bims-mimcad 2024-06-02 papers

bims-mimcad

Biomed News

on Mitochondrial metabolism and cardiometabolic diseases

Issue of 2024–06–02
seven papers selected by
Henver Brunetta, University of Guelph

Reciprocal Regulation of Cardiac β-Oxidation and Pyruvate Dehydrogenase by Insulin.
The novel adrenergic agonist ATR-127 targets skeletal muscle and brown adipose tissue to tackle diabesity and steatohepatitis.
Inflammation causes insulin resistance in mice via interferon regulatory factor 3 (IRF3)-mediated reduction in FAHFA levels.
Beta2-agonist impairs muscle insulin sensitivity in persons with insulin resistance.
Semaglutide and NT-proBNP in Obesity-Related HFpEF: Insights From the STEP-HFpEF Program.
Fasting alleviates metabolic alterations in mice with propionyl-CoA carboxylase deficiency due to Pcca mutation.
Associations between regional adipose tissue distribution and skeletal muscle bioenergetics in older men and women.

J Biol Chem. 2024 May 23. pii: S0021-9258(24)01913-6. [Epub ahead of print] 107412

Reciprocal Regulation of Cardiac β-Oxidation and Pyruvate Dehydrogenase by Insulin.

Abdallah Elnwasany, Heba A Ewida, Ivan Menendez-Montes, Monika Mizerska, Xiaorong Fu, Chai-Wan Kim, Jay D Horton, Shawn C Burgess, Beverly A Rothermel, Pamela A Szweda, Luke I Szweda.

  The heart alters the rate and relative oxidation of fatty acids and glucose based on availability and energetic demand. Insulin plays a crucial role in this process diminishing fatty acid and increasing glucose oxidation when glucose availability increases. Loss of insulin sensitivity and metabolic flexibility can result in cardiovascular disease. It is therefore important to identify mechanisms by which insulin regulates substrate utilization in the heart. Mitochondrial pyruvate dehydrogenase (PDH) is the key regulatory site for the oxidation of glucose for ATP production. Nevertheless, the impact of insulin on PDH activity has not been fully delineated, particularly in the heart. We sought in vivo evidence that insulin stimulates cardiac PDH and that this process is driven by inhibition of fatty acid oxidation. Mice injected with insulin exhibited dephosphorylation and activation of cardiac PDH. This was accompanied by an increase in the content of malonyl-CoA, an inhibitor of carnitine palmitoyltransferase 1 (CPT1) and, thus, mitochondrial import of fatty acids. Administration of the CPT1 inhibitor oxfenicine was sufficient to activate PDH. Malonyl-CoA is produced by acetyl-CoA carboxylase (ACC). Pharmacologic inhibition or knockout of cardiac ACC diminished insulin-dependent production of malonyl-CoA and activation of PDH. Finally, circulating insulin and cardiac glucose utilization exhibit daily rhythms reflective of nutritional status. We demonstrate that time of day-dependent changes in PDH activity are mediated, in part, by ACC-dependent production of malonyl-CoA. Thus, by inhibiting fatty acid oxidation, insulin reciprocally activates PDH. These studies identify potential molecular targets to promote cardiac glucose oxidation and treat heart disease.

Keywords:  Acetyl-CoA Carboxylase; Heart; Insulin; Malonyl-CoA; Mitochondria; Pyruvate Dehydrogenase; β-Oxidation

DOI:  https://doi.org/10.1016/j.jbc.2024.107412
Mol Metab. 2024 May 17. pii: S2212-8778(24)00062-0. [Epub ahead of print] 101931

The novel adrenergic agonist ATR-127 targets skeletal muscle and brown adipose tissue to tackle diabesity and steatohepatitis.

Emanuela Talamonti, Jelena Davegardh, Anastasia Kalinovich, Sten M M van Beek, Nodi Dehvari, Carina Halleskog, Hamza M Bokhari, Dana S Hutchinson, Seungmin Ham, Laura J Humphrys, Nicola C Dijon, Aikaterini Motso, Anna Sandstrom, Evelyn Zacharewicz, Ilga Mutule, Edgars Suna, Jana Spura, Karolina Ditrychova, Leigh A Stoddart, Nicholas D Holliday, Shane C Wright, Volker M Lauschke, Soren Nielsen, Camilla Scheele, Elizabeth Cheesman, Joris Hoeks, Peter Molenaar, Roger J Summers, Benjamin Pelcman, Gopala K Yakala, Tore Bengtsson.

   OBJECTIVE: Simultaneous activation of β2- and β3-adrenoceptors (ARs) improves whole-body metabolism via beneficial effects in skeletal muscle and brown adipose tissue (BAT). Nevertheless, high-efficacy agonists simultaneously targeting these receptors whilst limiting activation of β1-ARs - and thus inducing cardiovascular complications - are currently non-existent. Therefore, we here developed and evaluated the therapeutic potential of a novel β2-and β3-AR, named ATR-127, for the treatment of obesity and its associated metabolic perturbations in preclinical models.
METHODS: In the developmental phase, we assessed the impact of ATR-127's on cAMP accumulation in relation to the non-selective β-AR agonist isoprenaline across various rodent β-AR subtypes, including neonatal rat cardiomyocytes. Following these experiments, L6 muscle cells were stimulated with ATR-127 to assess the impact on GLUT4-mediated glucose uptake and intramyocellular cAMP accumulation. Additionally, in vitro, and in vivo assessments are conducted to measure ATR-127's effects on BAT glucose uptake and thermogenesis. Finally, diet-induced obese mice were treated with 5 mg/kg ATR-127 for 21 days to investigate the effects on glucose homeostasis, body weight, fat mass, skeletal muscle glucose uptake, BAT thermogenesis and hepatic steatosis.
RESULTS: Exposure of L6 muscle cells to ATR-127 robustly enhanced GLUT4-mediated glucose uptake despite low intramyocellular cAMP accumulation. Similarly, ATR-127 markedly increased BAT glucose uptake and thermogenesis both in vitro and in vivo. Prolonged treatment of diet-induced obese mice with ATR-127 dramatically improved glucose homeostasis, an effect accompanied by decreases in body weight and fat mass. These effects were paralleled by an enhanced skeletal muscle glucose uptake, BAT thermogenesis, and improvements in hepatic steatosis.
CONCLUSIONS: Our results demonstrate that ATR-127 is a highly effective, novel β2- and β3-ARs agonist holding great therapeutic promise for the treatment of obesity and its comorbidities, whilst potentially limiting cardiovascular complications. As such, the therapeutic effects of ATR-127 should be investigated in more detail in clinical studies.

Keywords:  Hepatic steatosis; Obesity; Skeletal muscle; Type 2 diabetes; β-Adrenergic agonists

DOI:  https://doi.org/10.1016/j.molmet.2024.101931
Nat Commun. 2024 May 30. 15(1): 4605

Inflammation causes insulin resistance in mice via interferon regulatory factor 3 (IRF3)-mediated reduction in FAHFA levels.

Shuai Yan, Anna Santoro, Micah J Niphakis, Antonio M Pinto, Christopher L Jacobs, Rasheed Ahmad, Radu M Suciu, Bryan R Fonslow, Rachel A Herbst-Graham, Nhi Ngo, Cassandra L Henry, Dylan M Herbst, Alan Saghatelian, Barbara B Kahn, Evan D Rosen.

Obesity-induced inflammation causes metabolic dysfunction, but the mechanisms remain elusive. Here we show that the innate immune transcription factor interferon regulatory factor (IRF3) adversely affects glucose homeostasis through induction of the endogenous FAHFA hydrolase androgen induced gene 1 (AIG1) in adipocytes. Adipocyte-specific knockout of IRF3 protects male mice against high-fat diet-induced insulin resistance, whereas overexpression of IRF3 or AIG1 in adipocytes promotes insulin resistance on a high-fat diet. Furthermore, pharmacological inhibition of AIG1 reversed obesity-induced insulin resistance and restored glucose homeostasis in the setting of adipocyte IRF3 overexpression. We, therefore, identify the adipocyte IRF3/AIG1 axis as a crucial link between obesity-induced inflammation and insulin resistance and suggest an approach for limiting the metabolic dysfunction accompanying obesity.

DOI: https://doi.org/10.1038/s41467-024-48220-5
J Clin Endocrinol Metab. 2024 May 31. pii: dgae381. [Epub ahead of print]

Beta2-agonist impairs muscle insulin sensitivity in persons with insulin resistance.

Johan Onslev, Matteo Fiorenza, Martin Thomassen, Jesper Havelund, Jens Bangsbo, Nils Færgeman, Jørgen F P Wojtaszewski, Morten Hostrup.

   CONTEXT: Given the promising effects of prolonged treatment with beta2-agonist on insulin sensitivity in animals and non-diabetic individuals, the beta2-adrenergic receptor has been proposed as a target to counter peripheral insulin resistance. On the other hand, rodent studies also reveal that beta2-agonists acutely impair insulin action, posing a potential caveat for their use in treating insulin resistance.
OBJECTIVE: To assess the impact of beta2-agonist on muscle insulin action and glucose metabolism and identify the underlying mechanism(s) in 10 insulin-resistant subjects.
METHODS AND PARTICIPANTS: In a cross-over design, we assessed the effect of beta2-agonist on insulin-stimulated muscle glucose uptake during a 3-h hyperinsulinemic isoglycemic clamp with and without intralipid infusion in 10 insulin-resistant overweight subjects. Two hours into the clamp, we infused beta2-agonist. We collected muscle biopsies before, two hours into and by the end of the clamp and analyzed them using metabolomic and lipidomic techniques.
RESULTS: We establish that beta2-agonist, independently from and additively to intralipid, impairs insulin-stimulated muscle glucose uptake via different mechanisms. In combination, beta2-agonist and intralipid nearly eliminates insulin-dependent muscle glucose uptake. While both beta2-agonist and intralipid elevated muscle glucose-6-phosphate, only intralipid caused accumulation of downstream muscle glycolytic intermediates, whereas beta2-agonist attenuated incorporation of glucose into glycogen.
CONCLUSIONS: Our findings suggest that beta2-agonist inhibits glycogenesis while intralipid inhibits glycolysis in skeletal muscle of insulin-resistant individuals. These results should be addressed in future treatment of insulin resistance with beta2-agonist.

Keywords:  Beta2-adrenergic agonists; Glucose-6-phosphate; glycogenesis; insulin resistance; intralipid; muscle glucose uptake

DOI:  https://doi.org/10.1210/clinem/dgae381
J Am Coll Cardiol. 2024 May 13. pii: S0735-1097(24)07020-7. [Epub ahead of print]

Semaglutide and NT-proBNP in Obesity-Related HFpEF: Insights From the STEP-HFpEF Program.

STEP-HFpEF Trial Committees and Investigators

   BACKGROUND: The glucagon-like peptide-1 receptor agonist, semaglutide, improved health status and reduced body weight in patients with obesity-related heart failure (HF) with preserved ejection fraction (HFpEF) in the STEP-HFpEF (Semaglutide Treatment Effect in People with Obesity and HFpEF) program. Whether benefits were due to mechanical unloading or effects on HF pathobiology is uncertain.
OBJECTIVES: This study sought to determine if semaglutide 2.4 mg reduced N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients with obesity-related HFpEF and compare treatment responses by baseline NT-proBNP.
METHODS: This was a prespecified secondary analysis of pooled data from 2 double-blind, placebo-controlled, randomized trials (STEP-HFpEF [Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity] and STEP-HFpEF DM [Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes]) testing effects of semaglutide in patients with obesity-related HFpEF. The main outcomes were change in NT-proBNP at 52 weeks and change in the dual primary endpoints of Kansas City Cardiomyopathy Questionnaire Clinical Summary Score and body weight by baseline NT-proBNP.
RESULTS: In total, 1,145 patients were randomized. Semaglutide compared with placebo reduced NT-proBNP at 52 weeks (estimated treatment ratio: 0.82; 95% CI: 0.74-0.91; P = 0.0002). Improvements in health status were more pronounced in those with higher vs lower baseline NT-proBNP (estimated difference: tertile 1: 4.5 points, 95% CI: 0.8-8.2; tertile 2: 6.2 points, 95% CI: 2.4-10.0; tertile 3: 11.9 points, 95% CI: 8.1-15.7; P interaction = 0.02; baseline NT-proBNP as a continuous variable: P interaction = 0.004). Reductions in body weight were consistent across baseline NT-proBNP levels (P interaction = 0.21).
CONCLUSIONS: In patients with obesity-related HFpEF, semaglutide reduced NT-proBNP. Participants with higher baseline NT-proBNP had a similar degree of weight loss but experienced larger reductions in HF-related symptoms and physical limitations with semaglutide than those with lower NT-proBNP.

Keywords:  N-terminal pro–B-type natriuretic peptide; heart failure with preserved ejection fraction; obesity; semaglutide

DOI:  https://doi.org/10.1016/j.jacc.2024.04.022
Commun Biol. 2024 May 29. 7(1): 659

Fasting alleviates metabolic alterations in mice with propionyl-CoA carboxylase deficiency due to Pcca mutation.

Wentao He, Hannah Marchuk, Dwight Koeberl, Takhar Kasumov, Xiaoxin Chen, Guo-Fang Zhang.

Propionic acidemia (PA), resulting from Pcca or Pccb gene mutations, impairs propionyl-CoA metabolism and induces metabolic alterations. While speculation exists that fasting might exacerbate metabolic crises in PA patients by accelerating the breakdown of odd-chain fatty acids and amino acids into propionyl-CoA, direct evidence is lacking. Our investigation into the metabolic effects of fasting in Pcca-/-(A138T) mice, a PA model, reveals surprising outcomes. Propionylcarnitine, a PA biomarker, decreases during fasting, along with the C3/C2 (propionylcarnitine/acetylcarnitine) ratio, ammonia, and methylcitrate. Although moderate amino acid catabolism to propionyl-CoA occurs with a 23-h fasting, a significant reduction in microbiome-produced propionate and increased fatty acid oxidation mitigate metabolic alterations by decreasing propionyl-CoA synthesis and enhancing acetyl-CoA synthesis. Fasting-induced gluconeogenesis further facilitates propionyl-CoA catabolism without changing propionyl-CoA carboxylase activity. These findings suggest that fasting may alleviate metabolic alterations in Pcca-/-(A138T) mice, prompting the need for clinical evaluation of its potential impact on PA patients.

DOI: https://doi.org/10.1038/s42003-024-06362-8
Obesity (Silver Spring). 2024 Jun;32(6): 1125-1135

Associations between regional adipose tissue distribution and skeletal muscle bioenergetics in older men and women.

Andrea M Brennan, Paul M Coen, Theresa Mau, Megan Hetherington-Rauth, Frederico G S Toledo, Erin E Kershaw, Peggy M Cawthon, Philip A Kramer, Sofhia V Ramos, Anne B Newman, Steven R Cummings, Daniel E Forman, Reichelle X Yeo, Giovanna Distefano, Iva Miljkovic, Jamie N Justice, Anthony J A Molina, Michael J Jurczak, Lauren M Sparks, Stephen B Kritchevsky, Bret H Goodpaster.

OBJECTIVE: The aim of this study was to examine associations of ectopic adipose tissue (AT) with skeletal muscle (SM) mitochondrial bioenergetics in older adults.
METHODS: Cross-sectional data from 829 adults ≥70 years of age were used. Abdominal, subcutaneous, and visceral AT and thigh muscle fat infiltration (MFI) were quantified by magnetic resonance imaging. SM mitochondrial energetics were characterized in vivo (31P-magnetic resonance spectroscopy; ATPmax) and ex vivo (high-resolution respirometry maximal oxidative phosphorylation [OXPHOS]). ActivPal was used to measure physical activity ([PA]; step count). Linear regression adjusted for covariates was applied, with sequential adjustment for BMI and PA.
RESULTS: Independent of BMI, total abdominal AT (standardized [Std.] β = -0.21; R2 = 0.09) and visceral AT (Std. β = -0.16; R2 = 0.09) were associated with ATPmax (p < 0.01; n = 770) but not following adjustment for PA (p ≥ 0.05; n = 658). Visceral AT (Std. β = -0.16; R2 = 0.25) and thigh MFI (Std. β = -0.11; R2 = 0.24) were associated with carbohydrate-supported maximal OXPHOS independent of BMI and PA (p < 0.05; n = 609). Total abdominal AT (Std. β = -0.19; R2 = 0.24) and visceral AT (Std. β = -0.17; R2 = 0.24) were associated with fatty acid-supported maximal OXPHOS independent of BMI and PA (p < 0.05; n = 447).
CONCLUSIONS: Skeletal MFI and abdominal visceral, but not subcutaneous, AT are inversely associated with SM mitochondrial bioenergetics in older adults independent of BMI. Associations between ectopic AT and in vivo mitochondrial bioenergetics are attenuated by PA.

DOI: https://doi.org/10.1002/oby.24008