bims-mimcad 2024-08-25 papers

bims-mimcad

Biomed News

on Mitochondrial metabolism and cardiometabolic diseases

Issue of 2024–08–25
eight papers selected by
Henver Brunetta, Karolinska Institutet

Natriuretic peptide receptor-C perturbs mitochondrial respiration in white adipose tissue.
Randomized Crossover Trial of 2-Week Ketone Ester Treatment in Patients With Type 2 Diabetes and Heart Failure With Preserved Ejection Fraction.
A transcriptional regulatory mechanism of genes in the tricarboxylic acid cycle in the heart.
Cytosolic calcium regulates hepatic mitochondrial oxidation, intrahepatic lipolysis, and gluconeogenesis via CAMKII activation.
Postprandial exercise regulates tissue-specific triglyceride uptake through angiopoietin-like proteins.
AI-recognized mitochondrial phenotype enables identification of drug targets.
Weight gain leads to greater adverse metabolic responses in South Asian compared with white European men: the GlasVEGAS study.
The microbiota-dependent tryptophan metabolite alleviates high-fat diet-induced insulin resistance through the hepatic AhR/TSC2/mTORC1 axis.

J Lipid Res. 2024 Aug 16. pii: S0022-2275(24)00128-7. [Epub ahead of print] 100623

Natriuretic peptide receptor-C perturbs mitochondrial respiration in white adipose tissue.

Shi-Jin Li, Jin-Qiu Wei, Yuan-Yuan Kang, Rui-Qi Wang, Wu-Wei Rong, Jia-Jia Zhao, Qian-Wan Deng, Ping-Jin Gao, Xiao-Dong Li, Ji-Guang Wang.

  Natriuretic peptide receptor-C (NPR-C) is highly expressed in adipose tissues, and regulates obesity related diseases, however the detailed mechanism remains unknown. In this research, we aimed to explore the potential role of NPR-C in cold exposure and high-fat/high-sugar (HF/HS) diet induced metabolic changes, especially in regulating white adipose tissue (WAT) mitochondrial function. Our findings showed that NPR-C expression, especially in epididymal WAT (eWAT), was reduced after cold exposure. Global Npr3 (gene encoding NPR-C protein) deficiency led to reduced body weight, increased WAT browning, thermogenesis, and enhanced expression of genes related to mitochondrial biogenesis. RNA-sequencing of eWAT showed that Npr3 deficiency enhanced expression of mitochondrial respiratory chain complex genes and promoted mitochondrial oxidative phosphorylation in response to cold exposure. In addition, Npr3 KO mice were able to resist obesity induced by HF/HS diet. Npr3 knockdown in stromal vascular fraction (SVF)-induced white adipocytes promoted the expression of proliferator-activated receptor gamma coactivator 1α (PGC1α), uncoupling protein 1 (UCP1) and mitochondrial respiratory chain complexes. Mechanistically, NPR-C inhibited cGMP and calcium signaling in an NPR-B-dependent manner but suppressed cAMP signaling in an NPR-B-independent manner. Moreover, Npr3 knockdown induced browning via AKT and p38 pathway activation, which were attenuated by Npr2 knockdown. Importantly, treatment with the NPR-C specific antagonist, AP-811, decreased WAT mass and increased PGC-1α, UCP1 and mitochondrial complex expression. These findings demonstrate that NPR-C deficiency enhances metabolic health by boosting energy expenditure in WAT, emphasizing the potential of NPR-C inhibition for treating obesity and related metabolic disorders.

Keywords:  Browning; Mitochondrial complex; Natriuretic peptide receptor C; Obesity; White adipose tissue

DOI:  https://doi.org/10.1016/j.jlr.2024.100623
Circulation. 2024 Aug 20.

Randomized Crossover Trial of 2-Week Ketone Ester Treatment in Patients With Type 2 Diabetes and Heart Failure With Preserved Ejection Fraction.

Nigopan Gopalasingam, Kristoffer Berg-Hansen, Kristian Hylleberg Christensen, Bertil T Ladefoged, Steen Hvitfeldt Poulsen, Mads Jønsson Andersen, Barry Borlaug, Roni Nielsen, Niels Møller, Henrik Wiggers.

   BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a major cause of morbidity and mortality in patients with type 2 diabetes (T2DM). Acute increases in circulating levels of ketone body 3-hydroxybutyrate have beneficial acute hemodynamic effects in patients without T2DM with chronic heart failure with reduced ejection fraction. However, the cardiovascular effects of prolonged oral ketone ester (KE) treatment in patients with T2DM and HFpEF remain unknown.
METHODS: A total of 24 patients with T2DM and HFpEF completed a 6-week randomized, double-blind crossover study. All patients received 2 weeks of KE treatment (25 g D-ß-hydroxybutyrate-(R)-1,3-butanediol × 4 daily) and isocaloric and isovolumic placebo, separated by a 2-week washout period. At the end of each treatment period, patients underwent right heart catheterization, echocardiography, and blood samples at trough levels of intervention, and then during a 4-hour resting period after a single dose. A subsequent second dose was administered, followed by an exercise test. The primary end point was cardiac output during the 4-hour rest period.
RESULTS: During the 4-hour resting period, circulating 3-hydroxybutyrate levels were 10-fold higher after KE treatment (1010±56 µmol/L; P<0.001) compared with placebo (91±55 µmol/L). Compared with placebo, KE treatment increased cardiac output by 0.2 L/min (95% CI, 0.1 to 0.3) during the 4-hour period and decreased pulmonary capillary wedge pressure at rest by 1 mm Hg (95% CI, -2 to 0) and at peak exercise by 5 mm Hg (95% CI, -9 to -1). KE treatment decreased the pressure-flow relationship (∆ pulmonary capillary wedge pressure/∆ cardiac output) significantly during exercise (P<0.001) and increased stroke volume by 10 mL (95% CI, 0 to 20) at peak exercise. KE right-shifted the left ventricular end-diastolic pressure-volume relationship, suggestive of reduced left ventricular stiffness and improved compliance. Favorable hemodynamic responses of KE treatment were also observed in patients treated with sodium-glucose transporter-2 inhibitors and glucagon-like peptide-1 analogs.
CONCLUSIONS: In patients with T2DM and HFpEF, a 2-week oral KE treatment increased cardiac output and reduced cardiac filling pressures and ventricular stiffness. At peak exercise, KE treatment markedly decreased pulmonary capillary wedge pressure and improved pressure-flow relationship. Modulation of circulating ketone levels is a potential new treatment modality for patients with T2DM and HFpEF.
REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT05236335.

Keywords:  3-hydroxybutyrate; cardiac output; exercise hemodynamics; heart failure with preserved ejection fraction; invasive hemodynamics; ketone ester; metabolism

DOI:  https://doi.org/10.1161/CIRCULATIONAHA.124.069732
J Biol Chem. 2024 Aug 14. pii: S0021-9258(24)02178-1. [Epub ahead of print] 107677

A transcriptional regulatory mechanism of genes in the tricarboxylic acid cycle in the heart.

Samta Veera, Fan Tang, Youssef Mourad, Samuel Kim, Tong Liu, Hong Li, Yunjue Wang, Junco S Warren, Jiyeon Park, Carter Van, Junichi Sadoshima, Shin-Ichi Oka.

  The tricarboxylic acid (TCA) cycle plays a crucial role in mitochondrial ATP production in the healthy heart. However, in heart failure, the TCA cycle becomes dysregulated. Understanding the mechanism by which TCA cycle genes are transcribed in the healthy heart is an important prerequisite to understanding how these genes become dysregulated in the failing heart. PGC-1α is a transcriptional coactivator that broadly induces genes involved in mitochondrial ATP production. PGC-1α potentiates its effects through coactivation of coupled transcription factors, such as ERR, Nrf1, Gabpa, and YY1. We hypothesized that PGC-1α plays an essential role in transcription of TCA cycle genes. Thus, by utilizing localization peaks of PGC-1α to TCA cycle gene promoters, it would allow the identification of coupled transcription factors. PGC-1α potentiated the transcription of 13 out of 14 TCA cycle genes, partly through ERR, Nrf1, Gabpa, and YY1. ChIP-sequencing showed PGC-1α localization peaks in TCA cycle gene promoters. Transcription factors with binding elements that were found proximal to PGC-1α peak localization were generally essential for transcription of the gene. These transcription factor binding elements were well conserved between mice and humans. Among the four transcription factors, ERR and Gabpa played a major role in potentiating transcription when compared to Nrf1 and YY1. These transcription factor-dependent PGC-1α recruitment was verified with Idh3a, Idh3g, and Sdha promoters with DNA binding assay. Taken together, this study clarifies the mechanism by which TCA cycle genes are transcribed, which could be useful to understand how those genes are dysregulated in pathological conditions.

Keywords:  ERR; Gabpa; Mitochondria; Nrf1; PGC-1α; YY1; transcription; tricarboxylic acid (TCA) cycle

DOI:  https://doi.org/10.1016/j.jbc.2024.107677
Cell Metab. 2024 Aug 13. pii: S1550-4131(24)00287-0. [Epub ahead of print]

Cytosolic calcium regulates hepatic mitochondrial oxidation, intrahepatic lipolysis, and gluconeogenesis via CAMKII activation.

Traci E LaMoia, Brandon T Hubbard, Mateus T Guerra, Ali Nasiri, Ikki Sakuma, Mario Kahn, Dongyan Zhang, Russell P Goodman, Michael H Nathanson, Yasemin Sancak, Mark Perelis, Vamsi K Mootha, Gerald I Shulman.

  To examine the roles of mitochondrial calcium Ca2+ ([Ca2+]mt) and cytosolic Ca2+ ([Ca2+]cyt) in the regulation of hepatic mitochondrial fat oxidation, we studied a liver-specific mitochondrial calcium uniporter knockout (MCU KO) mouse model with reduced [Ca2+]mt and increased [Ca2+]cyt content. Despite decreased [Ca2+]mt, deletion of hepatic MCU increased rates of isocitrate dehydrogenase flux, α-ketoglutarate dehydrogenase flux, and succinate dehydrogenase flux in vivo. Rates of [14C16]palmitate oxidation and intrahepatic lipolysis were increased in MCU KO liver slices, which led to decreased hepatic triacylglycerol content. These effects were recapitulated with activation of CAMKII and abrogated with CAMKII knockdown, demonstrating that [Ca2+]cyt activation of CAMKII may be the primary mechanism by which MCU deletion promotes increased hepatic mitochondrial oxidation. Together, these data demonstrate that hepatic mitochondrial oxidation can be dissociated from [Ca2+]mt and reveal a key role for [Ca2+]cyt in the regulation of hepatic fat mitochondrial oxidation, intrahepatic lipolysis, gluconeogenesis, and lipid accumulation.

Keywords:  CAMKII; Q-Flux; calcium; fat oxidation; glucose oxidation; isocitrate dehydrogenase flux; metabolic dysfunction-associated steatotic liver disease; mitochondria; mitochondrial calcium uniporter; succinate dehydrogenase flux; tricarboxylic acid cycle; type 2 diabetes; α-ketoglutarate dehydrogenase flux

DOI:  https://doi.org/10.1016/j.cmet.2024.07.016
JCI Insight. 2024 Aug 22. pii: e181553. [Epub ahead of print]9(16):

Postprandial exercise regulates tissue-specific triglyceride uptake through angiopoietin-like proteins.

Xiaomin Liu, Yiliang Zhang, Bingqian Han, Lin Li, Ying Li, Yifan Ma, Shijia Kang, Quan Li, Lingkai Kong, Kun Huang, Bao-Liang Song, Yong Liu, Yan Wang.

  Fuel substrate switching between carbohydrates and fat is essential for maintaining metabolic homeostasis. During aerobic exercise, the predominant energy source gradually shifts from carbohydrates to fat. While it is well known that exercise mobilizes fat storage from adipose tissues, it remains largely obscure how circulating lipids are distributed tissue-specifically according to distinct energy requirements. Here, we demonstrate that aerobic exercise is linked to nutrient availability to regulate tissue-specific activities of lipoprotein lipase (LPL), the key enzyme catabolizing circulating triglyceride (TG) for tissue uptake, through the differential actions of angiopoietin-like (ANGPTL) proteins. Exercise reduced the tissue binding of ANGPTL3 protein, increasing LPL activity and TG uptake in the heart and skeletal muscle in the postprandial state specifically. Mechanistically, exercise suppressed insulin secretion, attenuating hepatic Angptl8 transcription through the PI3K/mTOR/CEBPα pathway, which is imperative for the tissue binding of its partner ANGPTL3. Constitutive expression of ANGPTL8 hampered lipid utilization and resulted in cardiac dysfunction in response to exercise. Conversely, exercise promoted the expression of ANGPTL4 in white adipose tissues, overriding the regulatory actions of ANGPTL8/ANGPTL3 in suppressing adipose LPL activity, thereby diverting circulating TG away from storage. Collectively, our findings show an overlooked bifurcated ANGPTL-LPL network that orchestrates fuel switching in response to aerobic exercise.

Keywords:  Homeostasis; Insulin; Lipoproteins; Metabolism

DOI:  https://doi.org/10.1172/jci.insight.181553
Nat Comput Sci. 2024 Aug 22.

AI-recognized mitochondrial phenotype enables identification of drug targets.

DOI: https://doi.org/10.1038/s43588-024-00682-9
Nat Metab. 2024 Aug 16.

Weight gain leads to greater adverse metabolic responses in South Asian compared with white European men: the GlasVEGAS study.

James McLaren, Xuan Gao, Nazim Ghouri, Dilys J Freeman, Janice Richardson, Naveed Sattar, Jason M R Gill.

South Asians (SAs) develop type 2 diabetes at lower body mass index values than white Europeans (WEs). This basic human experimental study aimed to compare the metabolic consequences of weight gain in SA and WE men without overweight or obesity. Fourteen SAs and 21 WEs had assessments of body composition, metabolic responses to mixed-meal ingestion, cardiorespiratory fitness and physical activity, and a subcutaneous abdominal adipose tissue biopsy, before and after 4-6 weeks of overfeeding to induce 5-7% weight gain. Here we show that body mass index and whole-body adipose tissue volume increases similarly between ethnic groups, but SAs gain less lean tissue. SAs experience a substantially greater decrease in insulin sensitivity compared with WEs (38% versus 7% decrease, P = 0.009), have fewer small (37.1% versus 60.0%, P = 0.003) and more large (26.2% versus 9.1%, P = 0.005) adipocytes at baseline and have a smaller decrease in very small adipocytes with weight gain (-0.1% versus -1.9%, P < 0.0001). Ethnic differences in adipocyte morphology are associated with SA's greater adverse metabolic changes with weight gain. ClinicalTrials.gov registration: NCT02399423 .

DOI: https://doi.org/10.1038/s42255-024-01101-z
Proc Natl Acad Sci U S A. 2024 Aug 27. 121(35): e2400385121

The microbiota-dependent tryptophan metabolite alleviates high-fat diet-induced insulin resistance through the hepatic AhR/TSC2/mTORC1 axis.

Wei Du, Shanshan Jiang, Shengxiang Yin, Rongjiang Wang, Chunling Zhang, Bin-Cheng Yin, Jialin Li, Li Li, Nan Qi, Ying Zhou, Bang-Ce Ye.

  Type 2 diabetes (T2D) is potentially linked to disordered tryptophan metabolism that attributes to the intricate interplay among diet, gut microbiota, and host physiology. However, underlying mechanisms are substantially unknown. Comparing the gut microbiome and metabolome differences in mice fed a normal diet (ND) and high-fat diet (HFD), we uncover that the gut microbiota-dependent tryptophan metabolite 5-hydroxyindole-3-acetic acid (5-HIAA) is present at lower concentrations in mice with versus without insulin resistance. We further demonstrate that the microbial transformation of tryptophan into 5-HIAA is mediated by Burkholderia spp. Additionally, we show that the administration of 5-HIAA improves glucose intolerance and obesity in HFD-fed mice, while preserving hepatic insulin sensitivity. Mechanistically, 5-HIAA promotes hepatic insulin signaling by directly activating AhR, which stimulates TSC2 transcription and thus inhibits mTORC1 signaling. Moreover, T2D patients exhibit decreased fecal levels of 5-HIAA. Our findings identify a noncanonical pathway of microbially producing 5-HIAA from tryptophan and indicate that 5-HIAA might alleviate the pathogenesis of T2D.

Keywords:  gut microbiota; insulin signaling; tryptophan metabolism; type 2 diabetes

DOI:  https://doi.org/10.1073/pnas.2400385121