function. As mitochondrial biogenesis relies on the continuous import of nuclear-encoded proteins into mitochondria mediated by mitochondrial protein import complexes, oxidative stress triggered by mitochondria can rapidly and detrimentally affect mitochondrial biogenesis and homeostasis. Functional Mge1 is a homodimer and acts as a cochaperone and a nucleotide exchange factor of mitochondrial heat shock protein 70 (mHsp70), crucial for mitochondrial protein import. Oxidative stress like ROS, oxidizes Met 155 in Mge1, compromising its ability to dimerize and interact with mHsp70. The cell employs Methionine sulphoxide reductase 2 (Mxr2), a member of the methionine sulphoxide reductase family, to reduce oxidized Met 155 and thereby restore the essential function of Mge1. Oxidation of methionine as a regulated post-translational modification has been gaining traction. Future high throughput studies that can scan the entire mitochondrial proteome to interrogate methionine oxidation and reversal may increase the repertoire of mitochondrial proteins undergoing regulated oxidation and reduction. In this chapter, we describe the methods followed in our laboratory to study the oxidation of Mge1 and its reduction by Mxr2 in vitro.
    Keywords:  Cross linking; Methionine oxidation; Methionine sulfoixde reductase 2; Mge1; Mitochondria; Reactive Oxygen Species
    DOI:  https://doi.org/10.1016/bs.mie.2024.07.060
  3. Acta Physiol (Oxf). 2024 Nov 01. e14249
    Impaired suppression of fatty acid release by insulin is a strong predictor of reduced whole-body insulin-mediated glucose uptake and skeletal muscle insulin receptor activation.
    Michael W Schleh, Benjamin J Ryan, Cheehoon Ahn, Alison C Ludzki, Douglas W Van Pelt, Lisa M Pitchford, Olivia K Chugh, Austin T Luker, Kathryn E Luker, Dmitri Samovski, Nada A Abumrad, Charles F Burant, Jeffrey F Horowitz.
       AIM: To examine factors underlying why most, but not all, adults with obesity exhibit impaired insulin-mediated glucose uptake, we compared: (1) adipose tissue fatty acid (FA) release, (2) skeletal muscle lipid droplet (LD) characteristics, and (3) insulin signalling events, in skeletal muscle of adults with obesity with relatively high versus low insulin-mediated glucose uptake.
    METHODS: Seventeen adults with obesity (BMI: 36 ± 3 kg/m2) completed a 2 h hyperinsulinemic-euglycemic clamp with stable isotope tracer infusions to measure glucose rate of disappearance (glucose Rd) and FA rate of appearance (FA Ra). Skeletal muscle biopsies were collected at baseline and 30 min into the insulin infusion. Participants were stratified into HIGH (n = 7) and LOW (n = 10) insulin sensitivity cohorts by their glucose Rd during the hyperinsulinemic clamp (LOW< 400; HIGH >550 nmol/kgFFM/min/[μU/mL]).
    RESULTS: Insulin-mediated suppression of FA Ra was lower in LOW compared with HIGH (p < 0.01). In skeletal muscle, total intramyocellular lipid content did not differ between cohorts. However, the size of LDs in the subsarcolemmal region (SS) of type II muscle fibres was larger in LOW compared with HIGH (p = 0.01). Additionally, insulin receptor-β (IRβ) interactions with regulatory proteins CD36 and Fyn were lower in LOW versus HIGH (p < 0.01), which aligned with attenuated insulin-mediated Tyr phosphorylation of IRβ and downstream insulin-signalling proteins in LOW.
    CONCLUSION: Collectively, reduced ability for insulin to suppress FA mobilization, with accompanying modifications in intramyocellular LD size and distribution, and diminished IRβ interaction with key regulatory proteins may be key contributors to impaired insulin-mediated glucose uptake commonly found in adults with obesity.
    Keywords:  CD36; insulin resistance; lipid droplet; obesity; skeletal muscle
    DOI:  https://doi.org/10.1111/apha.14249
  4. Ann Transl Med. 2024 Oct 20. 12(5): 86
    Cardiovascular handgrip responses during treadmill exercise: randomized pilot trial.
    Marvyn de Santana do Sacramento, Josias Melo Leite, Maria Williane de Sousa Ribeiro, Ramon Martins Barbosa, Tailma Costa de Jesus, Pedro Elias Santos Souza, Alice Miranda de Oliveira, Jefferson Petto.
       Background: The isometric exercise performed using the handgrip (HG) acutely promotes elevation of systolic blood pressure (SBP) and diastolic blood pressure (DBP), and in a non-consensual manner among articles elevation or maintenance of heart rate (HR). Currently, although there is a vast literature on the hemodynamic effects of interval training and isometric exercise with HG alone, there is still no consistent evidence of such adjustments occurring in the association between the two. Therefore, the objective of this study was to describe the acute hemodynamic responses found only during interval training and when combined with isometric contraction with HG.
    Methods: This is a pilot study of a crossover clinical trial. Seven male volunteers, aged 24±3.9 years, underwent three protocols on an ergometric treadmill, with a 3-minute warm-up at 30% of heart rate reserve (HRR), four sprints 2 minutes at 50% HRR and active intervals at the same speed as the warm-up. Randomization was carried out in a simple random manner. The protocols were classified according to the use of HG during sprints, as follows: PI = without HG; PII = HG 30% of handgrip strength (HGS) and PIII = 60% of HGS). Variations (Δ) in HR, double product (DP), SBP and DBP were evaluated.
    Results: The presence of HG did not change HR behavior, but it increased DP (PI: 10,472±2,539 vs. PII: 12,217±1,933 vs. PIII: 13,369±3,089) through SBP, which in PI had a plateau behavior of 15±22.2 mmHg, while PII varied with an average of 41±12.2 mmHg and PIII 47±11.1 mmHg, in the 4th sprint. DBP fell in PI with 12±13.2 mmHg, while PII and PIII showed an drop of 0±19.6 and 6±13.0 mmHg in the last sprint, respectively.
    Conclusions: The use of HG during interval training directly modulates hemodynamic variables, promoting an increase in SBP elevation, attenuation of the drop in DBP and an increase in DP, without an increase in HR.
    Trial Registration: RBR-78fhyrf. Available in https://ensaiosclinicos.gov.br/rg/RBR-78fhyrf.
    Keywords:  Hemodynamics; isometric exercise; peripheral vascular resistance
    DOI:  https://doi.org/10.21037/atm-24-59
  5. Metabolism. 2024 Oct 26. pii: S0026-0495(24)00281-6. [Epub ahead of print] 156053
    Leptin in humans: Evidence from clinical studies and current and future clinical applications.
    Nikolaos Perakakis, Christos S Mantzoros.
      Leptin has been established as the prototype adipose tissue secreted hormone and as a major regulator of several human physiology functions. Here, we are primarily reviewing the findings from studies in humans involving leptin administration. We are describing the metabolic, endocrine and immunologic effects of leptin replacement in conditions of leptin deficiency, such as short-term fasting in healthy individuals, relative energy deficiency in sports (REDS), congenital leptin deficiency (CLD), generalized (GL) and partial lipodystrophy (PL), HIV-associated lipodystrophy (HIV-L) and of leptin treatment in conditions of leptin excess (common obesity, type 2 diabetes, steatotic liver disease). We are comparing the results with the findings from preclinical models and present the main conclusions regarding the role of leptin in human physiology, pathophysiology and therapeutics. We conclude that, in conditions of energy deficiency, leptin substitution effectively reduces body weight and fat mass through reduction of appetite, it improves hypertriglyceridemia, insulin resistance and hepatic steatosis (especially in GL and PL), it restores neuroendocrine function (especially the gonadotropic axis), it regulates adaptive immune system cell populations and it improves bone health. On the contrary, leptin treatment in conditions of leptin excess, such as common obesity and type 2 diabetes, does not improve any metabolic abnormalities. Strategies to overcome leptin tolerance/resistance in obesity and type 2 diabetes have provided promising results in animal studies, which should though be tested in humans in randomized clinical trials.
    Keywords:  Appetite; Diabetes; Energy; Expenditure; MASLD; Obesity
    DOI:  https://doi.org/10.1016/j.metabol.2024.156053
  6. Methods Enzymol. 2024 ;pii: S0076-6879(24)00365-3. [Epub ahead of print]707 543-564
    Methods to analyze the mitochondrial unfolded protein response (UPRmt).
    Avijit Mallick, Cole M Haynes.
      The mitochondrial unfolded protein response (UPRmt) is a mitochondria-to-nuclear signaling pathway that mediates the transcription of genes required to maintain mitochondrial function during development as well as during aging. In this chapter, we describe the approaches and techniques that we and others have used to elucidate the mechanism(s) by which cells detect mitochondrial stress or dysfunction and communicate with the nucleus to induce transcription of a protective stress response. We also describe approaches to evaluate the impact of UPRmt activation on mitochondrial function and mitochondrial biogenesis including imaging-based approaches as well as approaches to evaluate mitochondrial genome (mtDNA) copy number.
    Keywords:  Deleterious mtDNA heteroplasmy; Mito-nuclear communication; Mitochondrial biogenesis; Mitochondrial unfolded protein response; Molecular chaperones; MtDNA replication
    DOI:  https://doi.org/10.1016/bs.mie.2024.07.029
  7. World J Cardiol. 2024 Oct 26. 16(10): 608-610
    Heart failure with preserved ejection fraction and the first law of thermodynamics.
    Robert M Peters.
      In heart failure with preserved ejection fraction, significant left ventricular diastolic abnormalities are present, despite a normal systolic ejection fraction. This article will consider whether this is consistent with the law of conservation of energy, also know as the first law of thermodynamics.
    Keywords:  Diastolic dysfunction; Heart failure with preserved ejection fraction; Thermodynamics
    DOI:  https://doi.org/10.4330/wjc.v16.i10.608
  8. Nature. 2024 Nov 06.
    Division of labour: mitochondria split to meet energy demands.
    Lena Pernas.
      
    Keywords:  Cell biology; Metabolism
    DOI:  https://doi.org/10.1038/d41586-024-03469-0
  9. Food Sci Biotechnol. 2024 Dec;33(15): 3387-3400
    Molecular mechanism of skeletal muscle loss and its prevention by natural resources.
    Jin Tae Kim, Dong Hyeon Jeon, Hong Jin Lee.
      A skeletal muscle disorder has drawn attention due to the global aging issues. The loss of skeletal muscle mass has been suggested to be from the reduced muscle regeneration by dysfunction of muscle satellite cell/fibro-adipogenic progenitor cells and the muscle atrophy by dysfunction of mitochondria, ubiquitin-proteasome system, and autophagy. In this review, we highlighted the underlying mechanisms of skeletal muscle mass loss including Notch signaling, Wnt/β-catenin signaling, Hedgehog signaling, AMP-activated protein kinase (AMPK) signaling, and mammalian target of rapamycin (mTOR) signaling. In addition, we summarized accumulated studies of natural resources investigating their roles in ameliorating the loss of skeletal muscle mass and demonstrating the underlying mechanisms in vitro and in vivo. In conclusion, following the studies of natural resources exerting the preventive activity in muscle mass loss, the signaling-based approaches may accelerate the development of functional foods for sarcopenia prevention.
    Keywords:  Muscle atrophy; Muscle regeneration; Natural resources; Sarcopenia; Signaling pathway
    DOI:  https://doi.org/10.1007/s10068-024-01678-x
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