bims-mimbat 2023-09-10 papers

Nat Commun. 2023 Sep 06. 14(1): 5480

Cold-activated brown fat-derived extracellular vesicle-miR-378a-3p stimulates hepatic gluconeogenesis in male mice.

Jinhong Xu, Le Cui, Jiaqi Wang, Shasha Zheng, Huahua Zhang, Shuo Ke, Xiaoqin Cao, Yanteng Shi, Jing Li, Ke Zen, Antonio Vidal-Puig, Chen-Yu Zhang, Liang Li, Xiaohong Jiang.

During cold exposure, activated brown adipose tissue (BAT) takes up a large amount of circulating glucose to fuel non-shivering thermogenesis and defend against hypothermia. However, little is known about the endocrine function of BAT controlling glucose homoeostasis under this thermoregulatory challenge. Here, we show that in male mice, activated BAT-derived extracellular vesicles (BDEVs) reprogram systemic glucose metabolism by promoting hepatic gluconeogenesis during cold stress. Cold exposure facilitates the selective packaging of miR-378a-3p-one of the BAT-enriched miRNAs-into EVs and delivery into the liver. BAT-derived miR-378a-3p enhances gluconeogenesis by targeting p110α. miR-378 KO mice display reduced hepatic gluconeogenesis during cold exposure, while restoration of miR-378a-3p in iBAT induces the expression of gluconeogenic genes in the liver. These findings provide a mechanistic understanding of BDEV-miRNA as stress-induced batokine to coordinate systemic glucose homoeostasis. This miR-378a-3p-mediated interorgan communication highlights a novel endocrine function of BAT in preventing hypoglycemia during cold stress.

DOI: https://doi.org/10.1038/s41467-023-41160-6

Redox Biol. 2023 Sep 02. pii: S2213-2317(23)00275-6. [Epub ahead of print]66 102874

Adverse bioenergetic effects of N-acyl amino acids in human adipocytes overshadow beneficial mitochondrial uncoupling.

Marie Herrnhold, Isabel Hamp, Oliver Plettenburg, Martin Jastroch, Michaela Keuper.

OBJECTIVE: Enhancing energy turnover via uncoupled mitochondrial respiration in adipose tissue has great potential to improve human obesity and other metabolic complications. However, the amount of human brown adipose tissue and its uncoupling protein 1 (UCP1) is low in obese patients. Recently, a class of endogenous molecules, N-acyl amino acids (NAAs), was identified as mitochondrial uncouplers in murine adipocytes, presumably acting via the adenine nucleotide translocator (ANT). Given the translational potential, we investigated the bioenergetic effects of NAAs in human adipocytes, characterizing beneficial and adverse effects, dose ranges, amino acid derivatives and underlying mechanisms.
METHOD: NAAs with neutral (phenylalanine, leucine, isoleucine) and polar (lysine) residues were synthetized and assessed in intact and permeabilized human adipocytes using plate-based respirometry. The Seahorse technology was applied to measure bioenergetic parameters, dose-dependency, interference with UCP1 and adenine nucleotide translocase (ANT) activity, as well as differences to the established chemical uncouplers niclosamide ethanolamine (NEN) and 2,4-dinitrophenol (DNP).
RESULT: NAAs with neutral amino acid residues potently induce uncoupled respiration in human adipocytes in a dose-dependent manner, even in the presence of the UCP1-inhibitor guanosine diphosphate (GDP) and the ANT-inhibitor carboxyatractylate (CAT). However, neutral NAAs significantly reduce maximal oxidation rates, mitochondrial ATP-production, coupling efficiency and reduce adipocyte viability at concentrations above 25 μM. The in vitro therapeutic index (using induced proton leak and viability as determinants) of NAAs is lower than that of NEN and DNP.
CONCLUSION: NAAs are potent mitochondrial uncouplers in human adipocytes, independent of UCP1 and ANT. However, previously unnoticed adverse effects harm adipocyte functionality, reduce the therapeutic index of NAAs in vitro and therefore question their suitability as anti-obesity agents without further chemical modifications.

Keywords: Adipocytes; Metabolism; Mitochondria; Obesity; UCP1; Uncoupling

DOI: https://doi.org/10.1016/j.redox.2023.102874

Philos Trans R Soc Lond B Biol Sci. 2023 Oct 23. 378(1888): 20220220

Brown adipose tissue: can it keep us slim? A discussion of the evidence for and against the existence of diet-induced thermogenesis in mice and men.

Jan Nedergaard, Gabriella von Essen, Barbara Cannon.

The issue under discussion here is whether a decrease in the degree of UCP1 activity (and brown adipose tissue activity in general) could be a cause of obesity in humans. This possibility principally requires the existence of the phenomenon of diet-induced thermogenesis. Obesity could be a consequence of a reduced functionality of diet-induced thermogenesis. Experiments in mice indicate that diet-induced thermogenesis exists and is dependent on the presence of UCP1 and thus of brown adipose tissue activity. Accordingly, many (but not all) experiments indicate that in the absence of UCP1, mice become obese. Whether similar mechanisms exist in humans is still unknown. A series of studies have indicated a correlation between obesity and low brown adipose tissue activity, but it may be so that the obesity itself may influence the estimates of brown adipose tissue activity (generally glucose uptake), partly explaining the relationship. Estimates of brown adipose tissue catabolizing activity would seem to indicate that it may possess a capacity sufficient to help maintain body weight, and obesity would thus be aggravated in its absence. This article is part of a discussion meeting issue 'Causes of obesity: theories, conjectures and evidence (Part II)'.

Keywords: UCP1; brown adipose tissue; diet-induced thermogenesis

DOI: https://doi.org/10.1098/rstb.2022.0220

EMBO Rep. 2023 Sep 06. e57600

The obesity-linked human lncRNA AATBC stimulates mitochondrial function in adipocytes.

Adipocytes are critical regulators of metabolism and energy balance. While white adipocyte dysfunction is a hallmark of obesity-associated disorders, thermogenic adipocytes are linked to cardiometabolic health. As adipocytes dynamically adapt to environmental cues by functionally switching between white and thermogenic phenotypes, a molecular understanding of this plasticity could help improving metabolism. Here, we show that the lncRNA Apoptosis associated transcript in bladder cancer (AATBC) is a human-specific regulator of adipocyte plasticity. Comparing transcriptional profiles of human adipose tissues and cultured adipocytes we discovered that AATBC was enriched in thermogenic conditions. Using primary and immortalized human adipocytes we found that AATBC enhanced the thermogenic phenotype, which was linked to increased respiration and a more fragmented mitochondrial network. Expression of AATBC in adipose tissue of mice led to lower plasma leptin levels. Interestingly, this association was also present in human subjects, as AATBC in adipose tissue was inversely correlated with plasma leptin levels, BMI, and other measures of metabolic health. In conclusion, AATBC is a novel obesity-linked regulator of adipocyte plasticity and mitochondrial function in humans.

Keywords: adipocyte; mitochondrial dynamics; non-coding RNA; obesity; thermogenesis

DOI: https://doi.org/10.15252/embr.202357600

EBioMedicine. 2023 Aug 31. pii: S2352-3964(23)00337-7. [Epub ahead of print]96 104771

Effect of high-dose glucocorticoid treatment on human brown adipose tissue activity: a randomised, double-blinded, placebo-controlled cross-over trial in healthy men.

Claudia Irene Maushart, Wenfei Sun, Alaa Othman, Adhideb Ghosh, Jaël Rut Senn, Jonas Gabriel William Fischer, Philipp Madoerin, Rahel Catherina Loeliger, Robyn Melanie Benz, Martin Takes, Christoph Johannes Zech, Alin Chirindel, Felix Beuschlein, Martin Reincke, Damian Wild, Oliver Bieri, Nicola Zamboni, Christian Wolfrum, Matthias Johannes Betz.

BACKGROUND: Glucocorticoids (GCs) are widely applied anti-inflammatory drugs that are associated with adverse metabolic effects including insulin resistance and weight gain. Previous research indicates that GCs may negatively impact brown adipose tissue (BAT) activity in rodents and humans.
METHODS: We performed a randomised, double-blinded cross-over trial in 16 healthy men (clinicaltrials.govNCT03269747). Participants received 40 mg of prednisone per day for one week or placebo. After a washout period of four weeks, participants crossed-over to the other treatment arm. Primary endpoint was the increase in resting energy expenditure (EE) in response to a mild-cold stimulus (cold-induced thermogenesis, CIT). Secondary outcomes comprised mean 18F-FDG uptake into supraclavicular BAT (SUVmean) as determined by FDG-PET/CT, volume of the BAT depot as well as fat content determined by MRI. The plasma metabolome and the transcriptome of supraclavicular BAT and of skeletal muscle biopsies after each treatment period were analysed.
FINDINGS: Sixteen participants were recruited to the trial and completed it successfully per protocol. After prednisone treatment resting EE was higher both during warm and cold conditions. However, CIT was similar, 153 kcal/24 h (95% CI 40-266 kcal/24 h) after placebo and 186 kcal/24 h (95% CI 94-277 kcal/24 h, p = 0.38) after prednisone. SUVmean of BAT after cold exposure was not significantly affected by prednisone (3.36 g/ml, 95% CI 2.69-4.02 g/ml, vs 3.07 g/ml, 95% CI 2.52-3.62 g/ml, p = 0.28). Results of plasma metabolomics and BAT transcriptomics corroborated these findings. RNA sequencing of muscle biopsies revealed higher expression of genes involved in calcium cycling. No serious adverse events were reported and adverse events were evenly distributed between the two treatments.
INTERPRETATION: Prednisone increased EE in healthy men possibly by altering skeletal muscle calcium cycling. Cold-induced BAT activity was not affected by GC treatment, which indicates that the unfavourable metabolic effects of GCs are independent from thermogenic adipocytes.
FUNDING: Grants from Swiss National Science Foundation (PZ00P3_167823), Bangerter-Rhyner Foundation and from Nora van der Meeuwen-Häfliger Foundation to MJB. A fellowship-grant from the Swiss National Science Foundation (SNF211053) to WS. Grants from German Research Foundation (project number: 314061271-TRR 205) and Else Kröner-Fresenius (grant support 2012_A103 and 2015_A228) to MR.

Keywords: Brown adipose tissue; Cold-induced thermogenesis; Energy expenditure; Glucocorticoids; Prednisone

DOI: https://doi.org/10.1016/j.ebiom.2023.104771

bioRxiv. 2023 Aug 26. pii: 2023.08.26.554950. [Epub ahead of print]

Adrenergic Reprogramming of Preexisting Adipogenic Trajectories Steer Naïve Mural Cells Toward Beige Differentiation.

Kathleen Desevin, Briana N Cortez, Jean Z Lin, Dechen Lama, Matthew D Layne, Stephen R Farmer, Nabil Rabhi.

In adult white adipose tissue, cold or β3-adrenoceptor activation promotes the appearance of thermogenic beige adipocytes. Our comprehensive single-cell analysis revealed that these cells arise through the reprogramming of existing adipogenic trajectories, rather than from a single precursor. These trajectories predominantly arise from SM22-expressing vascular mural progenitor cells. Central in this transition is the activation of Adrb3 in mature adipocytes, leading to subsequent upregulation of Adrb1 in primed progenitors. Under thermoneutral conditions, synergistic activation of both Adrb3 and Adrb1 recapitulates the pattern of cold-induced SM22+ cell recruitment. Lipolysis-derived eicosanoids, specifically docosahexaenoic acid (DHA) and arachidonic acid (AA) prime these processes and in vitro, were sufficient to recapitulate progenitor cells priming. Collectively, our findings provide a robust model for cold-induced beige adipogenesis, emphasizing a profound relationship between mature adipocytes and mural cells during cold acclimation, and revealing the metabolic potential of this unique cellular reservoir.

DOI: https://doi.org/10.1101/2023.08.26.554950

Nat Struct Mol Biol. 2023 Sep 07.

Substrate binding and inhibition of the anion exchanger 1 transporter.

Michael J Capper, Shifan Yang, Alexander C Stone, Sezen Vatansever, Gregory Zilberg, Yamuna Kalyani Mathiharan, Raul Habib, Keino Hutchinson, Yihan Zhao, Avner Schlessinger, Mihaly Mezei, Roman Osman, Bin Zhang, Daniel Wacker.

Anion exchanger 1 (AE1), a member of the solute carrier (SLC) family, is the primary bicarbonate transporter in erythrocytes, regulating pH levels and CO2 transport between lungs and tissues. Previous studies characterized its role in erythrocyte structure and provided insight into transport regulation. However, key questions remain regarding substrate binding and transport, mechanisms of drug inhibition and modulation by membrane components. Here we present seven cryo-EM structures in apo, bicarbonate-bound and inhibitor-bound states. These, combined with uptake and computational studies, reveal important molecular features of substrate recognition and transport, and illuminate sterol binding sites, to elucidate distinct inhibitory mechanisms of research chemicals and prescription drugs. We further probe the substrate binding site via structure-based ligand screening, identifying an AE1 inhibitor. Together, our findings provide insight into mechanisms of solute carrier transport and inhibition.

DOI: https://doi.org/10.1038/s41594-023-01085-6