bims-mimbat 2022-09-25 papers

bims-mimbat

Biomed News

on Mitochondrial metabolism in brown adipose tissue

Issue of 2022–09–25
eight papers selected by
José Carlos de Lima-Júnior, University of California San Francisco

Adipocyte IRE1α promotes PGC1α mRNA decay and restrains adaptive thermogenesis.
High-fructose feeding suppresses cold-stimulated brown adipose tissue glucose uptake independently of changes in thermogenesis and the gut microbiome.
An oxytocinergic neural pathway that stimulates thermogenic and cardiac sympathetic outflow.
FAM96A is essential for maintaining organismal energy balance and adipose tissue homeostasis in mice.
Oxygen regulation of breathing is abolished in mitochondrial complex III-deficient arterial chemoreceptors.
Elucidation of the interaction proteome of mitochondrial chaperone Hsp78 highlights its role in protein aggregation during heat stress.
Improving the reproducibility of metabolic research.
"Blocking lipid uptake pathways does not prevent toxicity in adipose triglyceride lipase (ATGL) deficiency".

Nat Metab. 2022 Sep;4(9): 1166-1184

Adipocyte IRE1α promotes PGC1α mRNA decay and restrains adaptive thermogenesis.

Yong Chen, Zhuyin Wu, Shijia Huang, Xiaoxia Wang, Sijia He, Lin Liu, Yurong Hu, Li Chen, Peng Chen, Songzi Liu, Shengqi He, Bo Shan, Ling Zheng, Sheng-Zhong Duan, Zhiyin Song, Lei Jiang, Qiong A Wang, Zhenji Gan, Bao-Liang Song, Jianmiao Liu, Liangyou Rui, Mengle Shao, Yong Liu.

Adipose tissue undergoes thermogenic remodeling in response to thermal stress and metabolic cues, playing a crucial role in regulating energy expenditure and metabolic homeostasis. Endoplasmic reticulum (ER) stress is associated with adipose dysfunction in obesity and metabolic disease. It remains unclear, however, if ER stress-signaling in adipocytes mechanistically mediates dysregulation of thermogenic fat. Here we show that inositol-requiring enzyme 1α (IRE1α), a key ER stress sensor and signal transducer, acts in both white and beige adipocytes to impede beige fat activation. Ablation of adipocyte IRE1α promotes browning/beiging of subcutaneous white adipose tissue following cold exposure or β3-adrenergic stimulation. Loss of IRE1α alleviates diet-induced obesity and augments the anti-obesity effect of pharmacologic β3-adrenergic stimulation. Notably, IRE1α suppresses stimulated lipolysis and degrades Ppargc1a messenger RNA through its RNase activity to downregulate the thermogenic gene program. Hence, blocking IRE1α bears therapeutic potential in unlocking adipocytes' thermogenic capacity to combat obesity and metabolic disorders.

DOI: https://doi.org/10.1038/s42255-022-00631-8
Cell Rep Med. 2022 Sep 20. pii: S2666-3791(22)00291-9. [Epub ahead of print]3(9): 100742

High-fructose feeding suppresses cold-stimulated brown adipose tissue glucose uptake independently of changes in thermogenesis and the gut microbiome.

Gabriel Richard, Denis P Blondin, Saad A Syed, Laura Rossi, Michelle E Fontes, Mélanie Fortin, Serge Phoenix, Frédérique Frisch, Stéphanie Dubreuil, Brigitte Guérin, Éric E Turcotte, Martin Lepage, Michael G Surette, Jonathan D Schertzer, Gregory R Steinberg, Katherine M Morrison, André C Carpentier.

  Diets rich in added sugars are associated with metabolic diseases, and studies have shown a link between these pathologies and changes in the microbiome. Given the reported associations in animal models between the microbiome and brown adipose tissue (BAT) function, and the alterations in the microbiome induced by high-glucose or high-fructose diets, we investigated the potential causal link between high-glucose or -fructose diets and BAT dysfunction in humans. Primary outcomes are changes in BAT cold-induced thermogenesis and the fecal microbiome (clinicaltrials.gov, NCT03188835). We show that BAT glucose uptake, but not thermogenesis, is impaired by a high-fructose but not high-glucose diet, in the absence of changes in the gastrointestinal microbiome. We conclude that decreased BAT glucose metabolism occurs earlier than other pathophysiological abnormalities during fructose overconsumption in humans. This is a potential confounding factor for studies relying on 18F-FDG to assess BAT thermogenesis.

Keywords:  brown adipose tissue; fructose; glucose; magnetic resonance; metabolic dysfunction; microbiome; overfeeding; positron emission tomography; short-chain fatty acids; stable isotopes

DOI:  https://doi.org/10.1016/j.xcrm.2022.100742
Cell Rep. 2022 Sep 20. pii: S2211-1247(22)01215-3. [Epub ahead of print]40(12): 111380

An oxytocinergic neural pathway that stimulates thermogenic and cardiac sympathetic outflow.

Akihiro Fukushima, Naoya Kataoka, Kazuhiro Nakamura.

  Oxytocin alters autonomic functions besides social behaviors. However, the central neuronal links between hypothalamic oxytocinergic neurons and the autonomic nervous system remain unclear. Here we show that oxytocinergic neurons in the rat paraventricular hypothalamic nucleus (PVH), a pivotal site for energy homeostasis, innervate sympathetic premotor neurons in the rostral medullary raphe region (rMR) to stimulate brown adipose tissue (BAT) thermogenesis and cardiovascular functions. Oxytocin receptor stimulation in the rMR evokes BAT thermogenesis and tachycardia. In vivo optogenetic stimulation of the PVH→rMR long-range oxytocinergic pathway, using a virus-mediated system for amplified gene expression in oxytocinergic neurons, not only elicits BAT thermogenic and cardiac responses but also potentiates sympathetic responses evoked by glutamatergic transmission in the rMR. The PVH→rMR oxytocinergic pathway connects the hypothalamic circuit for energy homeostasis to thermogenic and cardiac sympathetic outflow, and, therefore, its defects may cause obesity and impaired thermoregulation, as seen in Prader-Willi syndrome.

Keywords:  CP: Metabolism; CP: Neuroscience; Prader-Willi syndrome; brown adipose tissue; cardiovascular; hypothalamus; medulla oblongata; metabolism; optogenetics; oxytocin; sympathetic nervous system; thermoregulation

DOI:  https://doi.org/10.1016/j.celrep.2022.111380
Free Radic Biol Med. 2022 Sep 20. pii: S0891-5849(22)00593-7. [Epub ahead of print]

FAM96A is essential for maintaining organismal energy balance and adipose tissue homeostasis in mice.

Zhuanzhuan Liu, Shihong Xu, Zhiwei Zhang, Hanying Wang, Qiyue Jing, Shenghan Zhang, Mengnan Liu, Jinzhi Han, Yanbo Kou, Yanxia Wei, Lu Wang, Yugang Wang.

  The iron (Fe) metabolism plays important role in regulating systemic metabolism and obesity development. The Fe inside cells can form iron-sulfur (Fe-S) clusters, which are usually assembled into target proteins with the help of a conserved cluster assembly machinery. Family with sequence similarity 96A (FAM96A; also designated CIAO2A) is a cytosolic Fe-S assembly protein involved in the regulation of cellular Fe homeostasis. However, the biological function of FAM96A in vivo is still incompletely defined. Here, we tested the role of FAM96A in regulating organismal Fe metabolism, which is relevant to obesity and adipose tissue homeostasis. We found that in mice genetically lacking FAM96A globally, intracellular Fe homeostasis was interrupted in both white and brown adipocytes, but the systemic Fe level was normal. FAM96A deficiency led to adipocyte hypertrophy and organismal energy expenditure reduction even under nonobesogenic normal chow diet-fed conditions. Mechanistically, FAM96A deficiency promoted mechanistic target of rapamycin (mTOR) signaling in adipocytes, leading to an elevation of de novo lipogenesis and, therefore, fat mass accumulation. Furthermore, it also caused mitochondrial defects, including defects in mitochondrial number, ultrastructure, redox activity, and metabolic function in brown adipocytes, which are known to be critical for the control of energy balance. Moreover, adipocyte-selective FAM96A knockout partially phenocopied global FAM96A deficiency with adipocyte hypertrophy and organismal energy expenditure defects but the mice were resistant to high-fat diet-induced weight gain. Thus, FAM96A in adipocytes may autonomously act as a critical gatekeeper of organismal energy balance by coupling Fe metabolism to adipose tissue homeostasis.

Keywords:  Adipose tissue; Energy expenditure; Iron metabolism; Iron-sulfur assembly protein; Mitochondria; brown adipocytes

DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.09.011
Proc Natl Acad Sci U S A. 2022 Sep 27. 119(39): e2202178119

Oxygen regulation of breathing is abolished in mitochondrial complex III-deficient arterial chemoreceptors.

Daniel Cabello-Rivera, Patricia Ortega-Sáenz, Lin Gao, Ana M Muñoz-Cabello, Victoria Bonilla-Henao, Paul T Schumacker, José López-Barneo.

  Acute oxygen (O2) sensing is essential for adaptation of organisms to hypoxic environments or medical conditions with restricted exchange of gases in the lung. The main acute O2-sensing organ is the carotid body (CB), which contains neurosecretory chemoreceptor (glomus) cells innervated by sensory fibers whose activation by hypoxia elicits hyperventilation and increased cardiac output. Glomus cells have mitochondria with specialized metabolic and electron transport chain (ETC) properties. Reduced mitochondrial complex (MC) IV activity by hypoxia leads to production of signaling molecules (NADH and reactive O2 species) in MCI and MCIII that modulate membrane ion channel activity. We studied mice with conditional genetic ablation of MCIII that disrupts the ETC in the CB and other catecholaminergic tissues. Glomus cells survived MCIII dysfunction but showed selective abolition of responsiveness to hypoxia (increased [Ca2+] and transmitter release) with normal responses to other stimuli. Mitochondrial hypoxic NADH and reactive O2 species signals were also suppressed. MCIII-deficient mice exhibited strong inhibition of the hypoxic ventilatory response and altered acclimatization to sustained hypoxia. These data indicate that a functional ETC, with coupling between MCI and MCIV, is required for acute O2 sensing. O2 regulation of breathing results from the integrated action of mitochondrial ETC complexes in arterial chemoreceptors.

Keywords:  acute O2 sensing; carotid body glomus cell; hypoxia; mitochondrial O2 sensing and signaling; mitochondrial complex III

DOI:  https://doi.org/10.1073/pnas.2202178119
J Biol Chem. 2022 Sep 14. pii: S0021-9258(22)00937-1. [Epub ahead of print] 102494

Elucidation of the interaction proteome of mitochondrial chaperone Hsp78 highlights its role in protein aggregation during heat stress.

Witold Jaworek, Marc Sylvester, Giovanna Cenini, Wolfgang Voos.

  Chaperones of the Hsp100/Clp family represent major components of protein homeostasis, conferring maintenance of protein activity under stress. The ClpB-type members of the family, present in bacteria, fungi, and plants, are able to resolubilize aggregated proteins. The mitochondrial member of the ClpB family in Saccharomyces cerevisiae is Hsp78. Although Hsp78 has been shown to contribute to proteostasis in elevated temperatures, the biochemical mechanisms underlying this mitochondria-specific thermotolerance are still largely unclear. To identify endogenous chaperone substrate proteins, here we generated an Hsp78-ATPase mutant with stabilized substrate binding behavior. We used two stable isotope labeling (SILAC)-based quantitative mass spectrometry approaches to analyze the role of Hsp78 during heat stress-induced mitochondrial protein aggregation and disaggregation on a proteomic level. We first identified the endogenous substrate spectrum of the Hsp78 chaperone, comprising a wide variety of proteins related to metabolic functions including energy production and protein synthesis, as well as other chaperones, indicating its crucial functions in mitochondrial stress resistance. We then compared these interaction data with aggregation and disaggregation processes in mitochondria under heat stress, which revealed specific aggregation-prone protein populations and demonstrated the direct quantitative impact of Hsp78 on stress-dependent protein solubility under different conditions. We conclude that Hsp78, together with its cofactors, represents a recovery system that protects major mitochondrial metabolic functions during heat stress as well as restores protein biogenesis capacity after the return to normal conditions.

Keywords:  Hsp78; cell biology; chaperone; heat stress; mitochondria; protein aggregation; proteostasis; yeast

DOI:  https://doi.org/10.1016/j.jbc.2022.102494
Nat Metab. 2022 Sep;4(9): 1085

Improving the reproducibility of metabolic research.

DOI: https://doi.org/10.1038/s42255-022-00653-2
J Lipid Res. 2022 Sep 14. pii: S0022-2275(22)00107-9. [Epub ahead of print] 100274

"Blocking lipid uptake pathways does not prevent toxicity in adipose triglyceride lipase (ATGL) deficiency".

Jide Oluwadare, Ainara G Cabodevilla, Ni-Huiping Son, Yunying Hu, Adam E Mullick, Michael Verano, Jose O Alemán, Ravichandran Ramasamy, Ira J Goldberg.

  Lipid accumulation in non-adipose tissues can cause lipotoxicity, leading to cell death and severe organ dysfunction. Adipose triglyceride lipase (ATGL) deficiency causes human Neutral Lipid Storage Disease and leads to cardiomyopathy; ATGL deficiency has no current treatment. One possible approach to alleviate this disorder has been to alter the diet and reduce the supply of dietary lipids and, hence, myocardial lipid uptake. However, in this study, when we supplied cardiac Atgl knockout mice a low- or high-fat diet, we found heart lipid accumulation, heart dysfunction, and death were not altered. We next deleted lipid uptake pathways in the ATGL-deficient mice through the generation of double knockout mice also deficient in either cardiac lipoprotein lipase (LpL) or cluster of differentiation (CD) 36, which is involved in an LpL-independent pathway for fatty acid uptake in the heart. We show neither deletion ameliorated ATGL-deficient heart dysfunction. Similarly, we determined non-lipid-containing media did not prevent lipid accumulation by cultured myocytes; rather, the cells switched to increased de novo fatty acid synthesis. Thus, we conclude pathological storage of lipids in ATGL deficiency cannot be corrected by reducing heart lipid uptake.

Keywords:  CD36; LpL; dietary fat; fatty acid synthesis; heart failure; lipid accumulation; lipid droplets; lipotoxicity; myocardial lipid uptake; storage diseases

DOI:  https://doi.org/10.1016/j.jlr.2022.100274