bims-mimbat 2024-10-13 papers

Issue of 2024‒10‒13
three papers selected by
José Carlos de Lima-Júnior, Washington University

bioRxiv. 2024 Sep 26. pii: 2024.09.24.613949. [Epub ahead of print]

Slit3 Fragments Orchestrate Neurovascular Expansion and Thermogenesis in Brown Adipose Tissue.

Tamires Duarte Afonso Serdan, Heidi Cervantes, Benjamin Frank, Qiyu Tian, Chan Hee J Choi, Anne Hoffmann, Paul Cohen, Matthias Blüher, Gary J Schwartz, Farnaz Shamsi.

Brown adipose tissue (BAT) represents an evolutionary innovation enabling placental mammals to regulate body temperature through adaptive thermogenesis. Brown adipocytes are surrounded by a dense network of blood vessels and sympathetic nerves that support their development and thermogenic function. Cold exposure stimulates BAT thermogenesis through the coordinated induction of brown adipogenesis, angiogenesis, and sympathetic innervation. However, how these distinct processes are coordinated remains unclear. Here, we identify Slit guidance ligand 3 (Slit3) as a new niche factor that mediates the crosstalk among adipocyte progenitors, endothelial cells, and sympathetic nerves. We show that adipocyte progenitors secrete Slit3 which regulates both angiogenesis and sympathetic innervation in BAT and is essential for BAT thermogenesis in vivo. Proteolytic cleavage of Slit3 generates secreted Slit3-N and Slit3-C fragments, which activate distinct receptors to stimulate angiogenesis and sympathetic innervation, respectively. Moreover, we introduce bone morphogenetic protein-1 (Bmp1) as the first Slit protease identified in vertebrates. In summary, this study underscores the essential role of Slit3-mediated neurovascular network expansion in enabling cold-induced BAT adaptation. The co-regulation of neurovascular expansion by Slit3 fragments provides a bifurcated yet harmonized approach to ensure a synchronized response of BAT to environmental challenges. This study presents the first evidence that adipocyte progenitors regulate tissue innervation, revealing a previously unrecognized dimension of cellular interaction within adipose tissue.

DOI: https://doi.org/10.1101/2024.09.24.613949

Commun Biol. 2024 Oct 10. 7(1): 1300

Loss of adipose ATF3 promotes adipose tissue lipolysis and the development of MASH.

Shuwei Hu, Fathima N Cassim Bawa, Yingdong Zhu, Xiaoli Pan, Hui Wang, Raja Gopoju, Yanyong Xu, Yanqiao Zhang.

The crosstalk between adipose tissue and the liver is finely controlled to maintain metabolic health. Yet, how adipose tissue controls toxic free fatty acid overflow into the liver remains incompletely understood. Here, we show that adipocyte activating transcription factor 3 (ATF3) was induced in human or mouse obesity. Adipocyte Atf3-/- (Atf3Adi-/-) mice developed obesity, glucose intolerance, and metabolic dysfunction-associated steatohepatitis (MASH) in chow diet, high-fat diet, or Western diet-fed mice. Blocking fatty acid flux by inhibiting hepatocyte CD36, but not the restoration of hepatic AMPK signaling, prevented the aggravation of MASH in Atf3Adi-/- mice. Further studies show that the loss of adipocyte ATF3 increased lipolysis via inducing adipose triglyceride lipase, which in turn induced lipogenesis and inflammation in hepatocytes. Moreover, Atf3Adi-/- mice had reduced energy expenditure and increased adipose lipogenesis and inflammation. Our data demonstrate that adipocyte ATF3 is a gatekeeper in counteracting MASH development under physiological and pathological conditions.

DOI: https://doi.org/10.1038/s42003-024-06915-x

Nat Commun. 2024 Oct 08. 15(1): 8666

Ribosomes hibernate on mitochondria during cellular stress.

Olivier Gemin, Maciej Gluc, Higor Rosa, Michael Purdy, Moritz Niemann, Yelena Peskova, Simone Mattei, Ahmad Jomaa.

Cell survival under nutrient-deprived conditions relies on cells' ability to adapt their organelles and rewire their metabolic pathways. In yeast, glucose depletion induces a stress response mediated by mitochondrial fragmentation and sequestration of cytosolic ribosomes on mitochondria. This cellular adaptation promotes survival under harsh environmental conditions; however, the underlying mechanism of this response remains unknown. Here, we demonstrate that upon glucose depletion protein synthesis is halted. Cryo-electron microscopy structure of the ribosomes show that they are devoid of both tRNA and mRNA, and a subset of the particles depicted a conformational change in rRNA H69 that could prevent tRNA binding. Our in situ structural analyses reveal that the hibernating ribosomes tether to fragmented mitochondria and establish eukaryotic-specific, higher-order storage structures by assembling into oligomeric arrays on the mitochondrial surface. Notably, we show that hibernating ribosomes exclusively bind to the outer mitochondrial membrane via the small ribosomal subunit during cellular stress. We identify the ribosomal protein Cpc2/RACK1 as the molecule mediating ribosomal tethering to mitochondria. This study unveils the molecular mechanism connecting mitochondrial stress with the shutdown of protein synthesis and broadens our understanding of cellular responses to nutrient scarcity and cell quiescence.

DOI: https://doi.org/10.1038/s41467-024-52911-4