bims-mimbat 2022-02-27 papers

bims-mimbat

Biomed News

on Mitochondrial metabolism in brown adipose tissue

Issue of 2022–02–27
eight papers selected by
José Carlos de Lima-Júnior, University of California San Francisco

Establishing the potency of N-acyl amino acids versus conventional fatty acids as thermogenic uncouplers in cells and mitochondria from different tissues.
Matrine counteracts obesity in mice via inducing adipose thermogenesis by activating HSF1/PGC-1α axis.
Brown adipose TRX2 deficiency activates mtDNA-NLRP3 to impair thermogenesis and protect against diet-induced insulin resistance.
RNA-binding protein YBX1 promotes brown adipogenesis and thermogenesis via PINK1/PRKN-mediated mitophagy.
The Uncoupling Proteins: A Systematic Review on the Mechanism Used in the Prevention of Oxidative Stress.
SENP2 suppresses browning of white adipose tissues by de-conjugating SUMO from C/EBPβ.
Free Fatty Acid Receptors (FFARs) in Adipose: Physiological Role and Therapeutic Outlook.
ATP Synthase K+- and H+-fluxes Drive ATP Synthesis and Enable Mitochondrial K+-"Uniporter" Function: II. Ion and ATP Synthase Flux Regulation.

Biochim Biophys Acta Bioenerg. 2022 Feb 19. pii: S0005-2728(22)00011-1. [Epub ahead of print] 148542

Establishing the potency of N-acyl amino acids versus conventional fatty acids as thermogenic uncouplers in cells and mitochondria from different tissues.

Yun Gao, Irina Shabalina, G Ruda F Braz, Barbara Cannon, Gongshe Yang, Jan Nedergaard.

  The possibility that N-acyl amino acids could function as brown or brite/beige adipose tissue-derived lipokines that could induce UCP1-independent thermogenesis by uncoupling mitochondrial respiration in several peripheral tissues is of significant physiological interest. To quantify the potency of N-acyl amino acids versus conventional fatty acids as thermogenic inducers, we have examined the affinity and efficacy of two pairs of such compounds: oleate versus N-oleoyl-leu and arachidonate versus N-arachidonoyl-gly in cells and mitochondria from different tissues. We found that in cultures of the muscle-derived L6 cell line, as well as in primary cultures of murine white, brite/beige and brown adipocytes, the N-acyl amino acids were proficient uncouplers but that they did not systematically display higher affinity or potency than the conventional fatty acids, and they were not as efficient uncouplers as classical protonophores (FCCP). Higher concentrations of the N-acyl amino acids (as well as of conventional fatty acids) were associated with signs of deleterious effects on the cells. In liver mitochondria, we found that the N-acyl amino acids uncoupled similarly to conventional fatty acids, thus apparently via activation of the adenine nucleotide transporter-2. In brown adipose tissue mitochondria, the N-acyl amino acids were able to activate UCP1, again similarly to conventional fatty acids. We thus conclude that the formation of the acyl-amino acid derivatives does not confer upon the corresponding fatty acids an enhanced ability to induce thermogenesis in peripheral tissues, and it is therefore unlikely that the N-acyl amino acids are of physiological relevance as UCP1-independent thermogenic compounds.

Keywords:  Adenine nucleotide transporter; Fatty acids; N-acyl amino acids, N-oleoyl-leu; Nonshivering thermogenesis; Uncoupling protein-1

DOI:  https://doi.org/10.1016/j.bbabio.2022.148542
Pharmacol Res. 2022 Feb 21. pii: S1043-6618(22)00081-0. [Epub ahead of print] 106136

Matrine counteracts obesity in mice via inducing adipose thermogenesis by activating HSF1/PGC-1α axis.

Chan Li, Yao-Hao Xu, Yu-Tao Hu, Xiu Zhou, Zhi-Shu Huang, Ji-Ming Ye, Yong Rao.

  Promoting energy expenditure is known to curb obesity and can be exploited for its treatment. Our previous study has demonstrated that activation of HSF1/PGC-1α axis efficiently induced mitochondrial biogenesis and adaptive oxidation and thus ameliorating lipid accumulation, however, whether it can be a therapeutic approach for metabolic disorders treatment needs explored. Here, a high-efficient and specific HSF1/PGC-1α activator screening system was established and the natural clinical liver-protecting agent matrine was identified as a robust HSF1/PGC-1α activator. Matrine treatment efficiently induced mitogenesis and thermogenic program in primary mouse adipose stem cell derived adipocytes by enriching HSF1 to the promoter of Pgc-1α. Deficiency of PGC-1α in adipocytes diminished the browning induction ability of matrine. Oral administration of matrine to the obese mice induced by high fat and high cholesterol diet increased energy expenditure and corrected the degeneration of thermogenesis in brown adipose tissue (BAT). Also, matrine treatment markedly induced the transformation of brown-like adipocytes in subcutaneous white adipose tissue (sWAT) via a mechanism of HSF1/PGC-1α, thereby attenuating obesity and myriads of metabolic disorders. This led to an improvement in adaptive thermogenesis to cold stimuli. These findings are of great significance in understanding the regulation mechanisms of the HSF1/PGC-1α axis in thermogenesis and providing a novel therapeutic approach for obesity treatment. Matrine may have potential therapeutic implications for the treatment of obesity in clinics.

Keywords:  HSF1/PGC-1α axis; matrine; obesity; thermogenesis; white adipose tissue

DOI:  https://doi.org/10.1016/j.phrs.2022.106136
J Clin Invest. 2022 Feb 24. pii: e148852. [Epub ahead of print]

Brown adipose TRX2 deficiency activates mtDNA-NLRP3 to impair thermogenesis and protect against diet-induced insulin resistance.

Yanrui Huang, Jenny H Zhou, Haifeng Zhang, Alberto Canfrán-Duque, Abhishek K Singh, Rachel J Perry, Gerald Shulman, Carlos Fernandez-Hernando, Wang Min.

  Brown adipose tissue (BAT), a crucial heat-generating organ, regulate whole-body energy metabolism by mediating thermogenesis. BAT inflammation is implicated in the pathogenesis of mitochondrial dysfunction and impaired thermogenesis. However, the link between BAT inflammation and systematic metabolism remains unclear. Herein, we use mice with BAT deficiency of thioredoxin-2 (TRX2), a protein that scavenges mitochondrial reactive oxygen species (ROS), to evaluate the impact of BAT inflammation on metabolism and thermogenesis and its underlying mechanism. Our results describe that BAT-specific TRX2 ablation improves systematic metabolic performance via enhancing lipid uptake, which protects mice from diet-induced obesity, hypertriglyceridemia, and insulin resistance. TRX2 deficiency impairs adaptive thermogenesis by suppressing fatty acid oxidation. Mechanistically, loss of TRX2 induces excessive mitochondrial ROS, mitochondrial integrity disruption, and cytosolic release of mitochondrial DNA, which in turn activate aberrant innate immune responses in BAT, including the cGAS-STING and the NLRP3 inflammasome pathways. We identify NLRP3 as a key converging point, as its inhibition reverses both the thermogenesis defect and the metabolic benefits seen under nutrient overload in BAT-specific Trx2-deficient mice. In conclusion, we identify TRX2 as a critical hub integrating oxidative stress, inflammation, and lipid metabolism in BAT; uncovering an adaptive mechanism underlying the link between BAT inflammation and systematic metabolism.

Keywords:  Adipose tissue; Inflammation; Innate immunity; Metabolism; Mitochondria

DOI:  https://doi.org/10.1172/JCI148852
FASEB J. 2022 03;36(3): e22219

RNA-binding protein YBX1 promotes brown adipogenesis and thermogenesis via PINK1/PRKN-mediated mitophagy.

Ruifan Wu, Shuting Cao, Fan Li, Shengchun Feng, Gang Shu, Lina Wang, Ping Gao, Xiaotong Zhu, Canjun Zhu, Songbo Wang, Qingyan Jiang.

  Promoting the thermogenic function of brown adipose tissue (BAT) is a promising strategy to combat obesity and metabolic disorders. While much is known about the transcriptional regulation of BAT activation, however, the underlying mechanism of post-transcriptional control by RNA binding proteins remains largely unknown. Here, we found that RNA binding protein Y-box binding protein 1 (YBX1) expression was abundant in BAT and induced by cold exposure and a β-adrenergic agonist in mice. Loss-of-function experiments showed that YBX1 deficiency inhibited mouse primary brown adipocyte differentiation and thermogenic function. Further study showed that YBX1 positively regulates thermogenesis through enhancing mitophagy. Mechanistically, RNA immunoprecipitation identified that YBX1 directly targeted the transcripts of PTEN-induced kinase 1 (Pink1) and parkin RBR E3 ubiquitin-protein ligase (Prkn), two key regulators of mitophagy. RNA decay assay proved that loss of YBX1 decreased mRNA stability of Pink1 and Prkn, leading to reduced protein expression, thereby alleviating mitophagy and inhibiting thermogenic program. Importantly, in vivo experiments demonstrated that YBX1 overexpression in BAT promoted thermogenesis and mitophagy in mice. Collectively, our results reveal novel insight into the molecular mechanism of YBX1 in post-transcriptional regulation of PINK1/PRKN-mediated mitophagy and highlight the critical role of YBX1 in brown adipogenesis and thermogenesis.

Keywords:  PINK1/PRKN; YBX1; adipogenesis; mitophagy; thermogenesis

DOI:  https://doi.org/10.1096/fj.202101810RR
Antioxidants (Basel). 2022 Feb 06. pii: 322. [Epub ahead of print]11(2):

The Uncoupling Proteins: A Systematic Review on the Mechanism Used in the Prevention of Oxidative Stress.

Jonathan Hirschenson, Emiliano Melgar-Bermudez, Ryan J Mailloux.

  Mitochondrial uncoupling proteins (UCP) 1-3 fulfill many physiological functions, ranging from non-shivering thermogenesis (UCP1) to glucose-stimulated insulin release (GSIS) and satiety signaling (UCP2) and muscle fuel metabolism (UCP3). Several studies have suggested that UCPs mediate these functions by facilitating proton return to the matrix. This would decrease protonic backpressure on the respiratory chain, lowering the production of hydrogen peroxide (H2O2), a second messenger. However, controlling mitochondrial H2O2 production to prevent oxidative stress by activating these leaks through these proteins is still enthusiastically debated. This is due to compelling evidence that UCP2/3 fulfill other function(s) and the inability to reproduce findings that UCP1-3 use inducible leaks to control reactive oxygen species (ROS) production. Further, other studies have found that UCP2/3 may serve as Ca2+. Therefore, we performed a systematic review aiming to summarize the results collected on the topic. A literature search using a list of curated keywords in Pubmed, BIOSIS Citation Index and Scopus was conducted. Potentially relevant references were screened, duplicate references eliminated, and then literature titles and abstracts were evaluated using Rayyan software. A total of 1101 eligible studies were identified for the review. From this total, 416 studies were evaluated based on our inclusion criteria. In general, most studies identified a role for UCPs in preventing oxidative stress, and in some cases, this may be related to the induction of leaks and lowering protonic backpressure on the respiratory chain. However, some studies also generated evidence that UCP2/3 may mitigate oxidative stress by transporting Ca2+ into the matrix, exporting lipid hydroperoxides, or by transporting C-4 metabolites. Additionally, some showed that activating UCP1 or 3 can increase mitochondrial ROS production, even though there is still augmented protection from oxidative stress. Conclusion: Overall, most available studies demonstrate that UCPs, particularly UCP2/3, prevent oxidative stress. However, the mechanism utilized to do so remains elusive and raises the question that UCP2/3 should be renamed, since they may still not be true "uncoupling proteins".

Keywords:  mitochondria; proton leaks; reactive oxygen species; uncoupling proteins

DOI:  https://doi.org/10.3390/antiox11020322
Cell Rep. 2022 Feb 22. pii: S2211-1247(22)00132-2. [Epub ahead of print]38(8): 110408

SENP2 suppresses browning of white adipose tissues by de-conjugating SUMO from C/EBPβ.

Ji Seon Lee, Sehyun Chae, Jinyan Nan, Young Do Koo, Seung-Ah Lee, Young Joo Park, Daehee Hwang, Weiping Han, Dong-Sup Lee, Young-Bum Kim, Sung Soo Chung, Kyong Soo Park.

  The adipose tissue is a key site regulating energy metabolism. One of the contributing factors behind this is browning of white adipose tissue (WAT). However, knowledge of the intracellular determinants of the browning process remains incomplete. By generating adipocyte-specific Senp2 knockout (Senp2-aKO) mice, here we show that SENP2 negatively regulates browning by de-conjugating small ubiquitin-like modifiers from C/EBPβ. Senp2-aKO mice are resistant to diet-induced obesity due to increased energy expenditure and heat production. Senp2 knockout promotes beige adipocyte accumulation in inguinal WAT by upregulation of thermogenic gene expression. In addition, SENP2 knockdown promotes thermogenic adipocyte differentiation of precursor cells isolated from inguinal and epididymal WATs. Mechanistically, sumoylated C/EBPβ, a target of SENP2, suppresses expression of HOXC10, a browning inhibitor, by recruiting a transcriptional repressor DAXX. These findings indicate that a SENP2-C/EBPβ-HOXC10 axis operates for the control of beige adipogenesis in inguinal WAT.

Keywords:  C/EBPβ; HOXC10; SENP2; SUMO; adipocytes; adipogenesis; browning; obesity; thermogenesis; transcription

DOI:  https://doi.org/10.1016/j.celrep.2022.110408
Cells. 2022 Feb 21. pii: 750. [Epub ahead of print]11(4):

Free Fatty Acid Receptors (FFARs) in Adipose: Physiological Role and Therapeutic Outlook.

Saeed Al Mahri, Shuja Shafi Malik, Maria Al Ibrahim, Esraa Haji, Ghida Dairi, Sameer Mohammad.

  Fatty acids (FFAs) are important biological molecules that serve as a major energy source and are key components of biological membranes. In addition, FFAs play important roles in metabolic regulation and contribute to the development and progression of metabolic disorders like diabetes. Recent studies have shown that FFAs can act as important ligands of G-protein-coupled receptors (GPCRs) on the surface of cells and impact key physiological processes. Free fatty acid-activated receptors include FFAR1 (GPR40), FFAR2 (GPR43), FFAR3 (GPR41), and FFAR4 (GPR120). FFAR2 and FFAR3 are activated by short-chain fatty acids like acetate, propionate, and butyrate, whereas FFAR1 and FFAR4 are activated by medium- and long-chain fatty acids like palmitate, oleate, linoleate, and others. FFARs have attracted considerable attention over the last few years and have become attractive pharmacological targets in the treatment of type 2 diabetes and metabolic syndrome. Several lines of evidence point to their importance in the regulation of whole-body metabolic homeostasis including adipose metabolism. Here, we summarize our current understanding of the physiological functions of FFAR isoforms in adipose biology and explore the prospect of FFAR-based therapies to treat patients with obesity and Type 2 diabetes.

Keywords:  G-protein-coupled receptors; adipogenesis; adipose tissue; free fatty acid receptors; thermogenesis

DOI:  https://doi.org/10.3390/cells11040750
Function (Oxf). 2022 ;3(2): zqac001

ATP Synthase K+- and H+-fluxes Drive ATP Synthesis and Enable Mitochondrial K+-"Uniporter" Function: II. Ion and ATP Synthase Flux Regulation.

Magdalena Juhaszova, Evgeny Kobrinsky, Dmitry B Zorov, H Bradley Nuss, Yael Yaniv, Kenneth W Fishbein, Rafael de Cabo, Lluis Montoliu, Sandra B Gabelli, Miguel A Aon, Sonia Cortassa, Steven J Sollott.

  We demonstrated that ATP synthase serves the functions of a primary mitochondrial K+ "uniporter," i.e., the primary way for K+ to enter mitochondria. This K+ entry is proportional to ATP synthesis, regulating matrix volume and energy supply-vs-demand matching. We show that ATP synthase can be upregulated by endogenous survival-related proteins via IF1. We identified a conserved BH3-like domain of IF1 which overlaps its "minimal inhibitory domain" that binds to the β-subunit of F1. Bcl-xL and Mcl-1 possess a BH3-binding-groove that can engage IF1 and exert effects, requiring this interaction, comparable to diazoxide to augment ATP synthase's H+ and K+ flux and ATP synthesis. Bcl-xL and Mcl-1, but not Bcl-2, serve as endogenous regulatory ligands of ATP synthase via interaction with IF1 at this BH3-like domain, to increase its chemo-mechanical efficiency, enabling its function as the recruitable mitochondrial KATP-channel that can limit ischemia-reperfusion injury. Using Bayesian phylogenetic analysis to examine potential bacterial IF1-progenitors, we found that IF1 is likely an ancient (∼2 Gya) Bcl-family member that evolved from primordial bacteria resident in eukaryotes, corresponding to their putative emergence as symbiotic mitochondria, and functioning to prevent their parasitic ATP consumption inside the host cell.

Keywords:  ATP synthase regulation; ATPase Inhibitory Factor-1 (IF₁); Bcl-2 family proteins; mitochondrial permeability transition pore; mitochondrial potassium transport; volume regulation

DOI:  https://doi.org/10.1093/function/zqac001