bims-mimcad 2024-09-22 papers

Issue of 2024–09–22
five papers selected by
Henver Brunetta, Karolinska Institutet

J Clin Endocrinol Metab. 2024 Sep 19. pii: dgae657. [Epub ahead of print]

Plasma endocannabinoids are independently associated with the metabolic function of white adipose tissue.

Dany Dion, Christophe Noll, Mélanie Fortin, Lounès Haroune, Sabrina Saibi, Philippe Sarret, André C Carpentier.

CONTEXT: Little is known about the link between the endocannabinoid system and the in vivo metabolic function of white adipose tissue (WAT).
OBJECTIVE: We aimed to evaluate whether endocannabinoids (EC) are linked to postprandial fatty acid metabolism and WAT metabolic function.
DESIGN: Men and women, with (IGT, n=20) or without impaired glucose tolerance (NGT, n=20) underwent meal testing with oral and intravenous stable isotope palmitate tracers and positron emission tomography with intravenous [11C]-palmitate and oral [18F]-fluoro-thia-heptadecanoic acid to determine systemic and organ-specific dietary fatty acid (DFA) and non-esterified fatty acid (NEFA) metabolism and partitioning. We determined fasting and postprandial plasma levels of EC by UHPLC-MS/MS.
RESULTS: All EC of the 2-monoacylglycerol (2-MAG) family displayed a progressive postprandial increase up to 360 min after meal intake that was more pronounced in women with IGT. N-acylethanolamine (NAE) levels decreased between fasting and 180 min, followed by a return to pre-prandial values at 360 min and were also increased in women with IGT. Postprandial area under the curve (AUC) of palmitate appearance rate was significantly and independently associated with postprandial AUC of anandamide (AEA; P=0.0003) and total energy expenditure (P=0.0009). DFA storage in abdominal subcutaneous adipose tissue was positively predicted by fasting 2-arachidonoylglycerol (2-AG; P<0.04).
CONCLUSION: EC levels of the NAE family independently follow plasma NEFA metabolism, whereas 2-MAG closely follow the spillover of triglyceride-rich lipoprotein intravascular lipolytic products. Whether these associations are causal requires further investigation.

Keywords: Endocannabinoids; dietary fatty acids; fatty acid spillover; impaired glucose tolerance; insulin resistance; nonesterified fatty acids; obesity; positron emission tomography; postprandial fatty acid metabolism; prediabetes

DOI: https://doi.org/10.1210/clinem/dgae657

Nat Commun. 2024 Sep 16. 15(1): 8114

Erythropoietin regulates energy metabolism through EPO-EpoR-RUNX1 axis.

Weiqin Yin, Praveen Kumar Rajvanshi, Heather M Rogers, Teruhiko Yoshida, Jeffrey B Kopp, Xiuli An, Max Gassmann, Constance T Noguchi.

Erythropoietin (EPO) plays a key role in energy metabolism, with EPO receptor (EpoR) expression in white adipose tissue (WAT) mediating its metabolic activity. Here, we show that male mice lacking EpoR in adipose tissue exhibit increased fat mass and susceptibility to diet-induced obesity. Our findings indicate that EpoR is present in WAT, brown adipose tissue, and skeletal muscle. Elevated EPO in male mice improves glucose tolerance and insulin sensitivity while reducing expression of lipogenic-associated genes in WAT, which is linked to an increase in transcription factor RUNX1 that directly inhibits lipogenic genes expression. EPO treatment in wild-type male mice decreases fat mass and lipogenic gene expression and increase in RUNX1 protein in adipose tissue which is not observed in adipose tissue EpoR ablation mice. EPO treatment decreases WAT ubiquitin ligase FBXW7 expression and increases RUNX1 stability, providing evidence that EPO regulates energy metabolism in male mice through the EPO-EpoR-RUNX1 axis.

DOI: https://doi.org/10.1038/s41467-024-52352-z

Nat Cardiovasc Res. 2024 Sep 18.

Cardiac NAD+ depletion in mice promotes hypertrophic cardiomyopathy and arrhythmias prior to impaired bioenergetics.

Nicotinamide adenine dinucleotide (NAD+) is an essential co-factor in metabolic reactions and co-substrate for signaling enzymes. Failing human hearts display decreased expression of the major NAD+ biosynthetic enzyme nicotinamide phosphoribosyltransferase (Nampt) and lower NAD+ levels, and supplementation with NAD+ precursors is protective in preclinical models. Here we show that Nampt loss in adult cardiomyocytes caused depletion of NAD+ along with marked metabolic derangements, hypertrophic remodeling and sudden cardiac deaths, despite unchanged ejection fraction, endurance and mitochondrial respiratory capacity. These effects were directly attributable to NAD+ loss as all were ameliorated by restoring cardiac NAD+ levels with the NAD+ precursor nicotinamide riboside (NR). Electrocardiograms revealed that loss of myocardial Nampt caused a shortening of QT intervals with spontaneous lethal arrhythmias causing sudden cardiac death. Thus, changes in NAD+ concentration can have a profound influence on cardiac physiology even at levels sufficient to maintain energetics.

DOI: https://doi.org/10.1038/s44161-024-00542-9

EMBO J. 2024 Sep 16.

IF1 is a cold-regulated switch of ATP synthase hydrolytic activity to support thermogenesis in brown fat.

Henver S Brunetta, Anna S Jung, Fernando Valdivieso-Rivera, Stepheny C de Campos Zani, Joel Guerra, Vanessa O Furino, Annelise Francisco, Marcelo Berçot, Pedro M Moraes-Vieira, Susanne Keipert, Martin Jastroch, Laurent O Martinez, Carlos H Sponton, Roger F Castilho, Marcelo A Mori, Alexander Bartelt.

While mechanisms controlling uncoupling protein-1 (UCP1) in thermogenic adipocytes play a pivotal role in non-shivering thermogenesis, it remains unclear whether F1Fo-ATP synthase function is also regulated in brown adipose tissue (BAT). Here, we show that inhibitory factor 1 (IF1, encoded by Atp5if1), an inhibitor of ATP synthase hydrolytic activity, is a critical negative regulator of brown adipocyte energy metabolism. In vivo, IF1 levels are diminished in BAT of cold-adapted mice compared to controls. Additionally, the capacity of ATP synthase to generate mitochondrial membrane potential (MMP) through ATP hydrolysis (the so-called "reverse mode" of ATP synthase) is increased in brown fat. In cultured brown adipocytes, IF1 overexpression results in an inability of mitochondria to sustain the MMP upon adrenergic stimulation, leading to a quiescent-like phenotype in brown adipocytes. In mice, adeno-associated virus-mediated IF1 overexpression in BAT suppresses adrenergic-stimulated thermogenesis and decreases mitochondrial respiration in BAT. Taken together, our work identifies downregulation of IF1 upon cold as a critical event for the facilitation of the reverse mode of ATP synthase as well as to enable energetic adaptation of BAT to effectively support non-shivering thermogenesis.

Keywords: Adipocytes; Metabolism; Mitochondria; Thermogenesis; UCP1

DOI: https://doi.org/10.1038/s44318-024-00215-0

Nat Commun. 2024 Sep 17. 15(1): 8136

Atomic vacancies of molybdenum disulfide nanoparticles stimulate mitochondrial biogenesis.

Kanwar Abhay Singh, John Soukar, Mohammad Zulkifli, Anna Kersey, Giriraj Lokhande, Sagnika Ghosh, Aparna Murali, Natalie M Garza, Harman Kaur, Justin N Keeney, Ramu Banavath, Hatice Ceylan Koydemir, Raquel Sitcheran, Irtisha Singh, Vishal M Gohil, Akhilesh K Gaharwar.

Diminished mitochondrial function underlies many rare inborn errors of energy metabolism and contributes to more common age-associated metabolic and neurodegenerative disorders. Thus, boosting mitochondrial biogenesis has been proposed as a potential therapeutic approach for these diseases; however, currently we have a limited arsenal of compounds that can stimulate mitochondrial function. In this study, we designed molybdenum disulfide (MoS2) nanoflowers with predefined atomic vacancies that are fabricated by self-assembly of individual two-dimensional MoS2 nanosheets. Treatment of mammalian cells with MoS2 nanoflowers increased mitochondrial biogenesis by induction of PGC-1α and TFAM, which resulted in increased mitochondrial DNA copy number, enhanced expression of nuclear and mitochondrial-DNA encoded genes, and increased levels of mitochondrial respiratory chain proteins. Consistent with increased mitochondrial biogenesis, treatment with MoS2 nanoflowers enhanced mitochondrial respiratory capacity and adenosine triphosphate production in multiple mammalian cell types. Taken together, this study reveals that predefined atomic vacancies in MoS2 nanoflowers stimulate mitochondrial function by upregulating the expression of genes required for mitochondrial biogenesis.

DOI: https://doi.org/10.1038/s41467-024-52276-8