bims-mimbat 2024-10-06 papers

bims-mimbat

Biomed News

on Mitochondrial metabolism in brown adipose tissue

Issue of 2024‒10‒06
seven papers selected by
José Carlos de Lima-Júnior, Washington University

In isolated brown adipose tissue mitochondria UCP1 is not essential for nor involved in the uncoupling effects of the classical uncouplers FCCP and DNP.
Sex-specific response of the human plasma lipidome to short-term cold exposure.
Small molecules targeting selective PCK1 and PGC-1α lysine acetylation cause anti-diabetic action through increased lactate oxidation.
Transcription factor PATZ1 promotes adipogenesis by controlling promoter regulatory loci of adipogenic factors.
Local adaptation, plasticity, and evolved resistance to hypoxic cold stress in high-altitude deer mice.
Adipocyte sphingosine kinase 1 regulates histone modifiers to disrupt circadian function.
Brain-body mitochondrial distribution patterns lack coherence and point to tissue-specific and individualized regulatory mechanisms.

Biochim Biophys Acta Bioenerg. 2024 Sep 30. pii: S0005-2728(24)00486-9. [Epub ahead of print] 149516

In isolated brown adipose tissue mitochondria UCP1 is not essential for nor involved in the uncoupling effects of the classical uncouplers FCCP and DNP.

Irina G Shabalina, Beatriz Jiménez, Celso Pereira Batista Sousa-Filho, Barbara Cannon, Jan Nedergaard.

  Recent patch-clamp studies of mitoplasts have challenged the traditional view that classical chemical uncoupling (by e.g. FCCP or DNP) is due to the protonophoric property of these substances themselves. These studies instead suggest that in brown-fat mitochondria, FCCP- and DNP-induced uncoupling is mediated through activation of UCP1 (and in other tissues by activation of the adenine nucleotide transporter). These studies thus advocate an entirely new paradigm for the interpretation of standard bioenergetic experiments. To examine whether these patch-clamp results obtained in brown-fat mitoplasts are directly transferable to classical isolated brown-fat mitochondria studies, we investigated the effects of FCCP and DNP in brown-fat mitochondria from wildtype and UCP1 KO mice, comparing the FCCP and DNP effects with those of a fatty acid (oleate), a bona fide activator of UCP1. Whereas the sensitivity of brown-fat mitochondria to oleate was much higher in UCP1-containing than in UCP1 KO mitochondria, there was no difference in sensitivity to FCCP and DNP between these mitochondria, neither in oxygen consumption rate nor in membrane potential studies. Correspondingly, the UCP1-dependent ability of GDP to competitively inhibit activation by oleate was not seen with FCCP and DNP. It would thus be premature to abandon the established bioenergetic interpretation of chemical uncoupler effects in classical isolated brown-fat mitochondria-and probably also generally in this type of mitochondrial study. Understanding the molecular and structural reasons for the different outcomes of mitoplast and mitochondrial studies is a challenging task in bioenergetics.

Keywords:  2,4-dinitrophenol (DNP); FCCP; Membrane potential; Methyl-β-cyclodextrin; Uncoupling protein 1 (UCP1); brown adipose tissue mitochondria

DOI:  https://doi.org/10.1016/j.bbabio.2024.149516
Biochim Biophys Acta Mol Cell Biol Lipids. 2024 Oct 02. pii: S1388-1981(24)00117-3. [Epub ahead of print] 159567

Sex-specific response of the human plasma lipidome to short-term cold exposure.

Marcus Höring, Sarah Brunner, Josef Scheiber, Julius Honecker, Gerhard Liebisch, Claudine Seeliger, Laura Schinhammer, Melina Claussnitzer, Ralph Burkhardt, Hans Hauner, Josef Ecker.

  Cold-induced lipolysis is widely studied as a potential therapeutic strategy to combat metabolic disease, but its effect on lipid homeostasis in humans remains largely unclear. Blood plasma comprises an enormous repertoire in lipids allowing insights into whole body lipid homeostasis. So far, reported results originate from studies carried out with small numbers of male participants. Here, the blood plasma's lipidome of 78 male and 93 female volunteers, who were exposed to cold below the shivering threshold for 2 h, was quantified by comprehensive lipidomics using high-resolution mass spectrometry. Short-term cold exposure increased the concentrations in 147 of 177 quantified circulating lipids and the response of the plasma's lipidome was sex-specific. In particular, the amounts of generated glycerophospholipid and sphingolipid species differed between the sexes. In women, the BMI could be related with the lipidome's response. A logistic regression model predicted with high sensitivity and specificity whether plasma samples were from male or female subjects based on the cold-induced response of phosphatidylcholine (PC), lysophosphatidylcholine (LPC), and sphingomyelin (SM) species. In summary, cold exposure promotes lipid synthesis by supplying fatty acids generated after lipolysis for all lipid classes. The plasma lipidome, i.e. PC, LPC and SM, shows a sex-specific response, indicating a different regulation of its metabolism in men and women. This supports the need for sex-specific research and avoidance of sex bias in clinical trials.

Keywords:  Cold exposure; Lipidomics; Lysophosphatidylcholine; Phosphatidylcholine; Plasma lipidome; Sex; Sphingomyelin

DOI:  https://doi.org/10.1016/j.bbalip.2024.159567
Cell Chem Biol. 2024 Sep 26. pii: S2451-9456(24)00393-3. [Epub ahead of print]

Small molecules targeting selective PCK1 and PGC-1α lysine acetylation cause anti-diabetic action through increased lactate oxidation.

Beste Mutlu, Kfir Sharabi, Jee Hyung Sohn, Bo Yuan, Pedro Latorre-Muro, Xin Qin, Jin-Seon Yook, Hua Lin, Deyang Yu, João Paulo G Camporez, Shingo Kajimura, Gerald I Shulman, Sheng Hui, Theodore M Kamenecka, Patrick R Griffin, Pere Puigserver.

Small molecules selectively inducing peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α acetylation and inhibiting glucagon-dependent gluconeogenesis causing anti-diabetic effects have been identified. However, how these small molecules selectively suppress the conversion of gluconeogenic metabolites into glucose without interfering with lipogenesis is unknown. Here, we show that a small molecule SR18292 inhibits hepatic glucose production by increasing lactate and glucose oxidation. SR18292 increases phosphoenolpyruvate carboxykinase 1 (PCK1) acetylation, which reverses its gluconeogenic reaction and favors oxaloacetate (OAA) synthesis from phosphoenolpyruvate. PCK1 reverse catalytic reaction induced by SR18292 supplies OAA to tricarboxylic acid (TCA) cycle and is required for increasing glucose and lactate oxidation and suppressing gluconeogenesis. Acetylation mimetic mutant PCK1 K91Q favors anaplerotic reaction and mimics the metabolic effects of SR18292 in hepatocytes. Liver-specific expression of PCK1 K91Q mutant ameliorates hyperglycemia in obese mice. Thus, SR18292 blocks gluconeogenesis by enhancing gluconeogenic substrate oxidation through PCK1 lysine acetylation, supporting the anti-diabetic effects of these small molecules.

DOI: https://doi.org/10.1016/j.chembiol.2024.09.001
Nat Commun. 2024 Oct 02. 15(1): 8533

Transcription factor PATZ1 promotes adipogenesis by controlling promoter regulatory loci of adipogenic factors.

Sanil Patel, Khatanzul Ganbold, Chung Hwan Cho, Juwairriyyah Siddiqui, Ramazan Yildiz, Njeri Sparman, Shani Sadeh, Christy M Nguyen, Jiexin Wang, Julian P Whitelegge, Susan K Fried, Hironori Waki, Claudio J Villanueva, Marcus M Seldin, Shinya Sakaguchi, Wilfried Ellmeier, Peter Tontonoz, Prashant Rajbhandari.

White adipose tissue (WAT) is essential for lipid storage and systemic energy homeostasis. Understanding adipocyte formation and stability is key to developing therapies for obesity and metabolic disorders. Through a high-throughput cDNA screen, we identified PATZ1, a POZ/BTB and AT-Hook Containing Zinc Finger 1 protein, as an important adipogenic transcription factor. PATZ1 is expressed in human and mouse adipocyte precursor cells (APCs) and adipocytes. In cellular models, PATZ1 promotes adipogenesis via protein-protein interactions and DNA binding. PATZ1 ablation in mouse adipocytes and APCs leads to a reduced APC pool, decreased fat mass, and hypertrophied adipocytes. ChIP-Seq and RNA-seq analyses show that PATZ1 supports adipogenesis by interacting with transcriptional machinery at the promoter regions of key early adipogenic factors. Mass-spec results show that PATZ1 associates with GTF2I, with GTF2I modulating PATZ1's function during differentiation. These findings underscore PATZ1's regulatory role in adipocyte differentiation and adiposity, offering insights into adipose tissue development.

DOI: https://doi.org/10.1038/s41467-024-52917-y
Proc Natl Acad Sci U S A. 2024 Oct 08. 121(41): e2412526121

Local adaptation, plasticity, and evolved resistance to hypoxic cold stress in high-altitude deer mice.

Naim M Bautista, Nathanael D Herrera, Ellen Shadowitz, Oliver H Wearing, Zachary A Cheviron, Graham R Scott, Jay F Storz.

  A fundamental question in evolutionary biology concerns the relative contributions of phenotypic plasticity vs. local adaptation (genotypic specialization) in enabling wide-ranging species to inhabit diverse environmental conditions. Here, we conduct a long-term hypoxia acclimation experiment to assess the relative roles of local adaptation and plasticity in enabling highland and lowland deer mice (Peromyscus maniculatus) to sustain aerobic thermogenesis at progressively increasing elevations. We assessed the relative physiological performance capacities of highland and lowland natives as they were exposed to progressive, stepwise increases in hypoxia, simulating the gradual ascent from sea level to an elevation of 6,000 m. The final elevation of 6,000 m far exceeds the highest attainable elevations within the species' range, and therefore tests the animals' ability to tolerate levels of hypoxia that surpass the prevailing conditions within their current distributional limits. Our results demonstrate that highland natives exhibit superior thermogenic capacities at the most severe levels of hypoxia, suggesting that the species' broad fundamental niche and its ability to inhabit such a broad range of elevational zones is attributable to genetically based local adaptation, including evolved changes in plasticity. Transcriptomic and physiological measurements identify evolved changes in the acclimation response to hypoxia that contribute to the enhanced thermogenic capacity of highland natives.

Keywords:  high altitude; hypoxia; local adaptation; phenotypic plasticity

DOI:  https://doi.org/10.1073/pnas.2412526121
bioRxiv. 2024 Sep 16. pii: 2024.09.13.612486. [Epub ahead of print]

Adipocyte sphingosine kinase 1 regulates histone modifiers to disrupt circadian function.

Andrea Anderson, Anna Kovilakath, Maryam Jamil, Johana Lambert, L Ashley Cowart.

Circadian rhythms align biological functions with the 24-hour day-night cycle, but modern artificial light disrupts these patterns, contributing to health issues like obesity and cardiovascular disease. The circadian clock operates through a transcriptional-translational feedback loop involving core components such as BMAL1 and CLOCK. Recent research has shown circadian variations in sphingolipid metabolism, specifically sphingosine-1-phosphate (S1P), which plays crucial signaling roles. This study investigates the sphingolipid enzyme, sphingosine kinase 1 (SphK1), which converts sphingosine to S1P, as a circadian-regulated gene in adipocytes. We find that SphK1 expression and activity follow a circadian rhythm, regulated by BMAL1 and CLOCK binding to its promoter. Adipocyte-specific SphK1 knockout mice exhibit disrupted circadian rhythms, and impaired adipocyte function. Additionally, SphK1 deficiency leads to reduced histone acetylation and altered histone deacetylase (HDAC) localization, affecting gene regulation. These results highlight the critical role of SphK1 in linking lipid metabolism with circadian biology.

DOI: https://doi.org/10.1101/2024.09.13.612486
bioRxiv. 2024 Sep 22. pii: 2024.09.20.614152. [Epub ahead of print]

Brain-body mitochondrial distribution patterns lack coherence and point to tissue-specific and individualized regulatory mechanisms.

Jack Devine, Anna S Monzel, David Shire, Ayelet M Rosenberg, Alex Junker, Alan A Cohen, Martin Picard.

Energy transformation capacity is generally assumed to be a coherent individual trait driven by genetic and environmental factors. This predicts that some individuals should have high and others low mitochondrial oxidative phosphorylation (OxPhos) capacity across organ systems. Here, we test this assumption using multi-tissue molecular and enzymatic activities in mice and humans. Across up to 22 mouse tissues, neither mitochondrial OxPhos capacity nor mtDNA density were correlated between tissues (median r = -0.01-0.16), indicating that animals with high mitochondrial capacity in one tissue can have low capacity in other tissues. Similarly, the multi-tissue correlation structure of RNAseq-based indices of mitochondrial gene expression across 45 tissues from 948 women and men (GTEx) showed small to moderate coherence between only some tissues (regions of the same brain), but not between brain-body tissue pairs in the same person (median r = 0.01). Mitochondrial DNA copy number (mtDNAcn) also lacked coherence across organs and tissues. Mechanistically, tissue-specific differences in mitochondrial gene expression were attributable in part to i) tissue-specific activation of canonical energy sensing pathways including the transcriptional coactivator PGC-111 and the integrated stress response (ISR), and ii) proliferative activity across tissues. Finally, we identify subgroups of individuals with high mitochondrial gene expression in some tissues (e.g., heart) but low expression in others (e.g., skeletal muscle) who display different clinical phenotypic patterns. Taken together, these data raise the possibility that tissue-specific energy sensing pathways may contribute to the idiosyncratic mitochondrial distribution patterns associated with the inter-organ heterogeneity and phenotypic diversity among individuals.

DOI: https://doi.org/10.1101/2024.09.20.614152